Input:
This will be a Phase 1 Open-label, dose escalation and expansion study of MT-6402 (an
 Engineered Toxin Body (ETB)) in subjects with advanced solid cancer that expresses PD-L1
 ;
 ;
 Inclusion Criteria:
 Part A
 1. Subject must be at least 18 years old and must have histologically confirmed,
 unresectable, locally advanced, or metastatic PD-L1-expressing solid cancer not
 amenable to standard treatment, or standard treatment is not available, or in the
 Investigator's opinion the standard treatment would not be in the subject's best
 interest. Any level of PD-L1 expression assessed by using any Food and Drug
 Administration (FDA) approved PD-L1 immunohistochemistry (IHC) assay is accepted. The
 assessment should have been performed on the most recent available tissue from a site
 of metastatic disease (if possible).
 2. Subject must have evaluable or measurable disease.
 Part B
 1. Subject must be at least 18 years old and must have histologically confirmed,
 unresectable, locally advanced or metastatic PD-L1-expressing solid cancer (defined
 below) not amenable to standard treatment, or standard treatment is not available, or
 in the Investigator's opinion the standard treatment would not be in the subject's
 best interest. PD-L1 expression must be assessed at screening by the study's central
 laboratory, using VENTANA SP263 PD-L1 assay on a tissue from a site of metastatic
 disease (if possible). For this purpose, recent archived tissue suitable for PD-L1
 expression assessment by IHC (obtained after the last treatment and within 6 months)
 or fresh biopsy material can be used. The PD-L1 assessment must show at least 5% vCPS
 (visually estimated Combined Positive Score) for eligibility.
 - Arm 1: Histologically confirmed recurrent or metastatic NSCLC not amenable to
 standard treatment, or standard treatment is not available, or in the
 Investigator's opinion the standard treatment would not be in the subject's best
 interest. NOTE: subjects with driver mutations are only eligible if they have
 received all appropriate targeted therapies.
 - Arm 2: Histologically confirmed recurrent or metastatic SCCHN (oral cavity,
 oropharynx, hypopharynx, or larynx) not amenable to standard treatment, or
 standard treatment is not available, or in the Investigator's opinion the
 standard treatment would not be in the subject's best interest. Subjects who
 refuse radical resection are eligible. NOTE: squamous cell carcinoma of any other
 primary anatomic location in the head and neck, subjects with SCCHN of unknown
 primary, and subjects with skin squamous cell carcinoma (SCC) of the head and
 neck are not eligible for this arm. The tumor must be platinum resistant or the
 subject ineligible for platinum therapy due to hypersensitivity or concerns with
 ototoxicity.
 - Arm 3: Subjects with any other relapsed or refractory PD-L1 positive solid tumor
 not amenable to standard treatment, or standard treatment is not available, or in
 the Investigator's opinion the standard treatment would not be in the subject's
 best interest, who received PD-1/PD-L1 treatment. Subjects with PD-L1 positive
 solid tumor types, for which PD-1/PD-L1 treatment is not approved, could be
 enrolled at the Investigator's discretion and after discussion with the Medical
 Monitor.
 2. Subject must have at least 1 measurable tumor lesion according to RECIST 1.1.
 Parts A and B
 3. Subject must have Eastern Cooperative Oncology Group (ECOG) performance score of 0 or
 1.
 4. Prior treatment must include a CPI (i.e., PD-1 inhibitors, PD-L1 inhibitors with or
 without CTLA-4 inhibitors) if there is an approved CPI for the specific cancer type.
 Subjects may also have received CPIs in an investigational setting. Subjects who have
 not received a CPI and where there is no approved CPI for the specific cancer type
 could be enrolled at the Investigator's discretion and after discussion with the
 Medical Monitor.
 5. Subject must have adequate bone marrow function (NOTE: administration of blood
 products and growth factors is not allowed within 2 weeks prior to screening
 laboratory tests):
 - absolute neutrophil count (ANC) ≥ 1,500/μL
 - platelet count ≥ 100,000/μL
 - hemoglobin ≥ 8.0 g/dL
 6. Subject must have adequate renal function, based on estimated creatinine clearance
 (eCrCl) ≥ 50 mL/min, calculated by the Cockcroft-Gault equation.
 NOTE: At the Investigator's discretion, the eCrCl result < 50 mL/min may be verified
 by measured creatinine clearance (mCrCl) based on the 24-hour urine collection.
 Subjects with mCrCl ≥ 50 mL/min will be eligible irrespective of the eCrCl result
 calculated by the Cockcroft-Gault equation.
 7. Subject must have adequate hepatic function, as determined by:
 - total bilirubin (or direct bilirubin for subjects with Gilbert's disease) < 1.5 ×
 upper limit of normal (ULN)
 - aspartate aminotransferase (AST) ≤ 3 × ULN (or ≤ 5 × ULN if liver metastasis)
 - alanine aminotransferase (ALT) ≤ 3 × ULN (or ≤ 5 × ULN if liver metastasis)
 8. Subject must have adequate serum albumin (albumin ≥ 2.5 g/dL)
 9. Women of reproductive potential must have a negative highly sensitive pregnancy test
 within 72 hours before the start of treatment. Women who are postmenopausal (> 1 year
 since last menstrual cycle) or permanently sterilized (e.g., bilateral tubal
 occlusion, hysterectomy, bilateral salpingectomy) may be considered as not of
 reproductive potential.
 10. Subjects of reproductive potential must agree either to abstain continuously from
 heterosexual intercourse or to use a highly effective birth control method from
 signing the informed consent until 30 days after the last dose of MT-6402 for females
 and until 90 days after the last dose of MT-6402 for males.
 Exclusion Criteria:
 Part A
 1. Subjects without available tissue from a site of metastatic disease or easily biopsiable
 lesion (biopsy sites of non significant risk, in the opinion of the Investigator) or
 unwilling to consent to biopsy.
 Part B
 1. Subjects without easily biopsiable lesions (biopsy sites of non significant risk, in
 the opinion of the Investigator) or unwilling to consent to biopsy.
 Parts A and B
 2. History or current evidence of another neoplastic disease, except cervical carcinoma
 in situ, superficial noninvasive bladder tumors, curatively treated Stage I to II non
 melanoma skin cancer or any previous cancer curatively treated > 2 years before the
 start of treatment.
 3. Active autoimmune disease currently under treatment or required systemic treatment
 within 2 years (replacement therapy, e.g., thyroxine, insulin, or physiologic
 corticosteroid replacement therapy for adrenal or pituitary insufficiency is allowed).
 Subjects who have not required systemic treatment of an auto-immune disease for at
 least 2 years may be enrolled if permission is provided after discussion with the
 Medical Monitor.
 4. Ongoing > Grade 1 immune related toxicity caused by prior CPI therapy (i.e., PD-1
 inhibitors, PD-L1 inhibitors, or CTLA-4 inhibitors). Subjects with stable
 endocrinological AEs, e.g., hypothyroidism, adrenal insufficiency, hypopituitarism, or
 diabetes mellitus, must have been on a stable dose of supplemental therapy for at
 least 2 weeks before screening to be eligible for this study.
 5. Evidence of active noninfectious ≥ Grade 2 pneumonitis or current evidence of ≥ Grade
 3 other underlying pulmonary disease.
 6. Received any of the following PD-L1 inhibitors within the following time periods prior
 to the first dose of MT-6402: atezolizumab - 12 months; durvalumab - 7 months;
 avelumab - 2 months.
 7. Any concurrent cancer treatment, apart from local treatment of non-target lesions for
 palliative intent (e.g., local surgery or radiotherapy).
 8. Prior radiation therapy within 4 weeks before the start of study treatment. NOTE: A
 lesion in a previously irradiated area can only be considered target lesion if there
 has been radiographical disease progression since the end of radiation therapy.
 9. Received approved or investigational treatment for the disease under study (except PD
 L1 inhibitors where exclusion criterion 6 applies) within 4 weeks before the start of
 treatment. For small molecules (MW < 0.9 kDa), the washout is 5 half-lives, but at
 least 2 weeks.
 10. Subjects who have had allogeneic tissue or solid organ transplantation.
 11. Current evidence of new or growing central nervous system (CNS) metastases during
 screening. Subjects with known asymptomatic CNS metastases will be eligible if they
 meet all the following criteria:
 1. Had radiotherapy or another appropriate therapy for the CNS metastases.
 2. Have stable CNS disease on the computed tomography (CT) or magnetic resonance
 imaging (MRI) scan within 4 weeks before screening compared with prior neuro
 imaging.
 12. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
 start of study treatment.
 13. History or current evidence of significant cardiovascular disease before the start of
 treatment, including but not limited to the following conditions:
 1. Angina pectoris requiring anti-anginal medication, (chest pain: Common
 Terminology Criteria for Adverse Events [CTCAE] Grade ≥ 2)
 2. Clinically significant valvular disease.
 3. Myocardial infarction within 12 months prior to the start of treatment.
 4. Arterial thrombosis or pulmonary embolism within 3 months before the start of
 treatment.
 5. History of Grade ≥ 2 symptomatic congestive heart failure (CHF) or New York Heart
 Association (NYHA) criteria Class ≥ II.
 6. Left ventricular ejection fraction (LVEF) < 55%, assessed preferably by
 echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan if ECHO is not
 available, within 28 days before starting study treatment.
 7. High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate >
 100/min at rest and upon repeated testing, significant ventricular arrhythmia
 (CTCAE Grade ≥ 2 [ventricular tachycardia], or higher-grade atrioventricular
 [AV]-block [second degree AV-block Type 2 [Mobitz 2] or third-degree AV-block])
 or left ventricular bundle branch block. Subjects receiving digoxin, calcium
 channel blockers, or beta adrenergic blockers are eligible at the Investigator's
 discretion after consultation with the Medical Monitor if the dose has been
 stable for ≥ 2 weeks before the start of treatment with MT-6402.
 8. Any of the following within 3 months before the start of treatment: pericarditis
 (any CTCAE Grade), pericardial effusion (CTCAE Grade ≥ 2), non-malignant pleural
 effusion (CTCAE Grade ≥ 2) or malignant pleural effusion (CTCAE Grade ≥ 3)
 (subjects with pleural effusion that is manageable and stable > 3 months prior to
 study are eligible).
 9. QT interval correction for heart rate using Fridericia's formula (QTcF) ≥ 470 ms
 (average from 3 QTcF values on the triplicate 12-lead electrocardiogram [ECG]) at
 screening. In subjects with right bundle branch blocks, additional corrections
 will be performed to calculate the QT equivalent JT, and depending on the result
 the subject may be eligible with the agreement of the Medical Monitor.
 14. Current evidence of uncontrolled human immunodeficiency virus (HIV), hepatitis B virus
 (HBV), or hepatitis C virus (HCV) at screening. Serology testing is not required if
 seronegativity is documented in the medical history, and if there are no clinical
 signs suggestive of HIV or hepatitis infections, or suspected exposure. The following
 exceptions apply for subjects with positive viral serology:
 1. Subjects with HIV and an undetectable viral load and CD4 + T-cell (CD4+) counts ≥
 350 cells/mL may be enrolled, but must be taking appropriate opportunistic
 infection prophylaxis, if clinically relevant.
 2. Subjects with positive HBV serology are eligible if they have an undetectable
 viral load and the subject will receive antiviral prophylaxis for potential HBV
 reactivation per institutional guidelines.
 3. Subjects with positive HCV serology are eligible if quantitative polymerase chain
 reaction (PCR) for plasma HCV RNA is below the lower limit of detection.
 Concurrent antiviral HCV treatment per institutional guidelines is allowed.
 15. Current treatment requiring systemic steroids at doses > 10 mg/day prednisone
 equivalent.
 16. Subjects with a history of hypersensitivity or serious toxic reactions to kanamycin or
 other aminoglycosides.
 17. Subjects with unintentional weight loss > 10% of their body weight over the preceding
 2 months or less before screening.
 18. Female subjects who are pregnant or breastfeeding.
 19. History or evidence of any other clinically significant disorder, condition or disease
 (with the exception of those outlined above) that, in the opinion of the Investigator
 or Medical Monitor, if consulted, would pose a risk to subject safety or interfere
 with the study evaluation, procedures or completion.


Input:
BRAF mutation exists in about 10-12% of colorectal cancer, among which BRAF V600E mutation is
 the most common type, which is an important biomarker for predicting the prognosis and
 precise treatment efficacy of metastatic colorectal cancer (mCRC). The prognosis of
 metastatic colorectal cancer with BRAF V600E mutation is very poor, with OS of about 6-9
 months. Previous studies have shown that single anti-BRAF inhibitor are ineffective, while
 multi-target inhibitions of Ras-Raf -MEK pathway is a possible effective strategy for BRAF
 V600E-mutant mCRC. Currently, the proven effective regimens include the VIC regimen
 (Vemurafenib + cetuximab + Irinotecan) and BEACON regimen (Encorafenib+ cetuximab +/-
 Binimetinib) from the SWOGS1406 study. Furthermore, BRAF inhibitor +MEK inhibitor combined
 with PD-1 monoclonal antibody has been shown to be an effective strategy in BRAF V600E-mutant
 malignant melanoma, which promote the study of the regimens for the treatment of BRAF
 V600E-mutant mCRC. Increasing basic and clinical studies have shown that cetuximab has ADCC
 effect, induces immunogenic cell death, promotes immune cell infiltration and other
 immunomodulatory effects, and has a synergistic effect with PD-1 monoclonal antibody in
 colorectal cancer. Based on those theories, we conducted the phase I study to explore the
 safety and preliminary efficacy of the regimen of Vemurafenib (BRAFi) plus cetuximab (EGFRi)
 combined with PD-1 monoclonal antibody in BRAF V600E-mutant /MSS type mCRC.
 ;NA;
 Inclusion Criteria:
 1. Male or female ≥ 18 years of age
 2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
 3. Participants must have histologically or cytologically confirmed diagnosis of
 adenocarcinoma of the colon or rectum, with clinical confirmation of unresectable
 and/or metastatic disease that is measurable according to Response Evaluation Criteria
 in Solid Tumors (RECIST 1.1) criteria
 4. Presence of BRAF V600E in tumor tissue determined by local assay at any time prior to
 screening and confirmed by central laboratory. And confirmation of MSS or pMMR status
 from immunohistochemistry or PCR or NGS;
 5. Prior treatment with at least one systemic treatment (chemotherapy or target therapy)
 for mCRC, and prior treatment did not include cetuximab
 6. Adequate organ and marrow function:
 - ①Hemoglobin (Hb) ≥ 90 g/L；Platelets (PLT) ≥ 75 x 10^9/L；Neutrophil ≥1.5 x 10^9/L
 - ②Total bilirubin ≤ 1.5 x upper limit of normal (ULN)；Aspartate aminotransferase
 (AST) ≤3 x ULN ；Alanine aminotransferase (ALT) ≤3 x ULN
 - ③Serum creatinine ≤ 1.5 x ULN, or calculated creatinine clearance (determined as
 per Cockcroft-Gault) ≥ 50 mL/min at screening
 - ④INR, APTT, and PT≤ 1.5 x ULN
 - ⑤Serum albumin≥ 28 g/L
 - ⑥ECG showed no evident abnormality
 7. Written informed consent
 Exclusion Criteria:
 1. Known hypersensitivity or contraindication to any component of cetuximab or PD-1
 monoclonal antibody or macromolecular protein reagent.
 2. A history of other malignancies with a disease-free survival of less than 5 years,
 with the following exceptions: adequately treated basal or squamous cell skin cancer,
 carcinoma in-situ of the cervix, and gastrointestinal tumors treated curatively with
 endoscopic mucosectomy;
 3. Any active autoimmune disease or a history of autoimmune disease
 4. Use of immunosuppressive medications or glucocorticoid therapy ≤2 weeks prior to entry
 5. Uncontrolled active infection requiring antibiotics
 6. Known history of HIV infection or active hepatitis
 7. Severe complications, including any of the following:
 - ①Massive gastrointestinal bleeding, perforation, or gastrointestinal obstruction
 - ②Symptomatic heart disease
 - ③Uncontrolled diabetes and hypertension
 - ④Uncontrolled diarrhea
 8. Women who are pregnant or lactating and people who do not agree to avoid pregnancy
 9. Patients with serious psychiatric that may interfere treatment.
 10. Other conditions which are inappropriate to participate in the study confirmed by
 investigators.


Input:
The purpose of this study is to evaluate the efficacy and safety of selinexor as a
 maintenance treatment in patients with p53 wt endometrial carcinoma (EC), who have achieved a
 partial response (PR) or complete response (CR) (per Response Evaluation Criteria in Solid
 Tumors version 1.1 [RECIST v 1.1]) after completing at least 12 weeks of platinum-based
 therapy. A total of 220 participants will be enrolled in the study and randomized in a 1:1
 ratio to maintenance therapy with either selinexor or placebo.
 ;NA;
 Inclusion Criteria:
 - At least 18 years of age at the time of signing informed consent.
 - Histologically confirmed EC including: endometrioid, serous, undifferentiated, and
 carcinosarcoma.
 - TP53 wt assessed by next generation sequencing (NGS), evaluated by a central vendor.
 - Completed a single line, at least 12 weeks of platinum-based therapy (not including
 adjuvant or neoadjuvant therapy for Stage I-III disease) and achieved confirmed
 partial or complete response (PR or CR) by imaging, according to RECIST version 1.1.
 The participants should have received treatment for:
 Primary Stage IV disease, defined as:
 - had a primary or later debulking surgery during first-line platinum-based therapy with
 R0 resection (R0 resection indicates a macroscopic complete resection of all visible
 tumor) and achieved CR after at least 12 weeks platinum-based therapy, OR
 - had a primary or later debulking surgery during first-line platinum-based therapy with
 R1 resection (R1 resection indicates incomplete removal of all macroscopic disease)
 and achieved PR or CR after at least 12 weeks platinum-based chemotherapy, OR
 - had no surgery and achieved PR or CR after at least 12 weeks platinum-based
 chemotherapy
 OR
 At first relapse (i.e., relapse after primary therapy including surgery and/or chemotherapy
 and/or immunotherapy for Stage I-IV disease), defined as:
 - had Stage I - III disease at diagnosis and received, at initial diagnosis, adjuvant
 chemotherapy and relapsed later. Participants should have PR or CR after at least 12
 weeks of platinum-based chemotherapy compared with the start of this chemotherapy at
 the time of relapse,
 - had Stage I-III disease at diagnosis and did not receive adjuvant chemotherapy at
 initial diagnosis and relapsed later. Participants should have PR or CR after at least
 12 weeks of platinum-based chemotherapy compared with the start of this chemotherapy
 at the time of relapse, OR
 - had Stage IV disease at diagnosis and received initially chemotherapy with or without
 surgery and relapsed later. At the time of relapse, participants should have PR or CR
 after at least 12 weeks of platinum-based chemotherapy compared with the start of this
 chemotherapy at the time of relapse.
 - Previous treatment with anti-programmed cell death protein 1(PD-1) or
 anti-programmed death-ligand 1(PD-L1) monoclonal antibody and concomitant
 biologic agents (e.g., bevacizumab, trastuzumab) is allowed.
 - Must be able to initiate study drug 3 to 8 weeks after completion of their final
 dose of chemotherapy.
 - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
 - Participants must have adequate bone marrow function and organ function within 2
 weeks before starting study drug as defined by the following laboratory criteria:
 - Hepatic function: total bilirubin up to less than (<) 3*upper limit of normal (ULN);
 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal
 to (<=) 2.5*ULN in participants without liver metastasis. For participants with known
 liver involvement of their tumor: AST and ALT (<=) 5*ULN
 - Hematopoietic function within 1 week: Absolute neutrophil count (ANC) greater than or
 equal to (>=) 1.5*10^9/liter (L); platelet count >= 100*10^9/L; hemoglobin >= 9.0 gram
 per deciliter (g/dL) per local laboratory results
 - Renal function: estimated creatinine clearance (CrCl) of >= 20 milliliter per minute
 (mL/min), calculated using the standard local formula, as applicable
 - In the opinion of the Investigator, the participant must:
 - Have a life expectancy of at least 12 weeks, and
 - Be fit to receive investigational therapy
 - Premenopausal females of childbearing potential must have a negative pregnancy
 test (serum β-human chorionic gonadotropin test) prior to the first dose of study
 drug. Female participants of childbearing potential must agree to use highly
 effective methods of contraception throughout the study and for 90 days following
 the last dose of study drug.
 - Written informed consent signed in accordance with federal, local, and
 institutional guidelines prior to the first screening procedure.
 Exclusion Criteria:
 - Participants meeting any of the following exclusion criteria are not eligible to
 enroll in this study:
 - Has any uterine sarcomas (carcinosarcomas - not excluded), clear cell or small cell
 carcinoma with neuroendocrine differentiation
 - Received a blood or platelet transfusion during the 2 weeks prior to Cycle 1 Day 1
 (C1D1). Participants' hemoglobin must be assessed within 2 weeks of screening and at
 least 1 week post transfusion
 - Concurrent systemic steroid therapy higher than physiologic dose (> 10 milligram per
 day [mg/day] of prednisone or equivalent). Systemic steroid therapy as pre-medication
 for taxane is allowed
 - Insufficient time since or not recovered from procedures or anti-cancer therapy,
 defined as:
 - Not recovered from major surgery <= 28 days prior to Day 1 dosing. Minor
 procedures, such as biopsies, dental work, or placement of a port or intravenous
 (IV) line for infusion are permitted
 - Having ongoing clinically significant anti-cancer therapy-related toxicities CTCAE
 Grade > 1, with the exception of alopecia. In specific cases, participants whose
 toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed
 following documented approval by the Sponsor's Medical Monitor
 - Palliative radiotherapy within 14 days of the intended C1D1. Palliative radiotherapy
 may be permitted for symptomatic control of pain from bone metastases, provided that
 the radiotherapy does not involve target lesions, and the reason for the radiotherapy
 does not reflect evidence of disease progression.
 - Any gastrointestinal dysfunctions that could interfere with the absorption of
 selinexor (e.g., bowel obstruction, inability to swallow tablets, malabsorption
 syndrome, unresolved nausea, vomiting, diarrhea CTCAE v 5.0 > grade 1).
 - Participants unable to tolerate two forms of antiemetics for at least 2 cycles will
 not be eligible for the trial.
 - Active, ongoing or uncontrolled active infection requiring parenteral antibiotics,
 antivirals, or antifungals within 1 week of screening.
 - Serious psychiatric or medical condition that could interfere with participation in
 the study or in the opinion of the Investigator would make study involvement
 unreasonably hazardous.
 - Previous treatment with an XPO1 inhibitor.
 - Stable disease or PD on the post-chemotherapy scan or clinical evidence of progression
 prior to randomization.
 - Participants who received any systemic anticancer therapy including investigational
 agents <= 3 weeks (or <= 5 half-lives of the drug [whichever is shorter]) prior to
 C1D1.
 - Major injuries or surgery within 14 days prior to C1D1 and/or planned major surgery
 during the on-treatment study period.
 - Other malignant disease with disease-free <= 3 years except: curatively treated
 carcinoma in situ of the cervix, basal cell carcinoma of the skin, or ductal carcinoma
 in situ (DCIS) of the breast.
 - History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to selinexor, or other agents used in the study.
 - Active brain metastases (e.g., stable for < 8 weeks, no adequate previous treatment
 with radiotherapy and/or surgery, symptomatic, requiring treatment with
 anti-convulsant therapy. Corticoid therapy is allowed if administered as stable dose
 for at least 1 month before randomization).
 - Females who are pregnant or lactating.
 - Any other life-threatening illness, active medical condition, organ system
 dysfunction, or serious active psychiatric issue which, in the Investigator's opinion,
 could compromise the participant's safety or the participant's ability to remain
 compliant with study procedures.


Input:
This study will be a single arm multicenter Phase II open-label, dose escalation study of
 asciminib in patients with CML-CP without T315I mutation who have had 1 prior TKIs for which
 they did not respond to treatment or were intolerant to treatment.
 ;
 ;
 Inclusion Criteria:
 Signed informed consent must be obtained prior to participation in the study 2. Chronic
 Myelogenous Leukemia (CML-CP,) no previous Accelerated Phase (AP) or Blast Crisis (BC) 3. ≥
 18 years of age 4. For CML-CP patients with treatment failure/resistance to first line (1L)
 Tyrosine Kinase Inhibitor (TKI,) BCR-ABL1IS at screening:
 1. >10% if 1L treatment duration between 6 and 12 months
 2. >1% if 1L treatment longer than 12 months 5. For CML-CP patients with treatment
 intolerance to 1L TKI, BCR-ABL1IS > 0.1% at screening 6. Previously treated with 1
 Adenosine triphosphate- (ATP)-binding site TKI for at least 6 months of therapy 7.
 Intolerance of TKI therapy and/or resistance to TKI therapy (European Leukemia Network
 (ELN) 2020)
 Intolerance is defined as:
 - Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or
 with persistent grade 2 toxicity, unresponsive to optimal management, including dose
 adjustments (unless dose reduction is not considered in the best interest of the
 patient if response is already suboptimal)
 - Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil
 count [ANC] or platelets) while on therapy that is recurrent after dose reduction to
 the lowest doses recommended by manufacturer
 Resistance/Failure is defined for CML-CP patients (CP at the time of initiation of last
 therapy) as follows . Patients must meet at least 1 of the following criteria:
 - Three months after the initiation of therapy: No Complete Hematological Response (CHR)
 or > 95% Philadelphia Chromosome Positive (Ph+) metaphases
 - Six months after the initiation of therapy: BCR-ABL1 ratio > 10% IS and/or >65% Ph+
 metaphases
 - Twelve months after initiation of therapy: BCR-ABL1 ratio > 1% IS and/or >35% Ph+
 metaphases
 - At any time after the initiation of therapy, loss of CHR, Complete Cytogenetic
 Response (CCyR) or Partial Cytogenetic Response (PCyR)
 - At any time after the initiation of therapy, the development of new BCR-ABL1 mutations
 which potentially cause resistance to study treatment
 - At any time after the initiation of therapy, confirmed loss of Major Molecular
 Response (MMR) in 2 consecutive tests, of which one must have a BCR-ABL1 ratio ≥ 1% IS
 - At any time after the initiation of therapy, new clonal chromosome abnormalities in
 Ph+ cells: CCA/Ph+ 8. Adequate end organ function within 12 days before the first dose
 of asciminib treatment. Patients with mild to moderate renal and hepatic impairment
 are eligible if:
 - Total bilirubin ≤ 3.0 x ULN without AST/ALT increase
 - Aspartate transaminase (AST) ≤ 5.0 x ULN
 - Alanine transaminase (ALT) ≤ 5.0 x ULN
 - Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN and ≤ 1.5 x ULN, value should be
 considered not clinically significant and not associated with risk factors for acute
 pancreatitis
 - Alkaline phosphatase ≤ 2.5 x ULN
 - Creatinine clearance ≥ 30 mL/min as calculated using Cockcroft-Gault formula
 Exclusion Criteria:
 - 1. Previous treatment with 2 or more ATP-binding site TKIs 2. Previous treatment with
 asciminib 3. Known presence of the T315I mutation at any time prior to study entry 4.
 Known second chronic phase of CML after previous progression to AP/BC 5. Previous
 treatment with a hematopoietic stem-cell transplantation 6. Patient planning to
 undergo allogeneic hematopoietic stem cell transplantation 7. Cardiac or cardiac
 repolarization abnormality, including any of the following:
 - History within 6 months prior to starting study treatment of myocardial
 infarction (MI), angina pectoris, coronary artery bypass graft (CABG)
 - Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),
 complete left bundle branch block, high-grade AV block (e.g., bifascicular block,
 Mobitz type II and third-degree AV block)
 - QTcF at screening ≥450 msec (male patients), ≥460 msec (female patients)
 - Long QT syndrome, family history of idiopathic sudden death or congenital long QT
 syndrome, or any of the following:
 - Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or
 hypomagnesemia, history of cardiac failure, or history of clinically
 significant/symptomatic bradycardia
 - Concomitant medication(s) with a "Known risk of Torsades de Pointes" per
 www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to
 starting study drug by safe alternative medication.
 - Inability to determine the QTcF interval 8. History of acute pancreatitis within
 1 year of study entry or past medical history of chronic pancreatitis 9.
 Participation in a prior investigational study within 30 days prior to
 randomization or within 5 half-lives of the investigational product, whichever is
 longer 10. Treatment with medications that meet one of the following criteria is
 not allowed and should be switched to an alternative at least one week prior to
 the start of treatment with study treatment:
 - Strong inducers of CYP3A for patients on the dose of 80 mg QD and 200mg QD
 - Strong inducers and inhibitors of CYP3A for patients on the dose of 200 mg BID
 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.
 - Highly effective contraception methods include:
 - Total abstinence (when this is in line with the preferred and usual lifestyle of
 the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
 post-ovulation methods) and withdrawal are not acceptable methods of
 contraception
 - Female sterilization (have had surgical bilateral oophorectomy (with or without
 hysterectomy) total hysterectomy or bilateral tubal ligation at least six weeks
 before taking study treatment). In case of oophorectomy alone, only when the
 reproductive status of the woman has been confirmed by follow up hormone level
 assessment
 - Male sterilization (at least 6 months prior to screening). The vasectomized male
 partner should be the sole partner for that subject
 - 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 use of oral contraception women should have been stable on the same
 pill for a minimum of 3 months before taking study treatment
 - Women are considered post-menopausal and not of child bearing potential if they
 have had 12 months of natural (spontaneous) amenorrhea with an appropriate
 clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
 had surgical bilateral oophorectomy (with or without hysterectomy), total
 hysterectomy or bilateral tubal ligation at least six weeks before taking study
 medication. In the case of oophorectomy alone, women are considered
 post-menopausal and not of child-bearing potential only when the reproductive
 status of the woman has been confirmed by follow up hormone level assessment.
 - Highly effective contraception for women should be maintained throughout the
 study and for at least 7 days after the last dose.
 13. Sexually active males unwilling to use a condom during intercourse while
 taking study treatment and for 7 days after stopping study (only for patients
 treated with asciminib). A condom is required for all sexually active male
 participants on asciminib treatment to prevent them from fathering a child AND to
 prevent delivery of study treatment via seminal fluid to their partner. In
 addition, these male participants must not donate sperm for the time period
 specified above.


Input:
This phase I trial studies the side effects of CD19/CD22 chimeric antigen receptor (CAR) T
 cells when given together with chemotherapy and NKTR-255, and to see how well they work in
 treating patients with CD19 positive B acute lymphoblastic leukemia that has come back or
 does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune
 cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22
 proteins. These proteins are commonly found on diffuse large B-cell lymphoma and B acute
 lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine
 phosphate, 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. NKTR-255 is an
 investigational IL-15 receptor agonist designed to boost the immune system's natural ability
 to fight cancer. Giving CD19/CD22-CAR T cells and chemotherapy in combination with NKTR-255
 may work better in treating patients with diffuse large B-cell lymphoma or B acute
 lymphoblastic leukemia.
 ;
 ;
 For B acute lymphoblastic leukemia (ALL)
 1. Confirmed diagnosis of relapsed or refractory B-cell ALL of one of the following
 types:
 - Chemotherapy refractory disease in subjects with B-ALL, defined as progression or
 stable disease after one line of therapy.
 - Recurrence of disease after achieving CR.
 2. Subjects with persistent or relapsed minimal residual disease (MRD) (by flow
 cytometry, PCR, FISH, or next generation sequencing) require verification of MRD
 positivity on two occasions at least 4 weeks apart.
 3. Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ALL)
 subjects are eligible if they progressed after receiving a tyrosine kinase inhibitor
 (TKI).
 4. Subjects with recurrence of isolated CNS relapse after achieving complete remission
 (CR); if relapsed with MRD, will require verification of MRD positivity on two
 occasions at least 4 weeks apart.
 5. CD19 positive expression- CD19 expression is required at any time since diagnosis. If
 patient has received anti-CD19 targeted therapy (i.e. Blinatumomab or CD19-CAR T
 cells), then CD19 expression must be subsequently demonstrated. CD19 expression may be
 detected by immunohistochemistry or by flow cytometry. The choice of whether to use
 flow cytometry or immunohistochemistry will be determined by what is the most easily
 available tissue sample in each subject. In general, immunohistochemistry will be used
 for lymph node biopsies, flow cytometry will be used for peripheral blood and bone
 marrow samples.
 6. Subjects who have undergone autologous SCT with disease progression or relapse
 following SCT are eligible. Subjects who have undergone allogeneic SCT will be
 eligible if, in addition to meeting other eligibility criteria, they have elelino
 evidence of GVHD and have been without immunosuppressive agents for at least 30 days.
 7. Subjects who have undergone prior anti-CD19 or anti-CD22 CAR therapy must be at least
 30 days post CAR infusion and may not have eficence of persistnce of CAR T cells in
 blood smples (circulating levels of genetically modified cels of >/= 5% by flow
 cytometry.
 8. Must have evaluable or measurable disease. Lesions that have been previously
 irradiated will be considered measurable only if progression has been documented
 following completion of radiation therapy.
 9. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any
 prior systemic therapy at the time the subject is planned for leukapheresis, except
 for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5
 half-lives.
 Exceptions:
 1. There is no time restriction with regard to prior intrathecal chemotherapy (incl.
 steroids) provided there is complete recovery from any acute toxic effects;
 2. Subjects who are on standard ALL maintenance type chemotherapy (vincristine,
 6-mercaptopurine or oral methotrexate) may be enrolled provided that chemotherapy
 is discontinued at least 1 week or 5 half-lives (whichever is shorter) prior to
 apheresis.
 3. Subjects receiving steroid therapy at physiologic replacement doses (≤5 mg/day of
 prednisone or equivalent doses of other corticosteroids) only are allowed
 provided there has been no increase in dose for at least 2 weeks prior to
 starting apheresis;
 4. For radiation therapy: Radiation therapy must have been completed at least 3
 weeks prior to apheresis, with the exception that there is no time restriction if
 the volume of bone marrow treated is less than 10% and also the subject has
 measurable/evaluable disease outside the radiation port.
 10. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for
 clinically non-significant toxicities such as alopecia)
 11. Age 18 or older
 12. Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2; or
 Karnofsky ≥ 60%
 13. Normal Organ and Marrow Function (supportive care is allowed per institutional
 standards, i.e. filgrastim, transfusion)
 1. ANC ≥ 1000/uL*
 2. Platelet count ≥ 50,000/uL*
 3. Absolute lymphocyte count ≥ 300/uL*
 4. Adequate renal, hepatic, pulmonary and cardiac function defined as:
 5. Creatinine ≤ 2 mg/dL or creatinine clearance ≥ 60 mL/min
 6. Serum ALT or AST ≤ 5x ULN (Elevated ALT/AST associated with leukemia or lymphoma
 involvement of the liver will not disqualify a subject; only one value required
 for eligibility).
 7. Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome.
 8. Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant
 pericardial effusion as determined by an ECHO, MUGA or Cardiac MRI [performed
 within 180 days or after most recent anthracycline based treatment or mediastinal
 radiation therapy (whichever is most recent)]
 9. No clinically significant ECG findings
 10. No clinically significant pleural effusion
 11. Baseline oxygen saturation > 92% on room air * A subject will not be excluded
 because of cytopenia if it is felt by the investigator to be due to underlying
 leukemia/lymphoma.
 14. Subjects with CNS involvement are eligible as long as there are no overt signs or
 symptoms that in the evaluation of the investigator would mask or interfere with the
 neurological assessment of toxicity.
 15. Females of childbearing potential must have a negative serum or urine pregnancy test
 (females who have undergone surgical sterilization or who have been postmenopausal for
 at least 2 years are not considered to be of childbearing potential)
 16. Subjects of child-bearing or child-fathering potential must be willing to practice
 birth control from the time of enrollment on this study and for four (4) months after
 receiving the preparative lymphodepletion regimen or 1 month after the last dose of
 NKTR_255, whichever is later.
 17. Ability to give informed consent. Must be able to give informed consent. Subjects
 unable to give informed consent will not be eligible for this study.
 =ELIGIBILITY TO RECEIVE NKTR-255=
 - Received a CD19/CD22 CAR-T infusion
 - No persisting grade ≥1 CRS or greater than grade 1 fever within 12 hours preceding
 NKTR-255 infusion
 - No grade 4 CRS within 96 hours preceding NKTR-255 infusion
 - No persisting grade ≥ 2 neurotoxicity on the day of NKTR-255 infusion
 - No previous grade ≥ 3 neurotoxicity of > 48 hours duration at any time preceding
 NKTR-255 infusion
 - ANC ≥ 1000/µL
 - No intervention with tocilizumab and/or dexamethasone within 48 hours preceding
 NKTR-255 infusion
 - No active, serious, and uncontrolled infection(s)
 - No contraindications according to the PI's assessment
 - Life expectancy > 30 days
 Exclusion Criteria:
 1. History of other malignancy, unless disease free for at least 3 years. At the
 discretion of the Principal Investigator, subjects in remission for 1-2 years prior to
 enrollment may be deemed eligible after considering the nature of other malignancy,
 likelihood of recurrence during one year following CAR therapy, and impact of prior
 treatment on risk of CD19/CD22-CAR T cells. Subjects in remission <1 year are not
 eligible.
 - Exception: Nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder,
 breast) is eligible.
 - Hormonal therapy in subjects in remission >1 year will be allowed.
 2. Presence of fungal, bacterial, viral, or other infection that is uncontrolled. Simple
 UTI and uncomplicated bacterial pharyngitis are permitted if responding to active
 treatment.
 3. Known history of infection with any of the following:
 - HIV
 - Hepatitis B (HBsAg positive)
 - Hepatitis C virus (anti-HCV positive) A history of hepatitis B or hepatitis C is
 permitted if the viral load is undetectable per quantitative PCR and/or nucleic
 acid testing.
 4. Presence of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia,
 cerebellar disease, or any autoimmune disease with CNS involvement that in the
 judgment of the investigator may impair the ability to evaluate neurotoxicity.
 5. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or
 other clinically significant cardiac disease within 12 months of enrollment
 6. Any medical condition that in the judgement of the investigator is likely to interfere
 with assessment of safety or efficacy of study treatment
 7. History of severe immediate hypersensitivity reaction to any of the agents used in
 this study
 8. Women who are pregnant or breastfeeding
 9. In the investigator's judgment, the subject is unlikely to complete all
 protocol-required study visits or procedures, including follow-up visits, or comply
 with the study requirements for participation.
 10. Previous treatment with interleukin-2 or interleukin-15.
 11. Confirmed diagnosis of relapsed/refractory biphenotypic BT cell ALL
 12. Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid
 arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease
 modifying agents within the last 2 years


Input:
Selitrectinib expanded access is for minor and adult patients with cancer having a change in
 a particular gene (NTRK1, NTRK2, or NTRK3 gene fusion). The patients are ineligible for an
 ongoing selitrectinib clinical trial or have other considerations that prevent access to
 selitrectinib through an existing clinical trial. Expanded access is intended to treat
 individual patients with different types of cancers with a NTRK gene fusion, including blood
 cancers, who have previously received tropomyosin receptor kinase (TRK) inhibitor therapy.
 ;NA;
 Inclusion Criteria:
 - Diagnosis of cancer with a NTRK1, NTRK2, and NTRK3 gene fusion
 - Previous treatment with a kinase inhibitor with known activity on TRK inhibition
 - Unable to participate in an ongoing selitrectinib clinical trial
 - Medically suitable for treatment with selitrectinib
 Exclusion Criteria:
 - Currently enrolled in an ongoing clinical study with a TRK inhibitor


Input:
This study is an open-label, single arm, dose escalation and dose expansion phase 1 study to
 evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of BPI-21668 in
 solid tumor patients. In dose escalation phase, biomarker status is not required, but in dose
 expansion phase patients are required to harbor PIK3CA mutation.
 ;NA;
 Inclusion Criteria:
 1. Age ≥18 and ≤70 years, male and female patients;
 2. Life expectancy ≥ 12 weeks;
 3. ECOG performance score 0-1;
 4. Locally advanced or relapsed/metastatic solid tumor patients, who had disease
 progression after standard therapy, intolerable to standard therapy or for whom no
 standard therapy exists, PIK3CA mutation status is required for dose expansion phase;
 5. Evaluable lesion required for dose escalation phase and measurable lesion as per
 RECIST 1.1 required for dose expansion phase;
 6. Adequate organ function;
 7. Signed informed consent.
 Exclusion Criteria:
 1. Prior use of PI3K、mTOR or AKT inhibitor;
 2. Prior other malignant tumor;
 3. Unstable, symptomatic primary CNS tumors/metastasis or leptomeningeal metastases ;
 4. Type I or type II diabetes;
 5. Inadequate wash-out of prior anti-cancer therapies;
 6. Cardiac disorders;
 7. Instable systemic diseases;
 8. Acute or chronic pancreatitis;
 9. Pregnancy or lactation;
 10. Other protocol specified criteria.


Input:
This phase Ib trial is to find out the best dose, possible benefits and/or side effects of
 talazoparib when given in combination with palbociclib, axitinib, or crizotinib in treating
 patients with solid tumors that has spread to nearby tissue or lymph nodes (locally advanced)
 or other places in the body (metastatic). PARPs are proteins that help repair damaged DNA,
 the genetic material that serves as the body's instruction book. PARP inhibitors, such as
 talazoparib, can keep PARP from working, so tumor cells can't repair themselves, and they may
 stop growing. Palbociclib, axitinib, and crizotinib may stop the growth of tumor cells by
 blocking some of the enzymes needed for cell growth. Giving talazoparib in combination with
 palbociclib, axitinib, or crizotinib may help control locally advanced or metastatic solid
 tumors.
 ;
 ;
 Inclusion Criteria:
 - Pathogenic or likely pathogenic germline or somatic gene defect as determined by local
 assessment and classification in at least one of the following:
 - Defect in DNA damage response (DDR) genes such as: BRCA1/2, PALB2, RAD51C/D, or
 other related genes at the discretion of the principal investigator in
 consultation with the MD Anderson Cancer Center Institute for Personalized Cancer
 Therapy Precision Oncology Decision Support (PODS) group (Arms A-C)
 - Defect in MET, ALK or ROS1, e.g. MET mutations or amplifications, high MET
 expression, ALK translocations, ROS1 translocations (eligible for Arm C:
 talazoparib + crizotinib)
 - NOTE: Patients with metastatic castration-resistant prostate cancer can enroll in
 Arm B with talazoparib + axitinib without a specific and/or selected mutation
 - Patients who are eligible for more than one Arm will be assigned according to
 physician preference
 - Histological or cytological diagnosis of a solid tumor that is advanced/metastatic,
 intolerable to standard therapy, resistant to effective standard therapy, or for which
 no standard therapy is available
 - Availability of a fresh or recent tumor tissue sample from a diagnostic biopsy/surgery
 or a metastatic tumor biopsy; the sample must have been obtained within 12 months
 prior to study enrollment. When only bone disease is present, an archival tumor tissue
 sample obtained within 5 years prior to study enrollment may be accepted for
 non-prostate cancer patients and a fresh bone biopsy may be accepted for prostate
 cancer patients only NOTE: A fresh biopsy should be encouraged for all patients at
 time of enrollment even if a previous biopsy is available. Optional on-treatment and
 at-progression biopsies will be encouraged for all patients
 - Have measurable disease at study enrollment as defined by RECIST v1.1 with at least 1
 measurable lesion that has not previously been irradiated; or patients may have bone
 metastatic disease evaluable by Prostate Cancer Working Group 2 (PCWG2) for subjects
 with metastatic castration-resistant prostate cancer (mCRPC), or according to the
 tumor evaluation criteria best suited and accepted for the tumor type being evaluated)
 - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1
 - Absolute Neutrophil Count (ANC) >= 1,500/mm^3 or >= 1.5 x 10^9/L (without
 hematopoietic growth factor or transfusion support within 14 days prior to study
 enrollment)
 - Platelets >= 100,000/mm^3 or >= 100 x 10^9/L (without hematopoietic growth factor or
 transfusion support within 14 days prior to study enrollment)
 - Hemoglobin >= 9 g/dL (>= 5.6 mmol/L) (without hematopoietic growth factor or
 transfusion support within 14 days prior to study enrollment)
 - estimated creatinine clearance >= 60 mL/min will be required during dose-escalation
 phase, according to the Cockcroft-Gault formula
 - Where creatinine clearance (CLCR) (creatinine clearance) is measured in mL/min,
 age is expressed in years, weight in kilograms (kg), and SCR (serum creatinine)
 in mg/dL
 - Or as measured by 24h urine assessment NOTE: Patients with moderate renal
 impairment (30-59 mL/min) will be considered during the dose expansion phase. A
 reduced starting dose for talazoparib will be considered in these patients
 - Total serum bilirubin =< 1.5 x the upper limit of normal range (ULN)
 - Aspartate and Alanine aminotransferase (aspartate aminotransferase [AST] and alanine
 aminotransferase [ALT]) =< 5 x ULN
 - Female Patients of childbearing potential must have negative serum pregnancy or urine
 pregnancy test at screening. Female patients of non-childbearing potential must meet
 at least one of the following criteria:
 - Achieved postmenopausal status, defined as follows: cessation of regular menses
 for at least 12 consecutive months with no alternative pathological or
 physiological cause and have a serum follicle-stimulating hormone (FSH) level
 confirming the postmenopausal state
 - Have undergone a documented hysterectomy and/or bilateral oophorectomy
 - Have medically confirmed ovarian failure All other female patients are considered
 to be of childbearing potential
 - Evidence of a personally signed and dated informed consent document, within > 28 days
 prior to enrollment, indicating that the patient has been informed of all pertinent
 aspects of the study
 - Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
 and other study procedures
 - Able to swallow the study drug, have no known intolerance to study drugs or
 excipients, and comply with study requirements
 Exclusion Criteria:
 - Prior anti-cancer therapy within 2 weeks prior to study enrollment or prior radiation
 therapy within 2 weeks prior to study enrollment. Prior palliative radiotherapy to
 metastatic lesion(s) is permitted, provided it has been completed at least 2 days
 prior to study enrollment and no clinically significant toxicities are expected (e.g.
 mucositis, esophagitis)
 - Major surgery within 4 weeks prior to study enrollment
 - Patients with known hypersensitivity to either talazoparib or the additional study
 drug to be received per treatment arm: palbociclib (Arm A), axitinib (Arm B),
 crizotinib (Arm C)
 - Diagnosis of myelodysplastic syndrome (MDS)
 - Known symptomatic brain metastases requiring steroids. Patients with previously
 diagnosed brain metastases are eligible if they have completed their treatment and
 have recovered from the acute effects of radiation therapy or surgery prior to study
 enrollment, have discontinued corticosteroid treatment for these metastases for at
 least 2 weeks, and are neurologically stable. Of note, patients who required a single
 dose of corticosteroids on days receiving radiation treatment do not require a 2-week
 washout
 - Participation in other studies involving investigational drug(s) within 4 weeks prior
 to study entry and/or during study participation
 - Persisting toxicity related to prior therapy (National Cancer Institute [NCI] Common
 Terminology Criteria for Adverse Events [CTCAE] version [v]5.0 Grade > 1). However,
 alopecia and sensory neuropathy Grade =< 2, or other Grade =< 2 adverse events not
 constituting a safety risk, based on the investigator's judgement, are acceptable
 - Active infection requiring systemic therapy. Minor infections, e.g. periodontal
 infection or urinary tract infection (UTI), which may be treated with short term oral
 antibiotics are allowed
 - Patients with known uncontrolled human immunodeficiency virus (HIV) virus or acquired
 immunodeficiency syndrome. Note: Patients with history of controlled HIV virus will be
 considered eligible for this trial
 - Patients with uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV)
 infection at screening. Note: Patients with controlled hepatitis B or hepatitis C will
 be considered eligible for this trial
 - Clinically significant cardiovascular disease, including any of the following:
 - Myocardial infarction or symptomatic cardiac ischemia within 6 months before
 screening
 - Congestive heart failure New York Heart Association class III or IV
 - History of clinically significant ventricular arrhythmias (eg, sustained
 ventricular tachycardia, ventricular fibrillation, torsade de pointes) within 1
 year before screening
 - History of Mobitz II second degree or third degree heart block unless a permanent
 pacemaker is in place
 - Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening
 - Bradycardia as indicated by a heart rate of <45 beats per minute on the screening
 electrocardiogram
 - Uncontrolled hypertension as indicated by systolic blood pressure > 170 mm Hg or
 diastolic blood pressure > 105 mm Hg at screening
 - Current use of potent P-gp inhibitors within 7 days prior to enrollment: amiodarone,
 carvedilol, clarithromycin, cobicistat, dronedarone, erythromycin,
 glecaprevir/pibrentasvir, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir,
 propafenone, quinidine, ranolazine, ritonavir, saquinavir,
 sofosbuvir/velpatasvir/voxilaprevir, telaprevir, tipranavir, valspodar, and verapamil.
 - NOTE: Patients who have recently been on enzalutamide require a 28 day washout
 period due to longer elimination half-life of this therapy
 - Patients treated within the last 7 days prior to enrollment with:
 - Food or drugs that are known to be strong CYP (cytochrome P-450) 3A4 inhibitors
 (ie, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine,
 diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole,
 lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole,
 ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and
 grapefruit or grapefruit juice). Drugs that are known to be strong CYP3A4
 inducers (ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin,
 primidone, rifabutin, rifampin, rifapentin, and St. John's wort
 - Inability to swallow capsules, known malabsorption syndrome, or other conditions that
 may impair absorption of study drugs
 - Bisphosphonate or denosumab dosage that was not stable (i.e. not the same) for at
 least 2 weeks before study enrollment for patients receiving these therapies
 - Other acute or chronic medical or psychiatric condition including recent (within the
 past year) or active suicidal ideation or behavior or laboratory abnormality that may
 increase the risk associated with study participation or investigational product
 administration or may interfere with the interpretation of study results and, in the
 judgement of the investigator, would make the patient inappropriate for entry into
 this study
 - Medical, psychological, or social conditions that may interfere with the patient's
 participation in the study, or with the evaluation of the study results
 - Diagnosis of any other malignancy within 2 years prior to study enrollment, except for
 adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of
 the breast, bladder, or cervix, or low grade (Gleason =< 6) prostate cancer on
 surveillance without any plans for treatment intervention (e.g. surgery, radiation, or
 castration), or other early-stage low risk cancers
 - Pregnant female patients; breastfeeding female patients; fertile male patients; and
 female patients of childbearing potential who are unwilling or unable to use 2 methods
 of contraception for the duration of the study and for at least 7 months after the
 last dose of study drugs for female patients or 4 months after the last dose of study
 drugs for male patients, whichever is later for the individual patient. Male patients
 are prohibited from sperm donation while enrolled in this study and for 4 months after
 the last dose of the study drugs. Highly effective methods of contraception are those
 that alone or in combination, result in a failure rate of less than 1% per year when
 used consistently and correctly. These methods include:
 - Established use of oral, inserted, or injected or implanted hormonal methods of
 contraception are allowed provided the patient remains on the same treatment
 throughout the entire study and has been using that hormonal contraceptive for an
 adequate period of time to ensure effectiveness
 - Correctly placed copper containing intrauterine device (IUD)
 - Male condom or female condom used with spermicide (i.e. foam, gel, film, cream or
 suppository)
 - Male sterilization with appropriately confirmed absence of sperm in the
 postvasectomy ejaculate
 - Bilateral tubal ligation or bilateral oophorectomy


Input:
This ComboMATCH phase II trial compares the usual treatment alone (fulvestrant) to using
 binimetinib plus the usual treatment in patients with hormone receptor positive breast cancer
 that has spread to other places in the body (metastatic) and has an NF1 genetic change.
 Fulvestrant is a hormonal therapy that binds to estrogen receptors in tumor cells, resulting
 in estrogen receptor destruction and decreased estrogen binding, which may inhibit the growth
 of estrogen-sensitive tumor cells. Binimetinib is a targeted therapy that may stop the growth
 of tumor cells by blocking some of the enzymes needed for cell growth. The addition of
 binimetinib to fulvestrant in breast cancers with an NF1 genetic change could increase the
 percentage of tumors that shrink as well as lengthen the time that the tumors remain stable
 (without progression) as compared to fulvestrant alone.
 ;
 ;
 Inclusion Criteria:
 - A COMBOMATCH TREATMENT TRIAL EAY191 ELIGIBILITY CRITERIA:
 - The patient must be enrolled on the ComboMATCH Master Registration Trial EAY191
 - Note: Patients must fulfill all eligibility criteria outlined in the ComboMATCH
 Registration Trial EAY191 at the time of registration to EAY191-N2. This includes
 submission of next-generation sequencing (NGS) data from one of the National
 Cancer Institute (NCI) credentialed designated laboratories for all potential
 patients prior to treatment trial assignment. Copy number and allele frequency
 cutoff as per the Registration protocol
 - Patients must have disease that can be safely biopsied and agree to a pre-treatment
 biopsy or, if disease cannot be safely biopsied, have archival tissue available from
 within 12 months prior to the date of registration on the ComboMATCH registration
 trial (EAY191)
 - Please note the current actionable marker of interest (aMOI)/actionable
 alteration list for this treatment trial can be found on the Cancer Trial Support
 Unit (CTSU) ComboMATCH Registration protocol page
 - Please note novel/Dynamic aMOI can be submitted for review per the process
 described in the ComboMATCH Registration protocol
 - A COMBOMATCH TREATMENT TRIAL EAY191-N2 ELIGIBILITY CRITERIA:
 - The patient or a legally authorized representative must provide study-specific
 informed consent prior to study entry and, for patients treated in the United States
 (U.S.), authorization permitting release of personal health information
 - Age >= 18
 - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 within 14 days prior
 to registration
 - Histologically or cytologically confirmed invasive breast carcinoma
 - Confirmed metastatic disease by either imaging or tissue diagnosis
 - Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and
 one additional lesion that can be biopsied (primary, metastatic both allowed)
 - Patients must have NF1 nonsense or frameshift mutation, or NF1 whole gene deletion
 detected in tumor as determined by the ComboMATCH screening assessment
 - The tumor must have been determined to be estrogen receptor (ER) and/or progesterone
 receptor (PgR) positive assessed by current American Society of Clinical Oncology
 (ASCO)/College of American Pathologists (CAP) guideline recommendations for hormone
 receptor testing. Patients with >= 1% ER or PgR staining by immunohistochemistry (IHC)
 are considered positive
 - The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines
 - Prior use of CDK4/6 inhibitor(i) is required
 - Prior use of fulvestrant regardless of duration is allowed and will determine
 treatment assignment
 - Up to one line of chemotherapy in metastatic setting is allowed
 - Absolute neutrophil count >= 1,500/mm^3 (within 14 days prior to registration)
 - Platelet count >= 100,000/ mm^3 (within 14 days prior to registration)
 - Hemoglobin level >= 10 g/dL (within 14 days prior to registration)
 - Measured or calculated creatinine clearance > 30 mL/min (within 14 days prior to
 registration)
 - Total bilirubin level =< institutional upper limit of normal (within 14 days prior to
 registration)
 - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 5.0 x
 ULN
 - Left ventricular ejection fraction (LVEF) assessment must be performed within 6 weeks
 prior to registration (LVEF assessment performed by echocardiogram is preferred;
 however, multi-gated acquisition scan [MUGA] scan may be substituted based on
 institutional/situational preferences). The LVEF must be >= 50% regardless of the
 cardiac imaging facility's lower limit of normal
 - Patients with a prior or concurrent malignancy whose natural history or treatment does
 not have the potential to interfere with the safety or efficacy assessment of the
 investigational regimen are eligible for this trial
 - Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
 therapy with undetectable viral load within 6 months of registration are eligible for
 this trial
 - ELIGIBILITY CRITERIA FOR COHORT 1, TREATMENT REGIMEN 2 PATIENTS WHO TRANSITION TO
 COHORT 2:
 - Patient's willingness to transition to Cohort 2 affirmed
 - The patient must have an ECOG performance status of 0-2
 - Absolute neutrophil count >= 1,500/mm^3 (within 14 days prior to second registration)
 - Platelet count >= 100,000/ mm^3 (within 14 days prior to second registration)
 - Hemoglobin level >= 10 g/dL (within 14 days prior to second registration)
 - Total bilirubin level =< institutional upper limit of normal (ULN) (within 14 days
 prior to second registration)
 - AST and ALT must be =< 5.0 x ULN
 - Measured or calculated creatinine clearance > 30 mL/min (within 14 days prior to
 second registration)
 - The LVEF performed within the last 3 months must be >= 50% regardless of the cardiac
 imaging facility's lower limit of normal (LVEF assessment performed by echocardiogram
 is preferred; however, MUGA scan may be substituted based on institutional/situational
 preferences)
 - Pregnancy test according to institutional standards done within 14 days before second
 registration must be negative (for patients of childbearing potential only)
 Exclusion Criteria:
 - Concurrent anticancer therapy
 - Active autoimmune disease requiring systemic treatment within the past 3 months,
 documented history of clinically severe autoimmune disease, or a syndrome that
 requires systemic steroids or immunosuppressive agents
 - Active brain metastasis. Brain metastases that have been stable for at least 1 month
 after completion of treatment are not an exclusion criterion
 - History of or evidence of retinal pathology on ophthalmologic examination that is
 considered a risk factor for neurosensory retinal detachment/central serous,
 chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular
 degeneration
 - Patients will be excluded if they currently have the following risk factors for RVO
 that are documented prior to the enrollment:
 - Uncontrolled glaucoma with intra-ocular pressures >= 21 mmHg
 - Serum cholesterol >= grade 2.
 - Hypertriglyceridemia >= grade 2
 - Hyperglycemia (fasting) >= grade 2
 - Patients with baseline QT corrected for heart rate (QTc) > 500 ms, either induced by
 medication or congenital long QT syndrome will be excluded due to known side effects
 of binimetinib
 - Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral
 sensory neuropathy) >= grade 2 within 14 days prior to registration. Patients with
 nervous system disorders that resolve to =< Grade 1 prior to registration are eligible
 - Patients with known history or current symptoms of cardiac disease, or history of
 treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
 function using the New York Heart Association Functional Classification. To be
 eligible for this trial, patients should be class 2B or better
 - Any other disease, metabolic dysfunction, physical examination finding, or clinical
 laboratory finding giving 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
 - Psychiatric or addictive disorders or other conditions that, in the opinion of the
 investigator, would preclude the patient from meeting the study requirements or
 interfere with interpretation of study results
 - Pregnancy or lactation at the time of registration or intention to become pregnant
 during the study (Note: Pregnancy testing according to institutional standards for
 patients of childbearing potential must be performed within 14 days prior to
 registration)
 - For binimetinib, highly effective contraception should be used for at least 30
 days after the last dose, and patients should not breastfeed for 3 days after the
 last dose
 - For fulvestrant, highly effective contraception should be used for 1 year after
 the last dose, and patients should not breastfeed for 1 year after the last dose
 - Use of any investigational product within 30 days prior to study entry
 - INELIGIBILITY CRITERIA FOR COHORT 1, TREATMENT REGIMEN 2 PATIENTS WHO TRANSITION TO
 COHORT 2
 - Not a candidate for binimetinib in the opinion of the treating investigator

NF1 nonsense mutation
ER positive
HER2 negative

NF1 frameshift mutation
ER positive
HER2 negative

NF1 nonsense mutation
PgR positive
HER2 negative

NF1 frameshift mutation
PgR positive
HER2 negative


Input:
This is a Phase 1/2a, nonrandomized, open-label, parallel assignment, dose-escalation, and
 dose-optimization study to evaluate the safety and clinical activity of PBCAR0191 in adults
 with r/r B ALL (Cohort A) and in adults with r/r B-cell NHL (Cohort N) and identify a
 treatment regimen most likely to result in clinical efficacy while maintaining a favorable
 safety profile.
 ;
 ;
 Key Inclusion Criteria*
 Criteria for B-ALL:
 - Subject has unequivocal r/r CD19+ B-ALL that has been confirmed by morphology, flow
 cytometry, or a validated minimal residual disease assay.
 - Subjects with Philadelphia chromosome positive disease can be eligible if they are
 intolerant to tyrosine kinase inhibitor therapy or if they have r/r disease.
 Criteria for NHL:
 - Subject has unequivocal aggressive CD19+ r/r B-cell NHL that is confirmed by archived
 tumor biopsy tissue from last relapse after CD19-directed therapy and corresponding
 pathology report. Alternatively, if at least 1 tumor involved site is accessible at
 time of Screening, the subject's diagnosis is confirmed by pretreatment biopsy
 (excisional when possible) or by flow cytometry of fine needle aspirate. If a subject
 never had a CR, a sample from the most recent biopsy is acceptable. NHL subtypes
 included but are not limited to:
 - Diffuse large B-cell lymphoma (DLBCL) including Richter's transformation
 - FL including Grade 3 or transformed FL
 - High-grade B-cell lymphoma
 - Primary mediastinal lymphoma
 - Subject has measurable or detectable (for example positron emission
 tomography-positive) disease according to the Lugano Classification.
 - Subject must have received at least 2 prior chemotherapy-containing regimens,
 consistent with standard of care treatment guidance (e.g., NCCN), unless no second
 line therapy of known benefit exists for a given subject. Other than those
 specifically prohibited, other therapies are allowed until 7 days prior to initiation
 of LD. In that case, all Screening safety laboratories and disease assessments must be
 performed after the last dose of prior therapy. For Richter's transformation, only 1
 prior line of therapy is required for the DLBCL component.
 - Subject has received no more than 7 systemic lines of anti-cancer therapy for the
 disease under study.
 - Subjects previously treated with CD19-directed autologous CAR T therapies have
 received no more than 2 lines of therapy after administration of their previous CAR T
 product.
 - Expansion cohort only: Subjects must have received autologous CD19-directed CAR T
 therapy and demonstrated clinical response to the treatment at Day 28 or later,
 followed by relapse.
 Criteria for both B-ALL and NHL:
 - Eastern Cooperative Oncology Group performance status score of 0 or 1.
 - An estimated life expectancy of at least 12 weeks according to the investigator's
 judgment.
 - Seronegative for human immunodeficiency virus antibody (i.e., intact immune function).
 - Subject has adequate bone marrow, renal, hepatic, pulmonary, and cardiac function
 defined as:
 1. Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 (calculated using
 the CKD-EPI equation [Levey et al, 2009]). If there is a concern that eGFR
 calculation is not an accurate reflection of renal function, a 24-hour urine
 collection for creatinine clearance may be used at the investigator's discretion.
 2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels both
 ≤3 times of upper limit of normal (ULN), unless there is suspected disease in the
 liver.
 3. Total bilirubin <2.0 mg/dL, except in subjects with Gilbert's syndrome.
 4. Platelet count ≥50,000/μL and absolute neutrophil count of ≥1000/ μL. Platelet
 transfusions within 14 days of screening are not allowed except for subjects in
 B-ALL disease cohort with extensive bone marrow disease burden, in which case
 adequate bone marrow recovery after prior treatment is required to be documented.
 5. C-reactive protein (CRP) <2x ULN; subjects with CRP elevation within 2x ULN,
 ruling out infectious cause will be required.
 6. Left ventricular ejection fraction >45% as assessed by echocardiogram (ECHO) or
 multiple gated acquisition scan performed within 1 month before starting
 lymphodepleting chemotherapy. ECHO results performed within 6 months before
 Screening and at least 28 days after the last cancer treatment may be acceptable
 if the subject has not received any treatment with cardiotoxicity risks.
 7. No clinically significant evidence of pericardial effusion or pleural effusion
 causing clinical symptoms and needing immediate intervention, based on the
 investigator's opinion. Any known effusion must be stable without need for
 drainage within 2 weeks of enrollment.
 8. No clinically significant renal/pulmonary comorbidities.
 9. Baseline oxygen saturation >92% on room air.
 Key Exclusion Criteria*
 Criteria for B-ALL:
 - Burkitt cell (L3 ALL) or mixed-lineage acute leukemia.
 - No active central nervous system (CNS) disease. Subjects with a history of CNS
 involvement must have a documented CR on at least 2 imaging studies at least 3 months
 apart (with no masses in parenchyma and no ocular involvement) and a negative
 cerebrospinal fluid cytology on at least 2 evaluations (one evaluation may be during
 the Screening Period and the other must be at least 3 months prior).
 Criteria for NHL:
 - No prior or active CNS disease.
 - Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or
 blood vessel compression.
 - Active hemolytic anemia.
 Criteria for B-ALL and NHL:
 - Subject has had a malignancy, besides the malignancies of inclusion (B-ALL or NHL),
 that in the investigator's opinion, has a high risk of relapse in the next 2 years. In
 the case of Richter's transformation, subjects may be enrolled with ongoing chronic
 lymphocytic leukemia/small lymphocytic lymphoma.
 - Uncontrolled and serious fungal, bacterial, viral, protozoal, or other infection that
 has not resolved and does require therapeutic anti-microbial medications at least 7
 days prior to LD. Subjects with elevated CRP must undergo infectious disease workup
 and the recommendations discussed with medical monitor to be considered on an
 individual basis. The CRP must be trending toward the normal range for the laboratory
 with the exception when it's deemed related to the underlying malignancy.
 - Any form of primary immunodeficiency (e.g., severe combined immunodeficiency disease).
 - Active hepatitis B or hepatitis C confirmed by PCR. Subject positive for inactive
 hepatitis B is allowed to enroll if on prophylactic treatment.
 1. Subject is seropositive for hepatitis B antigen with confirmation. If
 confirmatory tests are negative, the subject can be enrolled.
 2. Subject is seropositive for hepatitis C antibody unless antigen negative. If
 hepatitis C antibody test is positive, the subject must be tested for the
 presence of RNA by reverse transcription PCR and be hepatitis C virus-RNA
 negative.
 - Any known uncontrolled cardiovascular disease at the time of Screening that, in the
 investigator's opinion, renders the subject ineligible, including but not limited to:
 1. Active ventricular or atrial dysrhythmia ≥ Grade 2, bradycardia ≥ Grade 2.
 2. Myocardial infarction within 6 months before Screening.
 3. Pulmonary embolism, deep vein thrombosis, or any other significant coagulopathy
 including disseminated intravascular coagulation.
 - History of hypertension crisis or hypertensive encephalopathy within 3 months prior to
 Screening. In case of hypertensive crisis caused by omission of well-established
 treatment regimen, transient and promptly stabilized, enrollment must be discussed and
 agreed upon with sponsor and medical monitor.
 - History of severe immediate hypersensitivity reaction to any of the agents used in
 this study.
 - Presence of a CNS disorder that, in the opinion of the investigator, renders the
 subject ineligible for treatment.
 - Abnormal findings during the Screening Period or any other medical condition(s) or
 laboratory findings that, in the opinion of the investigator, might jeopardize the
 subject's safety.
 - History of concomitant genetic syndrome such as Fanconi anemia, Kostmann syndrome,
 Shwachman-Diamond syndrome, or any other known bone marrow failure syndrome.
 - Active uncontrolled autoimmune disease requiring active immunosuppression at the time
 of Screening (excluding subjects needing steroids for physiologic replacement).
 - Subject has received stem cell transplant within 90 days before Screening.
 - Subject has active GvHD symptoms.
 - Subject has received systemic biologic agent for treatment of disease under study
 within 28 days of LD or other systemic anti-cancer therapy within 10 days of LD Note:
 this criterion does not apply if the subject has clear evidence of disease progression
 after such an agent has been administered and all AEs have resolved to a Grade 2 or
 less in severity. This should be discussed with the medical monitor for confirmation.
 - Participation in noninterventional registries or epidemiological studies is not
 excluded.
 - Radiotherapy within 4 weeks before Screening should be discussed with monitor and
 determined on a case-by-case basis.
 - Presence of pleural/peritoneal/pericardial catheter, as well as biliary and ureteral
 stents (does not apply to intravenous lines).
 - Subject has received live vaccine within 4 weeks before Screening. Non-live virus
 vaccines are not excluded.
 - Subject has received CD19-directed therapy other than autologous CD19-directed CAR T
 therapy within 90 days of the anticipated start date of LD.
 - Additional criteria apply


Input:
TAK-981 is being tested in combination with anti-CD38 monoclonal antibodies (mAbs) to treat
 participants who have relapsed or refractory multiple myeloma (RRMM).
 The main aims of the study are to evaluate the safety and efficacy of TAK-981 in combination
 with anti-CD38 (mAbs) and to determine the recommended Phase 2 dose (RP2D).
 Participants will be on this combination treatment for 28-day cycles. They will continue with
 this treatment until disease progression or unacceptable toxicity.
 ;
 ;
 Inclusion Criteria:
 1. Participants must have RRMM with measurable disease:
 a) Has measurable disease defined as one of the following:
 - Serum M-protein ≥0.5 g/dL (≥5 g/L).
 - Urine M-protein ≥200 mg/24 hours.
 - In participants without measurable M-protein in serum protein electrophoresis
 (SPEP) or urine protein electrophoresis (UPEP), a serum free light chain (FLC)
 assay result with involved FLC level ≥10 mg/dL (≥100 mg/L), provided serum FLC
 ratio is abnormal.
 2. Has undergone stem cell transplant or is considered transplant ineligible.
 3. Has failed at least 3 prior lines of anti-myeloma treatments and is either refractory,
 or intolerant to at least 1 immunomodulatory drug ( IMiD); (ie, lenalidomide or
 pomalidomide [thalidomide excluded]), at least 1 proteasome inhibitor (ie, bortezomib,
 ixazomib or carfilzomib), and refractory to at least 1 anti-CD38 antibody and who have
 demonstrated disease progression with the last therapy.
 5.Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG)
 Performance Scale.
 6.Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy
 or have the toxicity established as sequela.
 Exclusion Criteria:
 1. Received treatment with systemic anticancer treatments within 14 days before the first
 dose of study drug.
 2. Current participation in another interventional study, including other clinical trials
 with investigational agents (including investigational vaccines or investigational
 medical device for disease under study) within 4 weeks of the first dose of TAK-981
 and throughout the duration of this trial.
 3. Prior radiation therapy within 14 days of the first dose of TAK-981.
 4. Major surgery within 4 weeks before C1D1. participants should be fully recovered from
 any surgically related complications.
 5. Plasmapheresis within 28 days of randomization.
 6. Diagnosis of primary amyloidosis, Waldenström's disease, monoclonal gammopathy of
 undetermined significance or smoldering multiple myeloma (SMM), plasma cell leukemia
 POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
 skin changes), myelodysplastic syndrome, or myeloproliferative syndrome.
 7. With disease where the only measurable parameter is plasmacytoma.
 8. Second malignancy within the previous 3 years, except treated basal cell or localized
 squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ,
 resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for
 which the participant is not on active anticancer therapy.
 9. Prior treatment with more than 1 anti-CD38 antibody.
 10. Requires the use of drugs known to prolong the corrected QT interval (QTc) (during
 Phase 1b only).
 11. History of QT interval with Fridericia's correction (QTcF) >480 ms.
 12. History of human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C
 infection.
 13. Systemic infection requiring systemic antibiotic therapy.
 14. Active or history pneumonitis.
 15. Receipt of any live vaccine (eg, varicella, pneumococcus) within 4 weeks of initiation
 of study drug.
 16. Receiving strong or moderate Cytochrome P450 (CYP) 3A4/5 inhibitors or inducers.
 17. History of unstable cardiac comorbidities in the following 6 months.


Input:
An open-label, multicenter phase II clinical study to evaluate safety, efficacy and PK of
 HLX208 for advanced melanoma with BRAF V600 mutation
 ;NA;
 Inclusion Criteria:
 - Age>=18Y
 - Good Organ Function
 - Expected survival time ≥ 3 months
 - advanced melanoma with BRAF V600 mutation that have been diagnosed
 - ECOG score 0-1;
 Exclusion Criteria:
 - Previous treatment with BRAF inhibitors or MEK inhibitors
 - Symptomatic brain or meningeal metastases (unless the patient has beenon > treatment
 for 3 months, has no evidence of progress on imagingwithin 4 weeks prior to initial
 administration, and tumor-related clinicalsymptoms are stable).
 - Severe active infections requiring systemic anti-infective therapy
 - A history of other malignancies within two years, except for cured carcinoma in situ
 of the cervix or basal cell carcinoma of the skin.


Input:
This is a Phase II study for patients with MIBG avid tumors. The study is to determine the
 response rate to <131>I-MIBG in patients with de novo, relapsed or refractory neuroblastoma
 or other MIBG avid malignant tumors 42 days post MIBG therapy. It will also be evaluating the
 tolerability and safety of the study agent by evaluating the hematopoietic and
 non-hematopoietic toxicity of <131>I-MIBG therapy. Tumor response will be evaluated by
 comparing the patient's disease pre-treatment against the patient's day +42 post <131>I-MIBG
 treatment. The evaluations may include the following: <131>I-MIBG scan, CT or MRI, urine
 catecholamine, bone marrow analyses and any other tests considered standard of care for
 cancer evaluation. To be eligible for participation, patients must have tumors that are MIBG
 avid. Patients must also have a stem cell source for autologous rescue in the event of
 protracted therapy associated cytopenias. Peripheral stem cell collections are preferred as
 the hematopoietic cell source. Bone marrow harvests for a hematopoietic cell source is an
 alternative. This study will provide data for future clinical trials utilizing <131>I-MIBG
 therapies. A room on H12 has been prepared with lead lined walls, and many radiation safety
 components to accomodate this treatment. <131>I metaiodobenzlguanidine (<131>I-MIBG) is a
 radiopharmaceutical that concentrates within adrenomedullary tissue. The agent was initially
 used for tumor imaging due to its capability to locate pheochromocytomas, neuroblastomas and
 other neuroendocrine tumors. <131>I-MIBG was subsequently used as an therapeutic agent for
 these tumor types. Phase I and II therapeutic trials targeting neuroblastoma have reported
 response rates of 10-50%. Toxicities observed have been mainly hematopoietic, with ~50% of
 patients receiving 15mCi/kg requiring stem cell reinfusion. Observed non-hematopoietic
 toxicities have been mild. Most recently, trials have been conducted combining the study
 agent with myeloablative chemotherapy and stem cell reinfusion have been performed with
 initial response rates of ~50%.
 ;NA;
 Inclusion Criteria:
 - Patients must be between 12 months and 65 years at the time of enrollment
 - Diagnosis: diagnosis of neuroblastoma or at the time of relapse by histology and/or
 demonstration of clumps of tumor cells in bone marrow with elevated urinary
 catecholamine metabolites
 - Disease Status:
 1. The presence of refractory or progressive disease (PD)
 2. For patients with neuroblastoma, the presence of mixed response (MR), or no
 response (NR) following the completion of A3973 or equivalent induction therapy,
 or the presence of a partial response (PR) with high Curie score (>2) following
 induction therapy.
 3. Patients with de novo high risk neuroblastoma who have completed standard
 induction therapy and do not achieve a CR, VGPR, or PR with low Curie score post
 induction.
 - Patients must have evidence of MIBG avid disease as determined by diagnostic
 MIBG scan obtained within 4 weeks of study entry.
 - Patients who receive greater than 12 mCi/kg are required to have stem cell rescue
 products harvested prior to study treatment.
 - Performance Level and Life Expectancy: Patients must have a Lansky Play Scale17 of 60%
 (<16 yrs old), Karnofsky score 60% (>16 yrs old), or ECOG score of < or equal to 2 and
 a life expectancy of 2 months.
 - Patients may enter this study with or without salvage therapy for recurrent tumor.
 Patients must have fully recovered from the toxic effects of any prior therapy.
 - Organ Function requirements:
 Hematopoietic Criteria:
 1. Hemoglobin- 10 gl/dl (transfusion allowed)
 2. ANC- 550 / cu mm (off myeloid growth factors)
 3. Platelets- > 50,000/cu mm. (transfusion allowed - however patients must not require
 more than two platelet transfusions per week).
 Renal Function:
 a. Serum Creatinine- < 2 x ULN for age.
 Hepatic Function:
 Total bilirubin <1.5 x ULN for age SGPT (ALT) and SGOT (AST) < 10 x ULN for age
 Cardiac Function:
 For children with NBL: Normal ejection fraction (>55%) documented by echocardiogram or
 radionuclide MUGA evaluation OR normal fractional shortening (>27%) documented by
 echocardiogram.
 For subjects with paraganglioma/ pheochromocytoma: No clinically significant cardiac
 dysfunction.
 Pulmonary Function:
 Patients must have clinically normal lung function as manifested by no dyspnea at rest and
 no oxygen requirement
 Reproductive Function:
 1. Females of childbearing potential must have a negative pregnancy test within 1 week
 prior to treatment with 131I-MIBG.
 2. Patients of childbearing potential must agree to use an effective birth control
 method.
 3. Female patients who are lactating must agree to stop breast feeding
 Exclusion Criteria:
 - Pregnancy or breast feeding
 - Have undergone a prior allogeneic BMT.
 - Patients with disease of any major organ system that would compromise their ability to
 withstand therapy. Any significant organ impairment should be discussed with the Study
 Chair prior to patient entry.
 - Patients who are on hemodialysis.
 - Hepatitis B surface antigen (+) or Hepatitis C positive in preceding six months.
 - Patients with an active infection requiring intravenous antivirals, antibiotics or
 antifungals. Patients on prolonged antifungal therapy are still eligible if they are
 culture negative and biopsy negative in suspected residual radiographic lesions have
 stabilized or regressed and they meet other organ function criteria.
 - Prior total body irradiation, prior total abdominal or whole liver radiation
 - Any medical or psychological condition or situation deemed by the PI to put the
 patient at increased risk of complications or noncompliance.
 - Patients with curative treatment options.
 - Patients for whom busulfan/ melphalan consolidation therapy following treatment with
 131I-MIBG is planned.
 - Patients for who CEM (carboplatin, etoposide, melphalan) therapy is administered
 within 30 days prior to 131I-MIBG therapy or for whom this therapy is planned within
 30 days following administration of 131I-MIBG.


Input:
It is an exploratory clinical study aimed to evaluate the efficacy and safety of TACE
 combined with Camrelizumab in the treatment of patients with BCLC stage B and C HCC.Treatment
 will continue until disease progression or intolerable toxicity or patients withdrawal of
 consent,and the target sample size is 60 individuals.
 ;
 ;
 Inclusion Criteria:
 - 1.Patients voluntarily entered the study and signed informed consent form (ICF) 2.
 Age: 18 - 80 years old and life expectancy of at least 12 weeks.; 3. Clinically or
 histologically diagnosed as HCC; 4. There are measurable lesions that meet the
 RECIST1.1 standard on the baseline imaging examination; 5. Child-pugh classification A
 or B (score < 7); 6. The BCLC stage is stage B or C, and it is unable or unwilling to
 undergo surgical treatment; 7. ECOG : 0 ~ 1 ; 8. No previous immune checkpoint
 inhibitor treatment (including PD-1 / PD-L1 antibody and CTLA-4 inhibitor); 9.
 HBV-deoxyribonucleic acid (DNA) must be <500IU / mL, and receive at least 14 days of
 anti-HBV treatment before the start of study treatment Treatment;
 Exclusion Criteria:
 - 1. History of treatment with any local treatment (exception of liver transplantation),
 systemic .anti-cancer therapy, or immunotherapy; 2. Those whose tumor thrombus reaches
 or exceeds the main portal vein; 3. Existing or concurrently suffering from other
 malignant tumors, except for fully treated non-melanoma skin cancer, cervical
 carcinoma in situ, and papillary thyroid carcinoma; 4. There is any active autoimmune
 disease or has a history of autoimmune disease and may relapse; 5. Use strong CYP3A4 /
 CYP2C19 inducers including rifampicin and Hypericum perforatum or strong CYP3A4 /
 CYP2C19 inhibitors within 14 days before starting the study treatment; 6. Known
 history of severe allergy to any monoclonal antibody; 7. Patients who are going to
 undergo or have undergone organ or allogeneic bone marrow transplantation; 8.
 Non-compliance with TACE or Camrelizumab; 9. Moderate and severe ascites with clinical
 symptoms require therapeutic puncture, drainage, or Childa-Pugh score> 2 (except
 imaging only shows a small amount of ascites but not accompanied by clinical
 symptoms); uncontrolled or moderate and Above pleural effusion and pericardial
 effusion; 10. Abdominal fistula, gastrointestinal perforation or abdominal abscess
 occurred within 6 months before the start of the study treatment; 11. Thrombosis or
 embolism occurred within 6 months before the start of study treatment, such as
 cerebrovascular accident (including temporary ischemic attack, cerebral hemorrhage,
 cerebral infarction, pulmonary embolism, etc.) 12. Known inherited or acquired
 bleeding or thrombophilia ; currently or recently (10 days prior to the start of study
 treatment) have used full dose oral or Injection of anticoagulant drugs or
 thrombolytic drugs (prophylactic use of low-dose aspirin and low molecular weight
 heparin); 13. Major vascular disease within 6 months before the study treatment; 22.
 Past or present central nervous system metastasis; 14. Metastatic diseases involving
 major airways or blood vessels or a large mediastinal tumor mass in the center (<30 mm
 from the crest) 15. Those with a history of hepatic encephalopathy; 16. Palliative
 radiotherapy for non-target lesions allowed for symptom control must be completed at
 least 2 weeks before the start of study treatment. Adverse events caused by
 radiotherapy have not recovered to ≤CTCAE level 1; 17. There were severe infections
 within 4 weeks before starting the study treatment; 18. Patients with congenital or
 acquired immune deficiency (such as those infected with HIV); 19. Co-infection with
 hepatitis B and C; 20. For patients with bone metastases, the palliative radiotherapy
 area> 5% bone marrow area received within 4 weeks before participating in the study;


Input:
Numerous evidences verified that erlotinib could dramatically improve the PFS and OS of
 non-small cell lung cancers who harbor EGFR sensitive mutations, however, primary or
 secondary resistance will be developed after TKI treatment, doctors do plenty of researches
 to overcome TKI resistance. FAST ACT-2 study present that, first line erlotinib combined with
 chemotherapy could improved mOS to more than 30 months in NSCLCs who harbor EGFR sensitive
 mutations, several study shows that sensitive mutations still exist after TKI resistance,
 because of the next generation TKIs(such as BIBW2992) are not avaliable at present, agents
 for met amplification(such as Crizotinib) are so expensive that many Chinese patients could
 not support. Thus, the investigators hypothesis that, after first line TKI treatment, the
 patients who developed TKI resistance could still benefit from second line TKI combined with
 chemotherapy.
 ;
 ;
 Inclusion Criteria:
 - advanced non-small cell lung cancer, stage IIIB/IV
 - non-squamous
 - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R
 - received first line TKIs treatment and developed TKI resistance
 - ECOG 0-2
 Exclusion Criteria:
 - squamous non-small cell lung cancer
 - patients have unstable brain metastasis, predict survival less than 8 weeks
 - spinal-cord compression without evidence of stabilisation or treatment
 - women who were pregnant or lactating; women with a positive or no available pregnancy
 test result at baseline
 - patients have any unstable illness that could not receive further treatment


Input:
This phase II trial studies the side effects and how well azacitidine and enasidenib work in
 treating patients with IDH2-mutant myelodysplastic syndrome. Azacitidine and enasidenib may
 stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
 ;
 ;
 Inclusion Criteria:
 - Signed, informed consent must be obtained prior to any study specific procedures
 - Subjects with a histologically confirmed diagnosis of MDS, including both MDS and
 refractory anemia with excess blasts in transformation (RAEB-T) (acute myeloid
 leukemia [AML] with 20-30% blasts and multilineage dysplasia by
 French-American-British [FAB] criteria) by World Health Organization (WHO), and
 chronic myelomonocytic leukemia (CMML) are eligible
 - Subjects must have an IDH2 gene mutation (IDH2-R140 or R172) as determined by local
 laboratory result
 - (Arm A only): Subject must be hypomethylating agent naive (i.e. prior azacitidine,
 decitabine, SGI-110 is exclusionary). Receipt of other MDS-directed therapy such as
 lenalidomide is allowed
 - (Arm A only): Subjects with high-risk MDS (i.e. International Prostate Symptom Score
 [IPSS] intermediate-2 or high-risk; or revised [R]-IPSS high or very-high risk).
 Patients with intermediate-1 risk by IPSS or intermediate risk by R-IPSS with
 high-risk molecular features including TP53, ASXL1, EZH2, and/or RUNX1 mutations are
 also eligible
 - (Arm B only): Subject must be relapsed or refractory to prior hypomethylating agent
 therapy, defined as prior receipt of 6 cycles of HMA therapy with failure to attain a
 response, or relapse after prior response to HMA therapy
 - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
 - Serum bilirubin =< 2 x the upper limit of normal (ULN) (except for patients with
 Gilbert's disease)
 - Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =< 3 x the
 laboratory ULN
 - Serum creatinine =< 2 x the ULN
 - Able to understand and voluntarily sign a written informed consent, and willing and
 able to comply with protocol requirements
 - Resolution of all clinically significant treatment-related, non-hematological
 toxicities, except alopecia, from any previous cancer therapy to =< grade 1 prior to
 the first dose of study treatment
 - Female patients of childbearing potential must have a negative serum or urine
 pregnancy test within 7 days of the first dose of study drug and agree to use dual
 methods of contraception during the study and for a minimum of 3 months following the
 last dose of study drug. Post-menopausal females (> 45 years old and without menses
 for > 1 year) and surgically sterilized females are exempt from these requirements.
 Male patients must use an effective barrier method of contraception during the study
 and for a minimum of 3 months following the last dose of study drug if sexually active
 with a female of childbearing potential
 Exclusion Criteria:
 - Any prior or coexisting medical condition that in the investigator's judgment will
 substantially increase the risk associated with the subject's participation in the
 study
 - Subject has received a prior targeted IDH2 inhibitor
 - Psychiatric disorders or altered mental status precluding understanding of the
 informed consent process and/or completion of the necessary study procedures
 - Active uncontrolled infection at study enrollment including known diagnosis of human
 immunodeficiency virus or chronic active hepatitis B or C infection
 - Clinically significant gastrointestinal conditions or disorders that may interfere
 with study drug absorption, including prior gastrectomy
 - Patients with known active central nervous system (CNS) disease, including
 leptomeningeal involvement
 - Impaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant
 cardiac disease including the following: a) New York Heart Association grade III or IV
 congestive heart failure, b) myocardial infarction within the last 6 months
 - Subjects with a corrected QT (QTc) > 480 ms (QTc > 510 msec for subjects with a bundle
 branch block at baseline
 - Nursing or pregnant women
 - Subjects with known hypersensitivity to study drugs or their excipients