Input:
This is a phase I, multi-center, open-label, dose-escalation study to evaluate the safety,
 tolerability, pharmacokinetics and clinical activity of LP-168 in subjects with relapsed or
 refractory B-cell malignancies. LP-168 is a small molecule inhibitor.
 ;
 ;
 Inclusion Criteria:
 A subject will be eligible for study participation if he/she meets the following criteria:
 - Subjects are eligible with B-cell malignancies, WM, FL, MCL, MZL, DLBCL, HCL, CLL,
 SLL, based upon 2016 updated WHO classification. Those subjects with WM, FL, MCL,
 DLBCL, or HCL must have received at least 2 prior systemic therapies.
 - Low-grade B-cell lymphomas as follicular Grade 1, 2, or 3A, marginal zone or small
 lymphocytic lymphoma.
 - Subject must have adequate coagulation, renal, and hepatic function, per local
 laboratory reference ranges at Screening as follows:
 - Activated partial thromboplastin time (APTT) and prothrombin time (PT) not to
 exceed 1.5 × ULN
 - Calculated creatinine clearance (CrCl) ≥ 60 mL/min using 24-hour CrCl OR
 Cockcroft-Gault formula.
 - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 ×ULN;
 Bilirubin ≤ 1.5 × ULN (except subjects with Gilbert's Syndrome, who may have a
 bilirubin > 1.5 × ULN, per discussion between the Investigator and the Medical
 Monitor).
 - Subjects must have adequate bone marrow independent of growth factor support per local
 laboratory reference range at screening as follows:
 - Absolute Neutrophil Count (ANC) ≥1000/uL;
 - An exception is for subjects with an ANC<1000/uL and bone marrow heavily
 infiltrated with underlying disease (approximately 60% or more) may use growth
 factor to achieve the ANC eligibility criteria per discussion between the
 Investigator and the Medical Monitor.
 - Platelet count ≥ 50,000/µL - OR - Platelet count ≥ 20,000/ µL if thrombocytopenia
 is clearly due to CLL disease under study (per Investigator discretion)
 - Hemoglobin ≥8.0g/dL, and can be achieved by transfusion
 Exclusion Criteria:
 A subject will not be eligible for study participation if he/she meets any of the following
 criteria.
 - Subject has received any of the following therapies within 14 days or 5 half-lives
 (whichever is shorter) prior to the first dose of study drug, or has not recovered to
 ≤ Grade 1 clinically significant adverse effect(s)/toxicity(s) of the previous therapy
 (other than alopecia):
 - Any anti-cancer therapy including chemotherapy, biologic or immunotherapy,
 radiotherapy, etc;
 - Any investigational therapy, including targeted small molecule agents.
 - For CLL subjects who come off BCR antagonists (BTK inhibitors, PI3K inhibitors,
 etc.) treatment, allow washout for 2 days as these subjects progress quickly
 after treatment discontinuation and then remain eligible (steroids may be given
 during these two days to allow disease control).
 - Subjects who require immediate cytoreduction. However, subjects may receive up to two
 days of steroids for symptoms of impending organ impairment and remain eligible.
 - Subject has received the following medications or therapies within 7 days prior to the
 first dose of study drug:
 - Steroid therapy (at dosages equivalent to prednisone >20 mg/day) for
 anti-neoplastic intent (except as noted in exclusion criteria #3);
 - Cytochrome P450, family 3, subfamily A (CYP3A4) strong inhibitors and strong
 CYP2C8 inducers/inhibitors.
 - Potent CYP3A4 inducers such as rifampin, carbamazepine, phenytoin, and St. John's
 wort.
 - Subjects require treatment with systemic acid-reducing agents including H-2-receptor
 antagonists and proton pump inhibitors with the following exceptions:
 - Proton pump inhibitors should be discontinued at least 7 days prior and held
 throughout the study
 - If concurrent use of an H2 blocking agent is necessary, it must be administered
 only between 2 and 3 hours after the dose of LP-168. If not taken during this
 time, the dose of H2 blocking agents should not be taken again until 2-3 hours
 after the next dose of LP-168.
 - If concurrent use of a local antacid is necessary, it must be administered 2 or
 more hours before and/or 2 or more hours after the dose of LP-168.
 - Subject has significant screening electrocardiogram (ECG) abnormalities including. 2nd
 degree AV block type II 3rd degree block, Grade 2 or higher bradycardia, and corrected
 QT interval (QTc) ≥ 480ms.
 - Serum amylase > 1.5 × ULN or serum lipase > 1.5 × ULN.
 - Subject has any history of Richter's transformation for Phase 1a portion of the trial.
 - Subjects who have undergone autologous/allogeneic hematopoietic stem cell
 transplantation (HSCT) therapy within 90 days of the first dose of LP-168, or patients
 on immunosuppressive therapy post-HSCT at the time of Screening, or currently with
 clinically significant graft-versus-host disease (GVHD) as per treating physician
 (Patients in relapse after allogeneic transplantation must be off treatment with
 systemic immunosuppressive agents for at least 4 weeks. The use of topical steroids
 and/or up to 20 mg/day prednisone or equivalent systemic steroids for ongoing GVHD is
 permitted.
 - Subject has a history of other active malignancies other than B-cell malignancies
 within the past 3 years prior to study entry, with the exception of:
 - Adequately treated in situ carcinoma of the cervix uteri;
 - Basal cell carcinoma of the skin or localized squamous cell carcinoma of the
 skin;
 - Previous malignancy confined and surgically resected (or treated with other
 modalities) with curative intent.
 - Subject requires anticoagulation with Warfarin.


Input:
Flonoltinib Maleate (FM) targets Janus kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3).
 FM is a dual target inhibitor of JAK2/FLT3.FM has the activity of inhibiting JAK2 signaling
 pathway, and pharmacodynamics evaluation also confirmed that FM has a good therapeutic effect
 on the primary splenomegaly model of mice induced by JAK2V617 mutation.Therefore, FM has the
 potential to treat bone marrow proliferative tumors.The drug is intended to be used in
 patients with MPN, mainly including medium-risk or high-risk myelofibrosis (FM) (including
 primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PostPV-MF) and
 post-primary thrombocythemia myelofibrosis (postET-MF)), Polycythemia vera (PV) and essential
 thrombocythemia (ET) were the primary causes of thrombocythemia and thrombocythemia.
 FM has high inhibitory activity against JAK family and FLT3 kinase, suggesting that FM may
 have a certain therapeutic effect on AML disease.The IC50 of JAK2 kinase inhibition by FM was
 as low as 0.8 nM, while the IC50 of JAK1, JAK3 and Tyk2 kinase inhibition was 690 nM, 557 nM
 and 65nM, respectively. The selectivity of JAK2 kinase inhibition by FM was 862.5, 696.3 and
 81.3 times, respectively. Therefore, FM showed highly selective inhibition of JAK2 kinase.The
 IC50 for FLT3 kinase was 15 nM. FM has better inhibitory activity against JAK2 kinase than
 the listed Ruxolitinib and Fedratinib, and has better selectivity against JAK family.In order
 to determine whether FM has targets other than JAK2 and Flt3 kinases, we tested FM's
 inhibitory activity against 100 human kinases that are highly associated with tumors,
 including some common drug-resistant mutant kinases.The results showed that, except for
 CDK4/6, LCK and LN, FM had no obvious inhibitory activity against the screened kinases at 0.1
 μm, and no other targets were found.
 In vitro experiments on the proliferation of JAK2-dependent and Flt3-related tumor cell lines
 with FM showed that the tumor cell lines had a significant inhibitory effect. The IC50 of
 half of the tumor cell lines was less than 0.5 μm, which was better than or equal to the
 similar drugs Ruxolitinib and Fedratinib.
 The effect of FM on tumor cells from MPN patients indicated that FM has the potential to
 treat MPN disease.
 In multiple animal models of bone marrow proliferative tumors with JAK2V617F mutations, FM
 showed superior efficacy and low toxicity (no obvious VISCAL toxicity) than existing drugs on
 the market, and the tumor inhibition effect of FM showed a good dose-dependent relationship.
 Objectives of Study
 Main Purpose:
 1. Tolerance and safety of flonoltinib maleate Tablets tablets in patients with bone marrow
 proliferative tumors;
 2. To observe the possible dose-limiting toxicity(DLT) of flonoltinib maleate tablets in
 patients with bone marrow proliferative tumors,To determine the maximum tolerated
 dose(MTD) of flonoltinib maleate tablets,To provide the basis for the recommended dose
 and design scheme of the later clinical trial.
 Secondary Purpose:
 1. To evaluate the pharmacokinetic characteristics of single and repeated oral
 administration of flonoltinib maleate tablets in patients with bone marrow proliferative
 tumors;
 2. To evaluate the primary efficacy of single and multiple oral flonoltinib maleate tablets
 in patients with bone marrow proliferative tumors.
 ;NA;
 Inclusion Criteria:
 1. Age ≥18, gender unlimited;
 2. Patients diagnosed as PMF, PV (PV at least 24 weeks), ET according to WHO criteria
 (2016 edition), or post-PV-MF or post-ET-MF according to IWG-MRT criteria;
 3. Any of the following criteria is met :(1) Patients receiving treatment for myeloid
 fibrosis must be at least medium-risk -1 or high risk as assessed according to the
 DIPSS risk grouping criteria; (2) PV and ET patients who are resistant or intolerant
 to hydroxyurea and/or interferon therapy;
 4. No immediate plans for a stem cell transplant;
 5. At least 4 weeks or more than 5 half-lives (whichever is longer) after receiving the
 last antitumor therapy (chemotherapy, radiotherapy, biotherapy or immunotherapy)
 before enrollment;
 6. Expected survival ≥12 weeks;
 7. ECOG≤2;
 8. Splenomegaly: palpate the margin of the spleen (the farthest point of the spleen) at
 least 5 cm below the costal margin; Or not accessible due to body type (obesity), but
 confirmed by MRI (CT scan if necessary) spleen assessment at screening time, the
 volume is ≥450 cm3;
 9. Bone marrow primitive cells and peripheral blood primitive cells ≤10%;
 10. PLT≥75×109 /L, ANC≥1.0×109 /μL, HGB> without the assistance of colony stimulating
 factor, growth factor, thrombogenic factor or platelet infusion; 80 g/L. Subjects did
 not receive growth factor, colony-stimulating factor, thrombogenic factor or platelet
 transfusions within 2 weeks before examination.
 11. Heart, lung, liver, kidney, pancreas without serious organic lesions (LVEF (left
 ventricular ejection fraction) ≥45%; Total bilirubin ≤1.5×ULN; Serum creatinine
 ≤1.5×ULN or CCR> 40 ml/min. Alanine aminotransferase (ALT) ≤2×ULN; Aspartate
 aminotransferase (AST) ≤2×ULN;
 12. No severe coagulation abnormalities (PT≤1.5×ULN, APTT≤1.5×ULN, TT≤1.5×ULN);
 13. Those who agree to participate in the study and sign the informed consent;
 14. Agree to comply with the regulations of the hospital and research institution.
 Exclusion Criteria:
 1. The toxicity of previous anticancer therapy does not recover to grade I or below
 (except for hair loss), or does not fully recover from previous surgery (major surgery
 within 4 weeks);
 2. Allergic constitution, allergy to test drugs and their excipients;
 3. Any significant clinical or laboratory abnormalities that the investigator considers
 to affect the safety reviewer, such as: A. Uncontrolled diabetes - fasting glucose >
 250 mg/dL (13.9 mmol/L), b. Patients with hypertension who cannot be reduced to the
 following range after treatment with two or less antihypertensive drugs (systolic
 blood pressure < 160 mmHg, diastolic blood pressure < 100 mmHg), c. Peripheral
 neuropathy (NCI-CTC AE V5.0 Grade 2 or above);
 4. Patients with a history of congestive heart failure, unstable angina pectoris or
 myocardial infarction, cerebrovascular accidents, or pulmonary embolism within the
 first 6 months were screened;
 5. Patients with impaired heart function (Ejection fraction measured by ultrasonic
 electrocardiogram; ST segment descending in two or more channels in 45% or complete
 left bundle branch block > 1 mm or T wave inverted; Congenital ventricular arrhythmia,
 clinically significant tachycardia (>; 100 beats/min), bradycardia (lt; 50 times/min),
 ECG QTc > 450 ms (male), QTc > 480 MS (female) or clinically significant heart disease
 (such as unstable angina pectoris, congestive heart failure, myocardial infarction
 within 6 months);
 6. Arrhythmic disease requiring treatment, or QTC interphase (QTCB) > 480 ms;
 7. Any active infections requiring treatment at the time of screening;
 8. Patients who had previously undergone splenectomy or who had received radiotherapy in
 the splenic region within 12 months prior to screening;
 9. Positive HIV antibody, positive active hepatitis B virus (HBsAg positive, HBV-DNA
 positive or ≥1000 copies/mL), positive anti-HCV antibody or HCV-RNA at screening time;
 10. Screening patients with epilepsy or using psychotropic drugs or sedatives;
 11. Pregnant or lactating women, fertile women/men who refuse to use contraceptives during
 the trial and within 6 months after the trial;
 12. Patients who have had malignant tumors (except cured basal cell carcinoma of the skin
 and carcinoma in situ of the cervix) in the past 5 years;
 13. Concomitant with other serious diseases that the investigator believes may affect
 patient safety or compliance;
 14. Screening patients who participated in other new drugs or medical devices and took
 study drugs or used study devices within the previous 1 months;
 15. Within 2 weeks before randomization and into the group to use any drug for MF (JAK
 inhibitor, hydroxyurea), any immune modulators (such as Sally degree amine), any
 immune inhibitors, 10 mg/day or prednisone or equivalent strength of biological effect
 of glucocorticoid, growth factors, such as EPO therapy, or within six drug half-life
 of patients;
 16. Intravenous use of either a potent or moderate CYP3A inhibitor (such as ketoconazole,
 clarithromycin, itraconazole, nefazoldone, telimycin) or a potent CYP3A4 inducer
 (rifampicin perforatum) within two weeks prior to initial administration;
 17. Patients with a history of congenital or acquired bleeding diseases;
 18. Alcohol dependence or drug abuse;
 19. People who use grapefruit, star fruit or its products within 48 hours before taking
 the study drug for the first time, or who do not agree to prohibit the consumption of
 the above-mentioned food, drink or other special diet, which may affect the
 absorption, distribution, metabolism and excretion of the study drug;
 20. Other factors considered by the investigator to be unsuitable for participation in the
 study.


Input:
Depending on the variant of the disease, patients are divided into 3 groups: A, B and C.
 Group A include patients with acute myeloid leukemia (AML) inv(16)(p13.1q22) or
 t(16;16)(p13.1;q22); CBFB-MYH11, group B - AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1, AML
 with normal karyotype with or without gene mutations (FLT3, NPM1, CEBPa) regardless of the
 allele ratio, and also AML with cytogenetic abnormalities not classified as those within
 groups A/C, group C - AML with myelodysplasia-related changes. Patients from group A receive
 treatment according to the scheme: 2 courses "7+3", 2 courses "FLAG", then - 6 courses of
 maintenance therapy according to the scheme "5+5". Patients from group B are given one course
 of "7+3". After that, their minimal residual disease (MRD) status is assessed. In case MRD
 negativity is achieved after the 1st course of "7 +3", randomization is carried out: branch 1
 - therapy is similar to therapy for patients from group A (4 courses of induction and
 consolidation + 6 courses of maintenance chemotherapy (CT), allogeneic hematopoietic stem
 cell transplantation (allo-HSCT) is not planned), branch 2 - performing allo-HSCT should be
 done as soon as possible (before the start of maintenance CT is most desirable). If MRD
 negativity is not achieved after the 1st course of "7+3", the patient is given CT according
 to the standard program, followed by mandatory allo-HSCT. Patients from group C are treated
 either according to the "Aza-Ida-Ara-C" scheme, or according to the "Ven-DAC /AZA" scheme,
 followed by mandatory allo-HSCT.
 ;
 ;
 Inclusion Criteria:
 1. Newly diagnosed, previously untreated AML;
 2. Age from 18 to 59 years;
 3. Somatic status - ECOG < 3.
 Exclusion Criteria:
 1. previous chemotherapy for AML;
 2. pregnancy;
 3. relapses and refractory forms of AML;
 4. acute promyelocytic leukemia;
 5. blast crisis of chronic myeloid leukemia;
 6. de novo AML with t(9;22);
 7. AML transformed from MDS or MPN after treatment, for which a different protocol is
 provided;
 8. Blastoid plasmacytoid dendritic cell neoplasia (with the exception of cases when a
 small population of plasmacytoid dendritic progenitors is detected in the leukemic
 neoplasia).
 9. Undifferentiated acute leukemia


Input:
This phase II trial studies the effect of ASTX727 and dasatinib in treating patients with
 newly diagnosed Philadelphia chromosome or BCR-ABL positive chronic myeloid leukemia in
 chronic phase. Philadelphia chromosome positive and BCR-ABL positive are types of genetic
 mutations (changes). Chemotherapy drugs, such as ASTX727, work in different ways to stop the
 growth of cancer cells, either by killing the cells, by stopping them from dividing, or by
 stopping them from spreading. Dasatinib may stop the growth of cancer cells by blocking some
 of the enzymes needed for cell growth. ASTX727 and dasatinib may help to control Philadelphia
 chromosome-positive chronic myeloid leukemia or BCR-ABL positive chronic myeloid leukemia in
 chronic phase.
 ;
 ;
 Inclusion Criteria:
 - Diagnosis of Philadelphia chromosome (Ph)-positive or BCR-ABL positive CML in early
 chronic phase CML (i.e., time from diagnosis =< 12 months). Except for hydroxyurea
 and/or 1 to 2 doses of cytarabine patients must have received no or minimal prior
 therapy, defined as < 1 month (30 days) of prior Food and Drug Administration (FDA)
 approved tyrosine kinase inhibitor (TKI)
 - Clonal evolution defined as the presence of additional chromosomal abnormalities
 other than the Ph chromosome has historically been included as a criterion for
 accelerated phase. However, patients with clonal evolution as the only criterion
 of accelerated phase have a significantly better prognosis, and when present at
 diagnosis may not impact the prognosis at all. Thus, patients with clonal
 evolution and no other criteria for accelerated phase will be eligible for this
 study
 - Eastern Cooperative Oncology Group (ECOG) performance of 0-2
 - Total bilirubin < 1.5 x upper limit of normal (ULN) (unless secondary to Gilbert's
 disease, in which case should be < 2.5 x ULN)
 - Serum glutamic pyruvic transaminase (SGPT) < 3 x ULN
 - Creatinine < 1.5 x ULN
 - Patients must sign an informed consent indicating they are aware of the
 investigational nature of this study, in keeping with the policies of the hospital
 Exclusion Criteria:
 - New York Heart Association (NYHA) cardiac class 3-4 heart disease
 - Cardiac Symptoms: Patients meeting the following criteria are not eligible unless
 cleared by Cardiology:
 - Uncontrolled angina within 3 months
 - Diagnosed or suspected congenital long QT syndrome
 - Any history of clinically significant ventricular arrhythmias (such as
 ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
 - Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 460 msec)
 - History of significant bleeding disorder unrelated to cancer, including:
 - Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
 - Diagnosed acquired bleeding disorder within one year (e.g., acquired
 anti-factor VIII antibodies)
 - Patients with active, uncontrolled psychiatric disorders include: psychosis, major
 depression, and bipolar disorders
 - Subject is known to be positive for human immunodeficiency virus (HIV) (HIV testing is
 not required)
 - Evidence of other clinically significant uncontrolled condition(s) including, but not
 limited to:
 - Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
 - Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note:
 subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B
 surface [HBs] antigen negative-, anti-HBs antibody positive and anti-hepatitis B
 core [HBc] antibody negative) or positive anti-HBc antibody from intravenous
 immunoglobulins (IVIG) may participate
 - Women of pregnancy potential must practice an effective method of birth control during
 the course of the study, in a manner such that risk of failure is minimized. Prior to
 study enrollment, women of childbearing potential (WOCBP) must be advised of the
 importance of avoiding pregnancy during trial participation and the potential risk
 factors for an unintentional pregnancy. Postmenopausal women must be amenorrheic for
 at least 12 months to be considered of non-childbearing potential. Women must continue
 birth control for the duration of the trial and at least 3 months after the last dose
 of study drug. Pregnant or breast-feeding women are excluded. All WOCBP must have a
 negative pregnancy test prior to first receiving investigational product. If the
 pregnancy test is positive, the patient must not receive study drug and must not be
 enrolled in the study
 - Patients in late chronic phase (i.e., time from diagnosis to treatment > 12 months),
 accelerated (except as noted in inclusion criteria) or blast phase are excluded. The
 definitions of CML phases are as follows:
 - Early chronic phase: time from diagnosis to therapy =< 12 months
 - Late chronic phase: time from diagnosis to therapy > 12 months
 - Blastic phase: presence of 30% blasts or more in the peripheral blood or bone
 marrow
 - Accelerated phase CML: presence of any of the following features:
 - Peripheral or marrow blasts 15% or more
 - Peripheral or marrow basophils 20% or more
 - Thrombocytopenia < 100 x 10^9/L unrelated to therapy
 - Documented extramedullary blastic disease outside liver or spleen


Input:
The purpose of this Cohort Treatment Plan is to allow access to ceritinib for eligible
 patients diagnosed with ALK positive tumors, previously pre-treated with ALK inhibitors or
 naive. The patient's Treating Physician should follow the suggested treatment guidelines and
 comply with all local health authority regulations.
 ;NA;
 Inclusion Criteria:
 Patients eligible for inclusion in this Treatment Plan have to meet all of the following
 criteria:
 1. The patient is diagnosed with ALK-positive tumor.
 2. The patient has been previously pre-treated with ALK inhibitor or naive.
 3. The patient has progression of disease at screening or is intolerant to prior therapy
 and does not qualify or have access to LDK378 through a clinical trial.
 4. The patient has a performance status (WHO) of 0-2.
 5. The following laboratory criteria have been met:
 - Absolute neutrophil count (ANC) ≥1.5 x 10^9/L
 - Hemoglobin (Hgb) ≥ 8 g/dL
 - Platelets ≥75 x 10^9/L
 - Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN), except for patients
 with Gilbert's syndrome who may be included if total bilirubin ≤ 3.0 x ULN or
 direct bilirubin ≤ 1.5 x ULN
 - Aspartate transaminase (AST) ≤ 3.0 x ULN, except for patients with liver
 metastasis, who are only included if AST ≤ 5.0 x ULN;
 - Alanine transaminase (ALT) ≤3.0 x ULN, except for patients with liver metastasis,
 who are only included if ALT ≤ 5.0 x ULN;
 - alkaline phosphatase (ALP) ≤ 5.0 x ULN
 - Serum creatinine <1.5 mg/dL and or Calculated creatinine clearance (CrCL) (using
 Cockcroft-Gault formula) ≥ 30 mL/min
 - Serum amylase ≤ 2 x ULN
 - Serum lipase ≤ ULN
 - Fasting plasma glucose ≤175 mg/dL (≤9.8 mmol/L)
 6. Patient must have the following laboratory values within normal limits or corrected to
 within normal limits with supplements before the first dose of ceritinib:
 - Potassium
 - Magnesium
 - Phosphorus
 - Total calcium (corrected for serum albumin) Written patient informed consent must
 be obtained prior to start of treatment.
 Exclusion Criteria:
 Patients eligible for this Treatment Plan must not meet any of the following criteria:
 1. A history of pancreatitis or history of increased amylase or lipase that was due to
 pancreatic disease.
 2. Other concurrent severe, acute, or chronic and/or uncontrolled medical conditions
 (e.g. diabetes mellitus or psychiatric conditions or laboratory abnormalities
 uncontrolled heart disease in the last 6 months, active or uncontrolled infection)
 that, in the opinion of the treating physician, could cause unacceptable safety risks,
 interfere with the interpretation of the results or compromise compliance with the
 treatment plan.
 3. Patient who has received thoracic radiotherapy to lung fields ≤4 weeks prior to
 starting the study treatment or patients who have not recovered from
 radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy
 to thoracic vertebrae and ribs) radiotherapy ≤2 weeks prior to starting the study
 treatment or has not recovered from radiotherapy-related toxicities. Palliative
 radiotherapy for bone lesions ≤2 weeks prior to starting study treatment is allowed.
 4. Known history of interstitial lung disease or interstitial pneumonitis including
 clinically significant radiation pneumonitis (i.e. affecting activities of daily
 living or requiring therapeutic intervention).
 5. Clinically significant, uncontrolled heart disease and/or recent cardiac event (within
 6 months), such as:
 - Unstable angina within 6 months prior to screening.
 - Myocardial infarction within 6 months prior to screening.
 - History of documented congestive heart failure (New York Heart Association
 functional classification III-IV).
 - Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥160 mm Hg
 and/or Diastolic Blood Pressure (DBP) ≥100 mm Hg, with or without
 antihypertensive medication. Initiation or adjustment of antihypertensive
 medication (s) is allowed prior to screening.
 - Ventricular arrhythmias
 - Supraventricular and nodal arrhythmias not controlled with medication.
 - Other cardiac arrhythmia not controlled with medication.
 - Corrected QT (QTcF) >470 ms using Fridericia's correction on the screening ECG
 (as mean of triplicate ECGs).
 6. Known hypersensitivity to any excipients of LDK378 (microcrystalline cellulose,
 mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
 7. Impaired GI function or GI disease that may significantly alter absorption of LDK378
 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption
 syndrome).
 8. Patient must not be participating in other ongoing trials, or ALK inhibitors trials or
 other compassionate use programs. Patients eligible for this program are also
 ineligible for other ALK inhibitors trials.
 9. Receiving medications that meet one of the following criteria and that cannot be
 discontinued at least 1 week prior to the start of treatment with LDK378 and for the
 duration of the program:
 - Strong inhibitors or strong inducers of CYP3A4/5
 - Medications with a low therapeutic index that are primarily metabolized by
 CYP3A4/5 and/or CYP2C9
 - Medications with a known risk of prolonging the QT interval or inducing Torsades
 de Pointes.
 - Receiving treatment with warfarin sodium (Coumadin) or any other coumadinderived
 anti-coagulant
 - Receiving unstable or increasing doses of corticosteroids. If patients are on
 corticosteroids for endocrine deficiencies or tumor-associated symptoms (non-
 CNS), dose must have been stabilized (or decreasing) for at least 5 days before
 first dose of treatment.
 - Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or
 intra-pelvic) within 4 weeks prior to starting treatment or has not recovered
 from side effects of such procedure. Video-assisted thoracic surgery (VATS) and
 mediastinoscopy will not be counted as major surgery and patients can receive
 treatment ≥1 week after these procedures
 - Receiving enzyme-inducing anticonvulsives that cannot be discontinued at least 1
 week before first dose of treatment, and for the duration of the treatment.
 Patients on non-enzyme-inducing anticonvulsants are eligible.
 10. Sexually active males unless they use a condom during intercourse while taking the
 drug and for 3 months after the last dose of program drug. Patient should not father a
 child in this period. A condom is required to be used also by vasectomized men in
 order to prevent delivery of the drug via seminal fluid.
 11. Pregnant or nursing (lactating) women
 12. Women of child-bearing potential, defined as all women physiologically capable of
 becoming pregnant, unless they are using highly effective methods of contraception
 during dosing and for 3 months after stopping medication. Highly effective
 contraception methods include:
 - Total abstinence (no sexual relations), when this is in line with your preferred
 and usual lifestyle. Periodic abstinence like calendar, ovulation, symptothermal,
 postovulation methods, and withdrawal are not acceptable methods of
 contraception.
 - Female sterilization, when you have been already surgically sterilized prior to
 the program by surgical removal of both ovaries (woman's reproductive system that
 stores and releases eggs for fertilization and produces female sex hormones),
 total hysterectomy (surgical removal of the uterus and cervix), or tubal ligation
 (getting your "tubes tied") at least six weeks before taking program treatment.
 - Your male partner has already been sterilized at least 6 months prior to
 screening with the appropriate documentation. The sterilized male partner should
 be your sole partner.
 - Use of oral, injected, or implanted hormonal methods of contraception or
 placement of an intrauterine device (IUD) or intrauterine system (IUS) or other
 forms of hormonal contraception that have comparable efficacy (failure rate <1%),
 for example hormone vaginal ring or transdermal hormone contraception (in case of
 oral contraception you should have been using the same pill on a stable dose for
 a minimum of 3 months before taking program treatment).
 In case of use of oral contraception, women should have been stable on the same pill for a
 minimum of 3 months before taking study treatment.


Input:
This is a phase 1, open-label, dose escalation and cohort expansion study and conducted in
 China and the United States to investigate the safety, tolerability and preliminary efficacy
 of QLH11811 in advanced or metastatic NSCLC patients who have progressed after prior EGFR-TKI
 treatment. The study consists of the following 2 phases: phase 1: dose escalation (1a) and
 phase 2: cohort expansion (1b).
 ;NA;
 Inclusion Criteria:
 1. Patients who participate voluntarily, sign informed consent form (ICF), and will be
 able to follow the study procedures;
 2. Aged ≥ 18 years;
 3. Patients who are histologically or cytologically diagnosed with EGFR mutation and have
 unresectable locally advanced or recurrent/metastatic NSCLC;
 4. EGFR mutation requirements:
 Dose escalation phase (phase 1a): NSCLC patients who have progressed after standard
 EGFR-TKI treatment or cannot tolerate standard of care;
 Cohort expansion phase (phase 1b):
 1. Cohort 1: advanced NSCLC patients who have progressed after treatment with
 third-generation EGFR-TKIs and have EGFR C797S mutation.
 2. Cohort 2: advanced NSCLC patients who have progressed after standard EGFR-TKI
 treatment but have no other additional driver gene mutation(s).
 3. Cohort 3: advanced NSCLC patients who have progressed after EGFR-TKI treatment
 and have T790M mutation.
 4. Cohort 4: patients with locally progressed, unresectable or recurrent metastatic
 NSCLC who are naive to EGFR-TKI treatment and have 19del or 21L858R mutation
 among EGFR sensitive mutations.
 5. Patients who agree to provide tumor samples (fresh tissues or archived samples) for
 analysis of EGFR gene.
 Dose escalation phase: tumor samples collected from the progression site of disease
 during or after PD after the last TKI treatment should be provided for new genetic
 testing The subjects who fail to provide tumor samples will be allowed to enroll only
 after communication and consultation with the sponsor.
 Cohort expansion phase:
 Cohort1: tumor samples collected from the progression site of disease during or after
 PD after the last TKI treatment should be provided for genetic testing at central
 laboratory.
 Cohorts 2 and 3: tumor samples collected from the progression site of disease during
 or after PD after the last TKI treatment should be provided for genetic testing. The
 genetic testing will be exempted if subjects have the test results meeting the above
 requirements before their enrollment.
 Cohort 4: tumor samples collected from the progression site of disease during or after
 PD after the last treatment should be provided for genetic testing (of EGFR mutation);
 and if subjects are treatment-naive, they will be required to provide the tumor
 samples only during the screen period. The genetic testing will be exempted if
 subjects have the test results meeting the above requirements before their enrollment.
 6. ECOG ≤ 1 point (for details, refer to Appendix 2 ECOG performance status score);
 7. Life expectancy ≥ 12 weeks;
 8. Patients who have been diagnosed according to RECIST v1.1 and have measurable lesions
 as documented by computed tomography (CT) and/or magnetic resonance imaging (MRI)
 (note: subjects who do not have measurable lesions are allowed to be enrolled in phase
 1a study). Note: a measurable lesion for response evaluation has to meet the following
 criteria: a) it is not in an area that has been involved in prior radiotherapy, or b)
 there is notable radiographic evidence of progression after the completion of
 radiotherapy and before study enrollment;
 9. Patients who have adequate organ functions and meet the following criteria:
 1. Hematology:
 Absolute neutrophil count ≥ 1.5 × 109/L; platelet count ≥ 100 × 109/L; hemoglobin
 ≥ 90 g/L (no blood transfusion and no use of granulocyte colony stimulating
 factor in the 14 days prior to the screening);
 2. Coagulation:
 For patients who have not received anticoagulant therapy: international
 normalized ratio (INR) of prothrombin time and partial thromboplastin time ≤ 1.5
 × ULN;
 3. Liver:
 Alanine aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3.0 × ULN. For
 patients with liver metastases: ALT and AST ≤ 5 × ULN, total bilirubin ≤ 1.5 ×
 ULN. For patients with Gilbert syndrome: conjugated bilirubin within normal
 range;
 4. Kidney:
 Serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min (calculated
 according to Cockcroft-Gault formula, refer to Appendix 4 Creatinine clearance
 calculation formula).
 10. All acute toxic reactions arising from prior antineoplastic therapy or surgery have
 resolved to baseline or reduced in severity to ≤ Grade 1 according to NCI CTCAE V5.0
 (except for alopecia or other toxicities which, in the opinion of the investigator,
 pose no safety risk to the patient);
 11. Patients (both female and male) who agree to take effective contraceptive measures
 from their signing of ICF to 6 months after the last dose of the study drug. For women
 of childbearing potential: negative serum pregnancy test result in 7 days prior to the
 start of treatment is required.
 Exclusion Criteria:
 1. Patients who have received systemic anticancer therapies (e.g., chemotherapy,
 molecularly targeted therapy, radiotherapy, biotherapy, hormone therapy, vaccine
 therapy), or antineoplastic TCM therapy in the 2 weeks prior to the first dose of
 study treatment; or who have received immune-checkpoint inhibitor therapy in the 4
 weeks prior to the first dose of study treatment;
 2. Patients who have received radical radiotherapy (including radiotherapy of more than
 25% of bone marrow) in the 4 weeks prior to the first dose, or who have received local
 palliative radiotherapy for bone metastatic lesions in the 1 week prior to the first
 dose;
 3. Patients who have received strong or moderate CYP3A, P-gp inhibitors in the 1 week
 prior to the first dose or in 5 half-lives of these drugs (whichever is longer), or
 need to continue to receive these drugs during the study; and who have received strong
 or moderate CYP2B6, CYP1A2 and CYP3A inducers in the 4 weeks prior to the first dose;
 4. Patients who are in the treatment period of other interventional clinical studies in
 the 4 weeks prior to the first dose. However, participants of non-interventional
 clinical studies (e.g., epidemiologic studies) are eligible for enrollment in this
 study. Patients in the survival follow-up period of interventional clinical studies
 are also eligible for enrollment in this study;
 5. Patients who have active bacterial, fungal or viral infection requiring systemic
 therapies within the 1 week prior to the first dose;
 6. Patients who have underwent a major operation (e.g., a surgical operation requiring
 local or general anesthesia and hospitalization) in the 3 weeks prior to the start of
 study treatment;
 7. Patients with a history of chronic diarrhea, including but not limited to Crohn's
 disease, irritable bowel syndrome, etc.;
 8. Patients who have experienced > CTCAE Grade 1 continuous diarrhea within the 1 week
 prior to the first dose;
 9. Patients with serious respiratory disorders, e.g. interstitial lung disease, radiation
 pneumonitis, drug-induced pneumonia (however, patients whose conditions have resolved
 and stabilized for 3 months or more are eligible for enrollment);
 10. Patients with symptomatic metastasis to central nervous system (CNS) and/or with
 meningitis carcinomatosa.
 Note: patients with brain metastases whose clinical symptoms have stabilized after
 treatment are eligible for participation in the study, provided that their conditions
 are radiographically stabilized (defined as stability demonstrated by 2 brain images
 acquired by the same imaging technique after treatment of brain metastases). These
 imaging scans should be carried out at an interval of at least 4 weeks, and show no
 signs of intracranial progression. Furthermore, brain metastases or its treatment
 induced neurologic symptoms need to regress to baseline level or resolve. All steroids
 administered as a part of the treatment must be completed ≥ 3 days prior to the
 administration of study treatment.
 11. Patients with clinically significant cardiovascular and cerebrovascular diseases,
 including but not limited to:
 1. Myocardial infarction or unstable angina in the 6 months prior to the first dose;
 2. Stroke or transient ischemic attack in the 6 months prior to the first dose;
 3. Any clinically significant abnormalities in resting ECG in terms of cardiac
 rhythm, heart rate, conduction or morphology, e.g. complete left bundle branch
 block, third-degree conduction block, second-degree conduction block, PR interval
 > 250 ms, etc.;
 4. Uncontrolled hypertension after active treatment: systolic pressure > 180 mmHg or
 diastolic pressure > 100 mmHg;
 5. Congestive cardiac failure (NYHA functional class III-IV);
 6. Pericarditis or clinically significant pericardial effusion;
 7. Myocarditis;
 8. 12-lead ECG shows that mean QT interval (QTcF) > 450 ms (male) or > 470 ms
 (female) before the first dose of investigational drug;
 9. Failure to discontinue the drugs that may cause QTc prolongation or torsades de
 pointes (e.g., antiarrhythmics) during the study.
 12. Patients with clinically uncontrolled serous effusion(e.g., pleural fluid that cannot
 be controlled by drainage or other methods).
 13. Patients with active gastrointestinal disorders or other conditions that have serious
 interference with the drug absorption.
 14. Patients with any condition that have an adverse impact on the swallowing of the drug
 or on the absorption or PK parameters of the investigational drug;
 15. Patients with known serious allergy to the study drug or any excipient of the drug;
 16. Patients with known HIV test positive result and/or treponema pallidum antibody test
 positive result (except for those whose infection has been cured after treatment).
 17. Patients with HBsAg positive result and HBV DNA > 2000 IU/mL or 104 copies/mL (for
 sites which only provide the qualitative testing, HBV DNA test result is positive or
 higher than lower limit of detection); or with HCV antibody positive and HCV RNA
 positive results.
 18. Patients who experienced other malignancies (with the exceptions of Bowen's disease;
 cured basal cell or squamous cell skin cancer; prostate cancer with a Gleason score of
 6; treated cervical carcinoma in situ) in the 2 years prior to the study enrollment.
 19. Pregnant or lactating women. Lactating female subjects need to stop breast-feeding
 before the first dose of study treatment, which cannot be resumed throughout the study
 and in the 6 months after the last dose of study treatment.
 20. Patients with any existing serious or unstable diseases (except for the
 above-mentioned malignancies), psychiatric disorders or any disease or medical
 condition which, in the investigator's opinion, may have an adverse impact on the
 subject safety, the signing of ICF or the compliance with the study procedures.
 21. Patients who are currently participating in a clinical study of other investigational
 therapies.


Input:
This is a Phase 1 dose-finding study of FT538 in combination with monoclonal antibodies.
 ;
 ;
 Inclusion Criteria:
 Subjects with locally advanced or metastatic disease who have progressed after at least one
 line of therapy and diagnosis of one of the following by treatment cohort:
 - Cohort A: The following solid tumor malignancies where anti-PD-1/PD-L1 antibodies are
 approved: cutaneous melanoma, non-small cell/small cell lung cancer, renal cell
 carcinoma, head and neck squamous cell cancer, microsatellite instability-high/
 mismatch repair deficient cancer, gastric cancer, esophageal cancer, cervical cancer,
 merkel cell carcinoma, endometrial carcinoma, tumor mutation burden-high ≥ 10
 mutations/megabase], cutaneous squamous cell carcinoma, triple-negative breast cancer.
 - Cohort B: HER2+ breast cancer that has relapsed or progressed on trastuzumab and
 progressed on either pertuzumab or HER2-targeting antibody drug conjugate; HER2+
 gastric cancer that has relapsed or progressed on trastuzumab-containing therapy; OR
 any other HER2+ solid tumor having progressed on at least one line of standard-of-care
 therapy. For any tumor type in this cohort, HER2 status must be documented by a U.S.
 Food and Administration (FDA) approved test to be ≥2+ IHC or Average HER2 copy number
 ≥4 signals per cell by in situ hybridization.
 - Cohort C: CRC having progressed following prior cetuximab treatment or has KRAS/NRAS
 mutation; HNSCC having progressed following prior cetuximab.
 Capable of giving signed informed consent
 Aged ~ 18 years old
 Willingness to comply with study procedures and duration
 Measurable disease per RECIST v1.1
 For subjects with >1 measurable lesion by RECIST v1.1 that can be safely accessed,
 willingness to undergo tumor biopsy
 Contraceptive use for women and men as defined in the protocol
 Exclusion Criteria:
 Pregnant or breast-feeding women
 ECOG performance status greater than or equal to 2
 Evidence of insufficient organ function
 Clinically significant cardiovascular disease including left-ventricular ejection fraction
 < 45%
 Receipt of therapy within 2 weeks prior to Day 1 or five half-lives, whichever is shorter
 or any investigational therapy within 28 days prior to Day 1
 Known active central nervous system (CNS) involvement by malignancy that hasn'thas not
 remained stable for at least 3 months following effective treatment for CNS disease
 Non-malignant CNS disease such as stroke, epilepsy, CNS vasculitis or neurodegenerative
 disease or receipt of medications for these conditions
 Currently receiving or likely to require immunosuppressive therapy Active bacterial,
 fungal, or viral infections including hep B, Hep C or HIV Live vaccine within 6 weeks prior
 to start of lympho-conditioning
 Known allergy to albumin (human) or DMSO


Input:
This is a multicenter, open label, pilot phase II study of the PI3K inhibitor copanlisib in
 combination with a ketogenic diet in the treatment of patients with one of the following
 malignancies: (a) relapsed or refractory (R/R) follicular lymphoma (FL), (b) R/R endometrial
 cancer (EC) with a documented activating mutation in PIK3CA or loss of phosphatase and tensin
 homolog (PTEN).
 ;
 ;
 Inclusion Criteria:
 - Be willing and able to provide written informed consent for the trial.
 - Be 18 years of age or older on day of signing informed consent.
 - For lymphoma, patients should have measurable disease based on the Lugano Criteria.
 - For FL patients must have received at least two lines of prior therapy. There is no
 upper limit for the number of prior therapies. Tumor tissues of all patients are
 encouraged to be submitted (optional) prospectively for whole or targeted exome
 sequencing of key cancer related genes, using the Columbia Combined Cancer Panel
 (CCCP) or a comparable sequencing platform, such as the MSK-IMPACT 468-gene oncopanel.
 - For EC the patients must have recurrent/advanced tumor for which surgical or the
 systemic curative treatments, or standard therapeutic approaches are not available.
 The following histologic subtypes are eligible: endometrioid, serous, clear cell,
 undifferentiated /dedifferentiated, mucinous, squamous, transitional, not-otherwise
 specified, and mixed celltype.
 - Fresh and or archived tumor tissues must be available to (a) establish the diagnosis
 of the respective malignancies as described in Inclusion Criteria, and (b) be
 investigated for biomarkers. Patients without historical material or fresh tissue
 biopsy that is adequate for both diagnosis and correlative studies will not be
 eligible for the clinical trial.
 - Left Ventricular Ejection Fraction (LVEF) > 50%.
 - A performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG)
 Performance Scale.
 - Demonstrate adequate organ function. All screening labs should be performed within 14
 days of treatment initiation.
 - HIV positive patients will be eligible as long as the viral load by polymerase chain
 reaction (PCR) testing is undetectable.
 - Female patients of childbearing potential must have a negative pregnancy test within 7
 days prior to treatment start.
 - Adequate contraception.
 Exclusion Criteria:
 - The following treatments are prohibited: (a) Chemotherapy (including PI3K inhibitors
 and other approved or investigational drugs) and monoclonal antibody within 3 weeks;
 (b) radiotherapy within 2 weeks prior to entering the study; (c) systemic steroids
 that have not been stabilized (≥ 5 days) to the equivalent of ≤10 mg/day prednisone
 prior to the start of the study drugs.
 - Patients that have not recovered from adverse events due to chemotherapy agents
 administered more than 3 weeks earlier.
 - Hypersensitivity to copanlisib or any of its excipients.
 - Type I diabetes
 - Uncontrolled Type II diabetes mellitus (HbA1c> 7.5%).
 - Type II diabetes requiring treatment with a sulfonylurea, meglitinide, or insulin.
 - Patients that received major surgery and have not recovered adequately from the
 toxicity and/or complications from the intervention prior to starting therapy.
 - Patients with active, clinically serious infections > CTCAE version 5 Grade 2.
 - Patients with known active concurrent malignancy with the following exception:
 nonmelanoma skin cancer, prostatic intraepithelial neoplasia, or carcinoma in situ of
 the cervix, prostate cancer that responds to androgen deprivation therapy and has no
 progression of disease for at least 12 months. If there is a history of prior
 malignancy, the patient must be disease-free for ≥ 3 years.
 - Uncontrolled hypertension, i.e., blood pressure (BP) of ≥ 150/90; patients who have a
 history of hypertension controlled by medication must be on a stable dose (for at
 least one month) and meet all other inclusion criteria.
 - Concomitant use of strong CYP3A4 inhibitors (defined in the protocol).
 - Uncontrolled moderate to severe hypertriglyceridemia (TG>300 mg/dL).
 - Myocardial infarction within 6 months of cycle 1, day 1.
 - Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV (see
 Appendix 5).
 - An ECG recorded at screening showing evidence of cardiac ischemia.
 - Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II
 to IV definitions and/or ejection fraction < 40% by multigated acquisition (MUGA) scan
 or < 50% by echocardiogram and/or magnetic resonance imaging (MRI);
 - Arterial or venous thrombotic or embolic events such as cerebrovascular accident
 (including transient ischemic attacks) within 6 months before the start of study
 medication.
 - Patients who are pregnant or breastfeeding, or expecting to conceive or father
 children within the projected duration of the trial, starting with the pre-screening
 or screening visit through at least 30 days after the last dose of trial treatment.
 - History of nephrolithiasis or nephrolithiasis incidentally discovered during CT
 screening. *Known selenium deficiency.
 - Body mass index (BMI) less than 20.
 - An allergy or intolerance to egg, gluten or milk protein.
 - History of serious or uncontrolled gout or hyperuricemia.
 - Pregnancy, lactation, or breastfeeding.
 - Any other disease, metabolic dysfunction, physical examination finding, or clinical
 laboratory finding that, in the investigators' opinion, gives reasonable suspicion of
 a disease or condition that contraindicates the use of an investigational drug or that
 may affect the interpretation of the results or render the patient at high risk from
 treatment complications.
 - Major surgical procedure or significant traumatic injury within 28 days prior to Day 1
 or anticipation of the need for major surgery during the course of study treatment.


Input:
Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML) and is the
 current standard of care in the treatment of patients with newly diagnosed CML. However,
 about 30% of patients still show drug resistance or disease progression. Currently, the most
 widely studied mechanism of TKI resistance in CML patients is mutations in the ABL kinase
 region. So far, more than 100 kinase domain mutations have been found in disease progression
 and imatinib resistance. It is estimated that more than 25% of CML patients will change TKI
 at least once in their lifetime due to drug resistance or intolerance. The 2020 edition of
 the "Guidelines for the Diagnosis and Treatment of Chronic Myelogenous Leukemia in China"
 proposes that patients with F317L/V/I/C, V299L and T315A mutations are more likely to obtain
 clinical efficacy by switching to the second-generation TKI nilotinib; patients with Y253H,
 E255K/V and F359C/V/I mutations are more likely to obtain clinical efficacy by switching to
 the second-generation TKI dasatinib; patients with T315I mutations are resistant to both
 nilotinib and dasatinib. Flumatinib has been shown to be a more potent inhibitor of BCR-ABL1
 tyrosine kinase than imatinib. In vitro studies, it has shown that flumatinib inhibits
 wild-type and common BCR-ABL mutations(Q252H, V299L, F317L/I, M351T, H396P, etc.) more
 potently, and the anti-mutation spectrum of flumatinib is similar to nilotinib. Therefore,
 this study is designed to provide clearer guidance for patients with suboptimal response or
 failure in the treatment of TKI as well as those who have specific ABL kinase domain
 mutations during CML treatment.
 ;NA;
 Inclusion Criteria:
 1. Male or female patients ≥18 years of age;
 2. CML-CP patients when enrolled
 Definition of diagnosis:
 Bone marrow cytogenetic confirmation of Philadelphia chromosome of t (9;22)
 translocations and/or the presence of P210 BCR-ABL1 transcripts via molecular
 assessment;
 Documented chronic phase CML will meet all the criteria defined as:
 < 15% blasts in peripheral blood and bone marrow < 30% blasts plus promyelocytes in
 peripheral blood and bone marrow < 20% basophils in the peripheral blood
 ≥ 100 x 109/L (≥ 100,000/mm3) platelets No evidence of extramedullary leukemic
 involvement, with the exception of hepatosplenomegaly
 3. CML-CP patients without optimal response(warning or failure) when treated with
 imatinib or dasatinib.
 4. Female patients of childbearing potential must have a negative serum pregnancy test;
 5. Ability to provide written informed consent prior to any study related screening
 procedures being performed.
 Exclusion Criteria:
 1. Treatment with other tyrosine kinase inhibitor(s) except imatinib and dasatinib prior
 to study entry;
 2. With any mutations as follows :T315I、Y253F/H、E255K/V、F359C/V/I (if there are any other
 mutations,at physicians' discretion );
 3. Entry into another therapeutic clinical trial;
 4. Concomitant diseases that, according to the investigator's judgment, pose a serious
 risk to the patient's safety or completion of the study;
 5. History of neurological or psychiatric disorders, including epilepsy or dementia;
 6. Major surgery within 4 weeks prior to Day 1 of study;
 7. Patients with another primary malignancy,unless the other primary malignancy is
 currently stable or does not need active intervention;
 8. Women of reproductive age or men who are unable to use adequate methods of
 contraception, including women who are pregnant or breastfeeding;
 9. ECOG≥3;
 10. Patients who are unable to compliance with study or follow-up procedures;
 11. Allergic to any of the components in this trial;
 12. Not appropriate to attend this trial judged by the investigator.

Philadelphia chromosome of t (9;22) translocation


Input:
Evaluate the safety and tolerability of RMC-6236 in adults with KRAS p.G12 mutant advanced
 solid tumors, KRAS p.G12C excluded.
 ;
 ;
 Inclusion Criteria:
 - Histologically confirmed advanced solid tumor with KRAS p.G12A, KRAS p.G12D, KRAS
 p.G12R, KRAS p.G12S, or KRAS p.G12V mutations identified through deoxyribonucleic acid
 (DNA) sequencing.
 - Received prior standard therapy appropriate for tumor type and stage
 - Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
 - Adequate organ function
 Exclusion Criteria:
 - Tumor harboring the KRAS p.G12C mutation
 - Primary central nervous system (CNS) tumors
 - Known or suspected leptomeningeal or brain metastases or spinal cord compression
 - Known or suspected impairment of gastrointestinal function that may prohibit ability
 to swallow or absorb an oral medication
 - History of any other unstable or clinically significant concurrent medical condition
 that would, in the opinion of the investigator, jeopardize the safety of a
 participant, impact their expected survival through the end of the study
 participation, and/or impact their ability to comply with the protocol
 prior/concomitant therapy


Input:
This study will collect medical records, scan results, and complete surveys to create a
 registry about people with a neurofibromatosis type 1-associated brain tumor (NF1-associated
 glioma). A registry is a collection of health information about individuals, and it is
 usually focused on a specific diagnosis or condition.
 This registry study will help the researchers learn more about the diagnosis, treatment, and
 quality of life of people with NF1-associated glioma. The researchers want to understand what
 happens as a result of different treatments for NF1-associated glioma and how these
 treatments and the disease itself affect people's lives over a period of time. Information
 collected during this study could affect how doctors diagnose, test, and treat NF1-associated
 glioma, and the study could help future patients with this type of cancer.
 ;NA;
 Inclusion Criteria:
 - Clinical diagnosis that meets NIH criteria for NF1 disease by either 1) documented
 clinical record establishing NF1 or 2) self-reported with supported documentation upon
 medical record collection.
 - Willing to have historical and future NF1 related health records sent to registry for
 review.
 - Radiologic or pathologically confirmed glioma.
 - Individuals ≥18 years of age on the date of informed consent.
 Exclusion Criteria:
 - Unwillingness to sign informed consent.
 - No proficiency in English or Spanish as determined by the Investigator.


Input:
This is an expanded access program (EAP) for eligible participants designed to provide access
 to ACE-011.
 ;NA;
 Inclusion Criteria:
 -
 Exclusion Criteria:
 -


Input:
This study is open to adults with different types of advanced or metastatic cancer (including
 lung cancer, colorectal cancer, pancreatic cancer, and bile duct cancer). This study is for
 people for whom previous treatment was not successful or no treatment exists.
 People who have a tumour with a KRAS mutation can participate in the study. A KRAS mutation
 makes tumours grow faster. BI 1823911 and BI 1701963 are medicines that may turn off KRAS,
 each in a different way. In this study, BI 1823911 is given to people for the first time.
 The purpose of this study is to find the highest dose of BI 1823911 that people can tolerate
 when taken alone and together with BI 1701963. The most suitable dose is used to find out
 whether BI 1823911 alone and in combination with BI 1701963 can make tumours shrink.
 Participants can stay in the study as long as they benefit from treatment and can tolerate
 it.
 During this time, participants take tablets of BI 1823911 alone or in combination with BI
 1701963 once a day. The doctors regularly monitor the size of the tumour. Doctors also
 regularly record any unwanted effects and check participant's health.
 ;NA;
 Inclusion Criteria:
 - Pathologically confirmed diagnosis of locally advanced or metastatic solid tumours,
 e.g. adenocarcinoma of the lung, colorectal cancer, pancreatic cancer or
 cholangiocarcinoma. Non-small cell lung cancer (NSCLC) patients with mixed histology
 are eligible if adenocarcinoma is the predominant histology.
 - Documented disease progression despite appropriate prior standard therapies or for
 whom no standard therapy exists for their tumour type and disease stage.
 - KRAS mutation status: Kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine
 (G12C) mutation in tumour tissue or blood based on previously performed local testing
 using a validated test.
 - Provision of archival tumour tissue, if available, to confirm retrospectively KRAS
 G12C mutation status and for biomarker assessment.
 - At least one target lesion that can be measured per Response Evaluation Criteria In
 Solid Tumours (RECIST) version 1.1 (radiated lesions do not qualify as target
 lesions). In patients who only have one target lesion, and a biopsy of the lesion is
 required, the baseline imaging must be performed before the biopsy or at the earliest
 two weeks after the biopsy.
 - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
 - Adequate organ function as follows:
 - Absolute neutrophil count (ANC) ≥1.5 x 10^9/L (equivalent values: ≥ 1.5 x 10³/μL
 or ≥ 1500/mm³); hemoglobin ≥9.0 g/dL (equivalent values: ≥ 90 g/L or ≥ 5.6
 mmol/L); platelets ≥100 x 10^9/L (equivalent values: ≥ 100 x 10³/μL or ≥ 100 x
 10³/mm³) without the use of haematopoietic growth factors.
 - Total bilirubin ≤1.5 times the upper limit of normal (ULN), or ≤4 x ULN for
 patients who are known to have Gilbert's syndrome.
 - Creatinine ≤1.5 x ULN. If creatinine is >1.5 x ULN, patient is eligible if
 concurrent creatinine clearance ≥50 mL/min (equivalent value: 0.84mL/s) (measured
 or calculated by Cockcroft-Gault formula).
 - Aspartate transaminase (AST) and alanine transaminase (ALT) ≤3 x ULN, for
 patients with liver metastases ≤5 x ULN.
 - Age ≥18 years of age, or over the legal age of consent as required by local
 legislation.
 Further inclusion criteria apply.
 Exclusion Criteria:
 - Previous anticancer chemotherapy within 3 weeks of the first administration of trial
 drug. Previous anticancer hormonal treatment or anticancer immunotherapy within 2
 weeks of the first administration of trial drug.
 - Previous treatment with Rat Sarcoma (RAS), Mitogen-activated protein kinase (MAPK) or
 Son of sevenless 1 (SOS1) targeting agents (only for monotherapy Parts A, B, and C).
 - Radiotherapy within 2 weeks prior to start of treatment, provided recovery from
 related toxicity.
 - Major surgery (major according to the investigator's assessment) performed within 4
 weeks prior to start of treatment or planned during the projected course of the trial,
 e.g. hip replacement.
 - Previous treatment with any investigational agent(s) or targeted treatment within 28
 days prior to start of treatment or 5 half-lives, whichever is shorter.
 - Known history of hypersensitivity to any of the excipients of BI 1823911 tablets, or
 any contraindication to Midazolam (for Monotherapy Part B only).
 - History or presence of cardiovascular abnormalities such as congestive heart failure
 New York Heart Association (NYHA) classification of ≥3, unstable angina or poorly
 controlled arrhythmia which are considered clinically relevant by the Investigator.
 Myocardial infarction within 6 months prior to start of treatment. Uncontrolled
 hypertension defined as: Blood pressure (BP) measured in a rested and relaxed
 condition, where systolic BP >=140 mmHg, or diastolic BP >= 90 mmHg, with or without
 medication.
 - Left ventricular ejection fraction (LVEF) <50%. Further exclusion criteria apply.


Input:
This is a single center and exploratory study, aiming to analyze the efficacy and safety of
 dacomitinib-a pan-HER and irreversible TKI in subjects with diagnosed stage IIIB/IV or
 recurrent NSCLC. All subjects will have tumors that test positive for at least one uncommon
 EGFR activating mutation (do not have drug-resistant pattern, e.g. 20 insertion or 20T790M).
 All patients will be of histo- and/or cytopathology confirmed. Determination of the EGFR
 mutation type will be performed in the pathological department of Shanghai Chest Hospital.
 Both ARMS method or targeted sequencing are acceptable. It is not acceptable for subjects
 with the presence of the exon 20T790M mutation or insertion together with either EGFR
 activating mutations (exon 19 deletion or the L858R mutation in exon 21) or uncommon EGFR
 mutations. 10ml peripheral blood must be available for concomitant study. All eligible
 subjects must have adequate renal, hepatic, and hematologic function, as defined in
 "inclusion criteria".
 Patients will receive continuous oral therapy with the study drugs (dacomitinib 45 mg) until
 progressive disease as defined by RECIST version 1.1 or judged by investigator that the
 patient no longer derives clinical benefit from study treatment. At the time of progression
 and removal from study treatment, the subject may receive any regulatory approved therapy at
 the judgment of the investigator. Timely and complete disease assessments in this study are
 important. Every effort should be made to ensure disease assessments performed as scheduled
 to prevent the introduction of bias into the assessment of efficacy. Failure to perform any
 of the required disease assessments will result in the inability to determine disease status
 for that time point. Frequent off schedule or incomplete disease assessments have the
 potential to weaken the study conclusion.
 Subjects who have progressive disease per RECIST version 1.1 confirmed by the investigator
 believes it is in their best interest to continue on their study therapy, will be allowed to
 continue on their therapy with or without local therapy (e.g. surgical removal and/or
 radiation of a single lesion), at the discretion of the investigator until any alternate or
 additional systemic anti-cancer therapy regimen is implemented. The subsequent new cancer
 therapy (including, for systemic therapy, drugs administered, date of initiation and
 discontinuation of each drug) and OS will be recorded. Each subject will be followed for
 survival status and subsequent cancer therapies up to 48 months from the date of first
 dosing. This data may be collected from subjects by telephone, and if collected should be
 entered into the CRF.
 ;NA;
 Inclusion criteria: Only patients who meet all of the following criteria will be enrolled
 into this study:
 1. According to the 8th edition of the AJCC/UICC TNM staging system for NSCLC, patients
 with locally advanced (stage III B/III C), metastatic or recurrent (stage IV) NSCLC
 confirmed by histology or cytology who are unable to undergo surgery and radical
 concomitant radiochemotherapy and are confirmed to have at least one measurable lesion
 according to RECIST 1.1.
 2. Patients harboring uncommon EGFR mutations. Uncommon EGFR mutations were defined as
 mutations in exon 18-21 but except for 19del, 21L858R and well-established drug
 resistant type (20 insertion, 20T790M, 19L747S, 19L747P, D761Y, 21T854A). Mutations
 should be previously reported that it was sensitive to first- or second-generation
 TKIs. Detailed mutation type including:
 Mutation in exon 18:
 G719X(X=A/C/S/D/E), 18del, E709X(X=G/M/V/H/DA/K), V689M, S720P/F, P699S, N700D, E709Q,
 G721A, V740A, L718P;
 Mutation in exon 19:
 Few exon 19 point mutations with unknown structure and kinase activity have been found
 in EGFR-TKI responders, however, a new class of sensitizing mutations, exon 19
 insertions, were recently found, these patients were also eligible for this study:
 I744_K745insKIPVAI, K745_E746insIPVAIK, K745_E746insVPVAIK, K745_E746insTPVAIK.
 Mutation in exon 20:
 Including S768I, V765A, T783A, V774A, S784P, R776C, R776H, V765M, G779C, G779F, G779S,
 T783A, T783I, L798F, L798H, K806E, Q812R, L814P
 Mutation in exon 21:
 L861Q, R831H, V834I, L838P, L861R.
 Others:
 Patients with complex mutation but do not have drug-resistant pattern (e.g.
 18G719A+20S768I, 18 E709X+21L861Q) are also eligible. However, individuals who have
 common mutation (e.g. 19del+21L861Q, 18G719X+21L858R) were not eligible.
 3. Age ≥18 years and ≤75 years;
 4. ECOG PS score: 0 to 2
 5. Previously untreated with EGFR-TKIs including first-, second- or third generation
 agents. Subjects who were only treated with chemotherapy were eligible. Patients who
 have received adjuvant chemotherapy but disease recurrence must have happened at least
 6 months after the last dose of chemotherapy. Palliative radiotherapy must be
 completed 7 days before the first dose of study drugs;
 6. The main organs function is normal, that is, the following criteria met:
 - Good hematopoietic function, defined as absolute neutrophil count ≥1.5×109 /L,
 platelet count≥100 ×109 /L, hemoglobin ≥90g/L [no blood transfusion or no
 erythropoietin (EPO) dependence within 7 days before enrollment]
 - Biochemical test results should meet the following criteria: BIL < 1.25 times the
 upper limit of normal value (ULN); ALT and AST < 2.5 × ULN; in case of liver
 metastases, ALT and AST < 5 × ULN; Cr ≤1.5×ULN or creatinine clearance (CCr)
 ≥60ml/min; Coagulation function is good, INR and PT ≤1.5 times ULN; if the
 subject is receiving anticoagulant treatment, PT should be within the prescribed
 range of use of anticoagulant drugs;
 7. Women of child-bearing age should agree to take contraceptive measures (such as
 intrauterine devices, contraceptives or condoms) during the study and within 6 months
 after the study; non-breast-feeding patients whose serum or urinary pregnancy test
 should be negative; male patients should agree to take contraceptive measures during
 the study and within 6 months after the study.
 8. Patients are voluntarily enrolled into the study, sign the informed consent form and
 have good compliance.
 Exclusion criteria
 Patients who meet any of the following criteria will be excluded:
 1. Small cell lung cancer (including mixed small cell and non-small cell lung cancer);
 2. Patients who have received EGFR-TKIs as adjuvant or salvaged treatment;
 3. Patients with 19del or 21L858R or well-established drug resistant type (20 insertion,
 20T790M, L747S, L747P, D761Y, T854A).
 4. Patients with many factors affecting oral medication, such as dysphagia,
 gastrointestinal resection, chronic diarrhea and intestinal obstruction;
 5. Patients who are known to have brain metastases including asymptomatic metastasis,
 spinal cord compression, carcinomatous meningitis, or brain or leptomeningeal disease
 diagnosed by CT or MRI at the time of screening;
 6. Patients with severe and / or uncontrolled diseases, such as:
 - Unstable angina pectoris, symptomatic congestive heart failure, myocardial
 infarction within 6 months before randomization, severe uncontrolled arrhythmias;
 uncontrolled blood pressure (systolic blood pressure > 140 mmHg, diastolic blood
 pressure > 90 mmHg);
 - Active or uncontrolled serious infection;
 - Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic
 active hepatitis;
 - Not completely controlled eye inflammation or eye infection, or any condition
 that may lead to the above-mentioned ocular diseases
 - Poorly controlled diabetes (fasting blood glucose (FBG) > 10mmol/L);
 - Routine urine test result indicates that urine protein ≥++, and 24-hour urine
 protein quantitation is confirmed to be > 1.0 g;
 - Active tuberculosis, etc.;
 - Uncontrolled hypercalcemia (> 1.5 mmol/L calcium ion or calcium > 12 mg/dL or
 corrected serum calcium > ULN), or symptomatic hypercalcemia requiring continued
 diphosphate therapy;
 - Long-term unhealed wounds or fractures;
 7. Patients who have a history of psychotropic drug abuse and cannot abstain from it or
 have mental disorders;
 8. Patients who are known to have severe allergies (≥ grade 3) to active ingredients and
 any excipients of dacomitinib
 9. Patients who have other malignant tumors (except radical cervical carcinoma in situ,
 non-melanoma skin cancer, etc.) at the same time; patients who are evaluated by the
 investigator to have concomitant diseases that seriously endanger the safety of the
 patients or affect the patients completing the study.
 10. The subjects or their sexual partners cannot or refuse to take effective contraceptive
 measures during the clinical trial
 11. Pregnant or breast-feeding women
 12. Patients in other situations who are evaluated by the investigator to be ineligible to
 be enrolled


Input:
This clinical trial is the first-in-human study of BBT-176. The purpose of this trial is to
 investigate the safety and tolerability of BBT-176 (Part 1) and to evaluate the anti-tumor
 activity of BBT-176 (Part 2).
 ;NA;
 Key Inclusion Criteria:
 - Provision of signed and dated, written informed consent before any study specific
 procedures, sampling and analyses
 - Histological or cytological confirmation of advanced and/or metastatic stage IIIB/IV
 NSCLC
 - Radiological documentation of disease progression while on a previous continuous (at
 least 30 days) treatment with an EGFR TKI monotherapy (including, but not limited to,
 osimertinib, afatinib, gefitinib, or erlotinib)
 - Patients must fulfill one of the following:
 - Confirmation that the tumor harbors an EGFR mutation known to be associated with
 EGFR TKI sensitivity (including, but not limited to, exon 19 deletion, L858R, or
 L861Q)
 - Documented partial or complete response or a significant and durable stable
 disease (at least 6 months), based on the RECIST or WHO criteria, after treatment
 of an EGFR TKI
 Key Exclusion Criteria:
 - Treatment with any of the following:
 - An EGFR TKI, including but not limited to osimertinib, afatinib, gefitinib, or
 erlotinib within 8 days of the first dose of study treatment.
 - Any cytotoxic chemotherapy, investigational agents, or anticancer drugs for the
 treatment of advanced NSCLC, between prior EGFR TKI treatment and BBT-176
 treatment
 - Major surgery (excluding placement of vascular access) within 4 weeks of the
 first dose of study treatment
 - Radiotherapy with a limited field of radiation for palliation within 1 week of
 the first dose of study treatment
 - Patients receiving radiation to more than 30% of the bone marrow or with a wide
 field of radiation within 6 weeks of the first dose of study treatment
 - Any unresolved toxicities from prior therapy greater than NCI Common Terminology
 Criteria for Adverse Events (CTCAE v5.0) Grade 1 at the time of starting study
 treatment, with the exception of alopecia and Grade 2 neuropathy related to prior
 platinum-therapy
 - Spinal cord compression or brain metastases, unless asymptomatic and stable


Input:
This phase II trial studies the effect of polatuzumab vedotin, venetoclax, and rituximab and
 hyaluronidase human in treating patients with mantle cell lymphoma that has come back
 (relapsed) or does not respond to treatment (refractory). Polatuzumab vedotin is a monoclonal
 antibody, polatuzumab, linked to a toxic agent called vedotin. Polatuzumab attaches to CD79B
 positive cancer cells in a targeted way and delivers vedotin to kill them. Venetoclax may
 stop the growth of cancer cells by blocking Bcl-2, a protein needed for cell growth.
 Rituximab hyaluronidase is a combination of rituximab and hyaluronidase. Rituximab binds to a
 molecule called CD20, which is found on B cells (a type of white blood cell) and some types
 of cancer cells. This may help the immune system kill cancer cells. Hyaluronidase allows
 rituximab to be given by injection under the skin. Giving rituximab and hyaluronidase by
 injection under the skin is faster than giving rituximab alone by infusion into the blood.
 Giving polatuzumab vedotin, venetoclax, and rituximab and hyaluronidase human may work better
 than standard therapy in treating patients with mantle cell lymphoma.
 ;
 ;
 Inclusion Criteria:
 - Pathologically confirmed relapsed or primary refractory mantle cell lymphoma with
 concurrent or prior tissue sample immunohistochemistry (IHC) positive for cyclin D1 or
 that is positive for fluorescence in situ hybridization (FISH) or cytogenetics for
 t(11;14)
 - NOTE: Safety Portion only: MCL or indolent B cell non-Hodgkin lymphoma (NHL)
 (follicular lymphoma [FL] [grades I-IIIa] marginal zone lymphoma [MZL]), or,
 small lymphocytic lymphoma (SLL) stratified as low risk for tumor lysis syndrome
 (TLS), relapsed or progressed after at least two lines of therapy (or one BTK
 inhibitor containing line of therapy). No limit to prior lines of therapy
 - NOTE: Expansion Portion only: MCL relapsed or progressed after at least two lines
 of therapy or one BTK inhibitor line of therapy. Prior autologous stem cell
 transplant (AutoSCT) is allowed. No limit to number of prior therapies. May have
 received prior BTK inhibitor therapy
 - Measurable disease as defined with at least one lesion measuring >= 1 x 1.5 cm
 - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
 - Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to
 registration)
 - Platelet count >= 75,000/mm^3 (obtained =< 14 days prior to registration)
 - Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration)
 - International normalized ratio =< 1.5 x upper limit of normal (ULN) for patients not
 receiving therapeutic anticoagulation (obtained =< 14 days prior to registration)
 - Partial thromboplastin time (PTT) or activated PTT (aPTT) =< 1.5 x ULN (obtained =< 14
 days prior to registration)
 - Calculated creatinine (Cr) clearance >= 45 ml/min using the modified Cockcroft-Gault
 formula (obtained =< 14 days prior to registration)
 - Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x ULN
 (obtained =< 14 days prior to registration)
 - Total bilirubin < 1.5 x ULN (or =< 3 x ULN for patients with documented Gilbert
 syndrome) (obtained =< 14 days prior to registration)
 - Negative serum pregnancy test done =< 7 days prior to registration, for women of
 childbearing potential only
 - Able to provide informed written consent, and ability to comply with study related
 procedures
 - Willing to return to enrolling institution for follow-up (during the Active Monitoring
 Phase of the study)
 - Willing to provide tissue samples for mandatory correlative research
 - For women of childbearing potential: agreement to remain abstinent (refrain from
 heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
 per year during the treatment period and for at least 30 days after the last dose of
 venetoclax or 18 months after the last dose of rituximab and hyaluronidase human,
 whichever is longer. For men: agreement to remain abstinent (refrain from heterosexual
 intercourse) or use contraceptive measures, and agreement to refrain from donating
 sperm, as defined below:
 - With female partners of childbearing potential, men must remain abstinent or use
 a condom plus an additional contraceptive method that together result in a
 failure rate of < 1% per year during the treatment period and for at least 6
 months after the last dose. Men must refrain from donating sperm during this same
 period.
 - With pregnant female partners, men must remain abstinent or use a condom during
 the treatment period and for at least 6 months after the last dose to avoid
 exposing the embryo
 Exclusion Criteria:
 - Any of the following because this study involves an investigational agent whose
 genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
 unknown:
 - Pregnant women
 - Nursing women
 - Men or women of childbearing potential who are unwilling to employ adequate
 contraception
 - Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
 of the investigator, would make the patient inappropriate for entry into this study or
 interfere significantly with the proper assessment of safety and toxicity of the
 prescribed regimens
 - Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations that would limit compliance with
 study requirements
 - Receiving any other investigational or chemotherapeutic agent which would be
 considered as a treatment for the primary neoplasm
 - Known CD20-negative status at relapse or progression
 - Prior allogeneic SCT
 - Completion of autologous SCT =< 100 days prior to registration
 - Radioimmunoconjugate =< 12 weeks prior to registration
 - Monoclonal antibody or antibody-drug conjugate (ADC) therapy within 5 half-lives or 4
 weeks prior to registration, whichever is longer
 - Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule therapy
 within 2 weeks prior to registration (with the exception of ibrutinib to prevent tumor
 flare, patients taking ibrutinib who are progressing must discontinue ibrutinib 2
 half-lives or 2 days prior to initiating protocol therapy)
 - Clinically significant toxicity (other than alopecia) from prior therapy that has not
 resolved to grade =< 2 (per National Cancer Institute [NCI] Common Terminology
 Criteria for Adverse Events [CTCAE] version [v]5.0) prior to registration
 - Current grade > 1 peripheral neuropathy
 - Any history of central nervous system (CNS) lymphoma or leptomeningeal infiltration
 - Treatment with systemic corticosteroids > 20 mg/day prednisone or equivalent Patients
 who are receiving corticosteroids =< 20 mg/day, prednisone or equivalent, for
 non-lymphoma treatment reasons must be documented to be on a stable dose for at >= 4
 weeks prior to registration. If corticosteroid treatment is urgently required for
 lymphoma symptom control prior to the start of study treatment, up to 100 mg/day of
 prednisone or equivalent can be given for a maximum of 5 days, but all tumor
 assessments must be completed prior to start of corticosteroid treatment
 - History of severe allergic or anaphylactic reaction or known sensitivity to humanized
 or murine monoclonal antibodies rituximab, polatuzumab vedotin, and venetoclax
 - Active bacterial, viral, fungal, or other infection
 - Requirement for warfarin treatment (because of potential drug-drug interactions [DDIs]
 that may increase the exposure of warfarin)
 - Treatment with the following agents =< 7 days prior to registration
 - Strong and moderate CYP3A inhibitors such as fluconazole, ketoconazole, and
 clarithromycin
 - Strong and moderate CYP3A inducers such as rifampin and carbamazepine. If taking
 proton pump inhibitors willing to avoid co-administration and stagger venetoclax
 dosing
 - Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade
 that contains Seville oranges), or star fruit =< 3 days prior to registration
 - Clinically significant history of liver disease, including viral or other hepatitis,
 current alcohol abuse, or cirrhosis
 - Active hepatitis B or hepatitis C infection. Patients who have been successfully
 treated and cleared their virus as evidenced a negative hepatitis (Hep) B or Hep C
 polymerase chain reaction (PCR) are eligible
 - Known history of human immunodeficiency virus (HIV) positive status or known infection
 with human T-cell leukemia virus 1. For patients with unknown HIV status, HIV testing
 will be performed at screening if required by local regulations
 - History of PML (progressive multifocal leukoencephalopathy)
 - Vaccination with a live virus vaccine =< 28 days prior to registration
 - History of other malignancy that could affect compliance with the protocol or
 interpretation of results, with the exception of the following: curatively treated
 carcinoma in situ of the cervix, good-prognosis ductal carcinoma in situ of the
 breast, basal- or squamous-cell skin cancer, stage I melanoma, or low-grade,
 early-stage localized prostate cancer
 - Any previously treated malignancy that has been in remission without treatment for =<
 3 years prior to registration
 - Evidence of any significant, uncontrolled concomitant disease that could affect
 compliance with the protocol or interpretation of results, including significant
 cardiovascular disease (such as New York Heart Association class III or IV cardiac
 disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or
 unstable angina) or significant pulmonary disease (such as obstructive pulmonary
 disease or history of bronchospasm)
 - Major surgical procedure other than for diagnosis =< 28 days prior to day 1 of cycle
 1, or anticipation of a major surgical procedure during the course of the study
 - Inability or unwillingness to swallow pills
 - History of malabsorption syndrome or other condition that would interfere with enteral
 absorption
 - History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) or
 active bowel inflammation (e.g., diverticulitis)


Input:
The objective of this study is to evaluate the safety, tolerability and PK profile of
 HMPL-295S1 and determine MTD and/or RP2D in patients with advanced malignant solid tumor. It
 will be extended to enroll 10-15 patients at this dose after RP2D is determined, as to
 further evaluate the safety of RP2D and the preliminary efficacy of HMPL-295S1. In addition,
 an exploratory study on the pharmacokinetic biomarkers of HMPL-295S1 is planned in this
 study.
 ;
 ;
 Inclusion Criteria:
 All the following conditions must be met for enrollment:
 1. Having understood this study adequately and being voluntary to sign the informed
 consent form;
 2. Aged 18~75 years (inclusive);
 3. Patients with histopathologically or cytologically confirmed advanced malignant solid
 tumors who have failure of standard of care or can not tolerate standard of care, or
 can not obtain standard of care for various reasons, or have no standard of care
 (regardless of previous surgery);
 4. Having at least one measurable lesion (in accordance with the RECIST 1.1 criteria);
 note: the lesion previously irradiated can not be regarded as target lesion, unless
 unequivocal progression of disease is shown in radiological evidence after
 radiotherapy;
 5. United States Eastern Cooperative Oncology Group (ECOG) Performance Status score ≤ 1;
 6. Life expectancy ≥12 weeks based on investigator's judgment;
 7. Having adequate bone marrow, hepatic and renal function (no transfusion of whole
 blood, blood components, blood products, no use of granulocyte colony-stimulating
 factor or other hematopoietic stimulator or drug for correction within two weeks prior
 to blood collection):
 - Absolute neutrophil count ≥1.5×109/L;
 - HGB≥90 g/L;
 - Platelet count ≥ 100×109/L;
 - Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) [alanine
 aminotransferase (ALT) and aspartate aminotransferase (AST) need to be normal,
 serum total bilirubin needs to be ≤3 × ULN in the patients with Gilbert disease];
 - Serum ALT and/or AST ≤2.5 × ULN in the patients without hepatic metastasis (ALT
 and AST ≤5 ×ULN for those with liver metastasis);
 - Creatinine clearance ≥ 60 mL/min (calculated according to Cockcroft-Gault
 formula, see Appendix 11);
 - International normalized ratio (INR) ≤1.5, and activated partial thromboplastin
 time (aPTT) ≤ 1.5 ULN.
 8. A man of childbearing potential and his heterosexual partner of childbearing age must
 agree to use effective contraceptive methods from the signature of informed consent
 form to 90 days after the last dose; any female of childbearing potential (including
 those who have received tubal ligation) must receive serum or urine pregnancy test and
 the result is negative within 7 days prior to the first dose of study drug; and she
 must agree to use effective contraceptive methods, for example, dual barrier
 contraceptive method, intrauterine device, etc., from the signature of informed
 consent form to 30 days after the last dose of study drug. Postmenopausal woman (age >
 50 years and menopause for 1 year or above, in the absence of other biological or
 physiological reasons) and the woman receiving irreversible sterilization operation
 (including hysterectomy, bilateral ovariectomy or bilateral salpingectomy, but
 excluding tubal ligation) who is regarded as infertile, will not be restricted by this
 condition.
 Exclusion Criteria:
 - The patients can not participate in this study if any of the following conditions is
 met:
 1. Previous antitumor therapy meeting any of the following:
 1. Previous treatment with a ERK inhibitor and having PD;
 2. Receiving approved systematic antitumor therapy within 4 weeks prior to the
 first dose, including chemotherapy, targeted therapy, immunotherapy,
 biotherapy, etc. (elution for two weeks for hormone therapy or treatment
 with traditional Chinese medicine and Chinese patent drug with clear
 antitumor indication);
 3. In the treatment period of other interventional clinical study (including
 small molecular chemical drug and macromolecular antibody) within 4 weeks
 prior to the first dose. Patients can be enrolled in this study if they are
 involved in non-interventional clinical study (e.g., epidemiological study);
 and can also be enrolled if they stay in the survival follow-up period of
 one interventional clinical study.
 4. Having received major surgery or radical radiotherapy (except for the
 palliative radiotherapy for bone metastasis) within 4 weeks prior to the
 first dose.
 2. Toxicity associated with previous antitumor therapy (including surgery,
 chemotherapy, radiotherapy, targeted therapy and immunotherapy) not recovered to
 ≤ CTCAE grade 1, except for alopecia and peripheral neuropathy. The peripheral
 neurotoxicity needs to be recovered to ≤ CTCAE grade 2 in the patients who have
 been previously treated with platinum;
 3. Patients with central nervous system (CNS) malignant tumor or malignant solid
 tumor with known CNS metastasis;
 4. Combined with other malignant tumor or having a history of other malignant tumor
 within 2 years prior to study screening (not including the basal or squamous cell
 carcinoma of skin, non-melanoma skin cancer, papillary thyroid carcinoma that
 have been appropriately treated, or radically resected cervical carcinoma in situ
 and ductal carcinoma in situ);
 5. Known history of clinically significant liver disease, including viral or other
 hepatitis, except the following patients:
 - HBsAg positive patients can be enrolled if the polymerase chain reaction
 (PCR) test of hepatitis B virus (HBV) DNA is negative. The investigator can
 provide preventive or therapeutic antiviral therapy based on patient's
 condition and diagnostic routines during study treatment;
 - Patients with positive hepatitis C virus (HCV) antibody can be enrolled if
 the PCR test of HCV RNA is negative.
 6. Patients infected by human immunodeficiency virus (HIV);
 7. Presence of active bacterial, fungal or viral infection requiring systematic
 treatment within one week prior to the first dose;
 8. Use of CYP3A potent inducer within 2 week or 5 half-lives (whichever is longer, 3
 weeks needed for St. John's wort) prior to the first dose, see (Appendix 5);
 9. Use of CYP3A, P-gp potent inhibitor or sensitive substrate of P-gp, BCRP, MATE
 2-K, CYP3A, CYP2C8/OATP1B1 and CYP2D6/CYP3A within one week or three half-lives
 (whichever is longer) prior to the first dose, this exclusion criterion will be
 adjusted in accordance with the actual dose of HMPL-295S1 and determined plasma
 concentration during the clinical study (see Appendix 5);
 10. Meeting any of the following criteria for cardiac examination:
 - Hereditary long QT syndrome or QTcF>480 msec (the formula is seen in
 Appendix 10), or currently taking the drugs that are known to prolong QT
 interval or lead to torsade de pointe arrhythmia (Appendix 6);
 - Serious arrhythmia or conduction abnormality requiring clinical
 intervention;
 - Impaired cardiac function or clinically significant cardiac disease,
 including but not limited to the acute myocardial infarction, unstable
 angina pectoris, coronary artery bypass grafting, New York Heart Association
 (NYHA, see Appendix 9) evaluated Grade III/IV congestive heart failure, left
 ventricular ejection fraction (LVEF) <50%, or uncontrollable hypertension
 within 6 months prior to enrollment.
 11. Pregnant or lactating women;
 12. Having multiple factors affecting absorption, distribution, metabolism or
 excretion of oral drugs, e.g., inability to swallow, frequent vomiting, chronic
 diarrhea, etc.;
 13. Currently known or previous retinopathy;
 14. Any other disease, metabolic abnormality, physical examination abnormality or
 clinically significant laboratory examination abnormality, one disease or state
 that may affect patient's compliance or provides a reason to suspect that the
 patient is not suitable to use the study drug, or will affect interpretation of
 the study results, or bring the patient at a high risk, according to
 investigator's judgment.


Input:
Patients with refractory and/or recurrent solid tumor have poor prognosis despite complex
 multimodel therapy and therefore, novel approaches are urgently needed. This study attempts
 to treat these diseases using T cells genetically modified with a 4th generation lentiviral
 chimeric antigen receptor (4SCAR fused with an inducible apoptotic caspase 9 domain)
 targeting CD276 (B7-H3). The 4SCAR-CD276-modified T cells (4SCAR-276) can recognize and kill
 tumor cells through the recognition of CD276, a surface protein expressed at high levels on
 many types of tumors but at low levels on normal tissues. This study will evaluate the side
 effects and effective doses of 4SCAR-276 in treating refractory and/or recurrent tumors.
 ;
 ;
 Inclusion Criteria:
 - Patients with tumors have received standard first-line therapy and have been judged to
 be non-resectable, metastatic, progressive or recurrent.
 - The CD276 antigen status of the tumor is determined for eligibility. Positive
 expression is defined by antibody staining results based on immunohistochemistry or
 flow cytometry analysis.
 - Body weight greater than or equal to 10 kg.
 - Age: ≥1 year and ≤ 75 years of age at the time of enrollment.
 - Life expectancy: at least 8 weeks.
 - Prior Therapy: 1) There is no limit to the number of prior treatment regimens. Any
 grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to
 grade 2 or less. 2) Must not have received hematopoietic growth factors for at least 1
 week prior to mononuclear cells collection. 3) At least 7 days must have elapsed since
 the completion of therapy with a biologic agent, targeted agent, tyrosine kinase
 inhibitor or a metronomic nonmyelosuppressive regimen. 4) At least 4 weeks must have
 elapsed since prior therapy that included a monoclonal antibody. 5) At least 1 week
 since any radiation therapy at the time of study entry.
 - Karnofsky/jansky score of 60% or greater.
 - Cardiac function: Left ventricular ejection fraction greater than or equal to 40/55
 percent .
 - Pulse Ox greater than or equal to 90% on room air.
 - Liver function: defined as alanine transaminase (ALT) <3x upper limit of normal (ULN),
 aspartate aminotransferase (AST) <3x ULN; serum bilirubin and alkaline phosphatase <2x
 ULN.
 - Renal function: Patients must have serum creatinine less than 3 times upper limit of
 normal.
 - Marrow function: White blood cell count ≥1000/ul, Absolute neutrophil count ≥500/ul,
 Absolute lymphocyte count ≥500/ul, Platelet count ≥25,000/ul (not achieved by
 transfusion).
 - Patients with known bone marrow metastatic disease will be eligible for study as long
 as they meet hematologic function criteria, and the marrow disease not evaluable to
 have hematologic toxicity.
 - For all patients enrolled in this study, themselves or their parents or legal
 guardians must sign an informed consent and assent.
 Exclusion Criteria:
 Existing severe illness (e.g. significant cardiac, pulmonary, hepatic diseases, etc.) or
 major organ dysfunction, or grade 3 hematologic toxicity.
 - Untreated central nervous system (CNS) metastasis: Patients with CNS tumor involvement
 that has been treated and/or is stable for at least 6 weeks following completion of
 therapy are eligible.
 - Previous treatment with other genetically engineered CD276-CAR T cells or CD276
 antibody therapy.
 - Active HIV, Hepatitis B virus (HBV), Hepatitis C virus (HCV) infection or uncontrolled
 infection.
 - Patients who require systemic corticosteroid or other immunosuppressive therapy.
 - Evidence of tumor potentially causing airway obstruction.
 - Inability to comply with protocol requirements.
 - Insufficient CAR T cells availability.


Input:
This intermediate-size IND will treat participants with incurable, advanced or metastatic
 cancer, harboring KRAS G12V mutation and appropriate HLA class II match (HLA-DRB1*07:01).
 ;
 ;
 Patients with incurable, advanced or metastatic cancer, harboring KRAS G12V mutation, and
 appropriate HLA class II match (HLA-DRB1*07:01)


Input:
This is an open-label, multi-center study to evaluate the safety, tolerability, and
 anti-tumor activity of SNK01 in combination with AFM24 in subjects with advanced or
 metastatic EGFR-expressing cancers.
 ;
 ;
 Key Inclusion Criteria:
 1. Capable of giving signed informed consent
 2. Males and females age ≥ 18 years
 3. Phase 1/Dose Escalation : any histologically confirmed advanced or metastatic
 EGFR-positive malignancy for which all standard of care treatment options have been
 received and are no longer effective or are considered inappropriate at the discretion
 of the investigator.
 4. Phase 2a/Expansion : histologically confirmed advanced or metastatic EGFR positive
 malignancy of mCRC (EXP-1 cohort), SCCHN (EXP-2 cohort) or NSCLC (EXP-3 cohort).
 5. Additional Criteria for Phase 2a/Expansion: subjects must have a disease history
 specific to their disease as listed below:
 1. EXP-1: mCRC. Metastatic colorectal cancer (mCRC) MSI low/DNA mismatch repair
 proficient. Subjects must have received ≥ 1 lines of previous combination therapy
 and must have been exposed to oxaliplatin, irinotecan, a fluoropyrimidine, a VEGF
 targeting agent and, if considered appropriate by the treating physician, an EGFR
 targeted antibody.
 2. EXP-2: SCCHN. Subjects with advanced or metastatic SCCHN whose disease has
 progressed after having received ≥ 1 prior lines of therapy for advanced disease,
 which must have included platinum-based therapy, fluoropyrimidine, and an anti PD
 1/PD-L1 antibody.
 3. EXP-3: NSCLC. Subjects with advanced or metastatic EGFR-expressing NSCLC (EGFR
 WT) whose disease has progressed after having received ≥ 1 prior lines of therapy
 for advanced disease. Subjects must have received at least a platinum-based
 doublet in combination with anti-PD1/PD-L1 antibody or must have received a
 platinum-based doublet followed by an anti-PD1/PD-L1 antibody.
 6. One or more measurable tumors lesions per RECIST v1.1
 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
 8. Adequate bone marrow, hepatic and renal function.
 Key Exclusion Criteria:
 1. Superior vena cava syndrome contra-indicating hydration
 2. Untreated or symptomatic central nervous system (CNS) metastases
 3. No resolution of specific toxicities related to any prior anti-cancer therapy to Grade
 ≤ 1 according to the NCI-CTCAE v.5.0 (except peripheral or motor neuropathy,
 lymphopenia and alopecia)
 4. Treatment with systemic anticancer therapy or an investigational device within 4 weeks
 (6 weeks if therapy was mitomycin C and/or nitrosoureas), or within 5 half-lives of
 the agent (if half-life is known and it is shorter) before the first dose of study
 treatment.
 5. Radiation therapy within 2 weeks before first dose of any study treatment or
 unresolved (NCI CTCAE v5.0 Grade > 1) toxicity from previous radiotherapy
 6. Clinically significant cardiovascular disease
 7. Major surgery within 4 weeks prior to any study treatment administration
 8. Any pulmonary, thyroid, renal, hepatic severe/uncontrolled concurrent medical disease
 that in the opinion of the Investigator could cause unacceptable safety risks or
 compromise compliance with the protocol
 9. Active uncontrolled viral, fungal, or bacterial infection requiring systematic therapy
 within 14 days prior to first dose of study treatment.
 10. Known history of testing positive for human immunodeficiency virus (HIV), and/or
 positive test for Hepatitis B virus surface antigen (HBsAg) and/or positive Hep C
 antibody result with detectable hepatitis C virus (HCV) ribonucleic acid (RNA)
 indicating acute or chronic infection.
 11. Autoimmune disease requiring therapy; immunodeficiency, or any disease process
 requiring systemic immunosuppressive therapy
 12. A serious nonmalignant disease that could compromise protocol objectives in the
 opinion of the Investigator and/or the Sponsor
 13. Any other condition that, in the opinion of the Investigator, would prohibit the
 subject from participating in the study