Input:
The Proseven trial is a prospective interventional study that will evaluate the toxicity and
 efficacy of MR-guided stereotactic body radiotherapy (SBRT) in the profound hypofractionated
 treatment of prostate cancer. Patients will be treated in 5 daily fractions within a short
 overall treatment time (OTT) of 7 days. A simultaneous integrated boost (SIB) will be
 delivered to the intraprostatic dominant lesion (if present) in this study. Besides a
 potential biological impact of this innovative prostate SBRT treatment, the reduced OTT
 offers also benefits in terms of patient convenience. The primary endpoint is clinician
 reported grade 2 or more acute gastrointestinal (GI) and genitourinary (GU) toxicity,
 assessed using CTCAE v 5.0 and RTOG, measured up to 3 months after the first treatment
 fraction.
 ;NA;
 Inclusion Criteria:
 - Age > 18 y
 - Histologically confirmed prostate adenocarcinoma
 - Low risk: cT1c-T2a, Gleason score 6, PSA < 10ng/mL
 - Favorable intermediate risk: 1 intermediate risk factor, Gleason 3+4 or less, < 50%
 positive biopsy cores)
 - Unfavorable intermediate risk: > 1 intermediate risk factor, Gleason 4+3, > 50%
 positive biopsy cores)
 - Limited high risk: cT3a with PSA < 40ng/mL or cT2a-c with a Gleason score > 7 and/or a
 PSA > 20ng/mL but < 40ng/mL
 - World Health Organization performance score 0-2
 - Written informed consent
 Intermediate risk factors: T2b-T2c, Gleason 7, PSA 10-20 ng/mL
 Exclusion Criteria:
 - Transurethral resection (TUR) < 3months before SBRT
 - International Prostate Symptom Score (IPSS) > 19
 - Prostate volume > 100cc on transrectal ultrasound (TRUS)
 - Stage cT3b-T4
 - N1 disease (clinically or pathologically)
 - M1 disease (clinically or pathologically)
 - PSA > 40ng/mL
 - inflammatory bowel disease
 - immunosuppressive medications
 - prior pelvic RT
 - contra-indications for MRI


Input:
To evaluate the anti cancer effect of VK 2019 in subjects with EBV related nasopharyngeal
 carcinoma (NPC) for whom there is no other standard treatment available
 ;
 ;
 Inclusion Criteria:
 - 1 Informed consent obtained prior to any protocol mandated study specific procedures
 in accordance with institutional policies.
 - 2 Either loco regionally recurrent or metastatic EBV positive RECIST evaluable
 nasopharyngeal carcinoma not amenable to curative treatment with no accepted effective
 standard of care therapeutic option.
 Addendum for phase 2 exploratory cohorts: subjects with PTLD or EBV lymphoma not amenable
 to curative treatment with no accepted effective standard of care therapeutic option.
 - 3 Not eligible for other approved or standard therapies
 - 4.Prior palliative radiation must have been completed at least 2 weeks prior to study
 Cycle 1 Day 0
 - 5.Prior anti cancer systemic treatment must have been completed greater than 4 weeks
 prior to the first dose of VK 2019 or subjects must have recovered from all acute
 prior treatment related AEs
 - 6.Toxicities related to prior anti cancer therapy must have returned to Grade 1 or
 less. Peripheral neuropathy must be Grade 2 or less. Chronic but stable toxicities
 Grade > 1 (eg, dysphasia, G tube dependence, etc.) are permissible.
 - 7.Age ≥ 18
 - 8.Absolute neutrophil count > 1500/µL (stable off any growth factor for at least 1
 week of study drug administration)
 - 9.Hemoglobin > 9g/dL (transfusion to achieve this level is permitted)
 - 10.Platelet count > 75 x 103/ µL (transfusion to achieve this level is NOT permitted)
 - 11.Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2.5 x
 upper limit of normal (ULN) .Total serum bilirubin ≤ 1.5 x ULN
 - 12.Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min as calculated per
 Cockcroft Gault equation
 - 13.Urinary protein < 2+ by dipstick. If dipstick ≥ 2+, then a 24 hour urine collection
 can be done and the subject may enter only if urinary protein is < 1 g/24 hour
 - 14.Sexually active subjects must agree to utilize birth control method during
 treatment and for 18 weeks after the last dose of VK 2019.
 - 15.Eastern Cooperative Oncology Group (ECOG) performance status 2 or less.
 - 16.Ability to understand and the willingness to personally sign the written IRB
 approved informed consent document.
 Exclusion Criteria:
 - 1.Prior therapy restrictions.
 - 2.Concurrent treatment with systemic cancer directed therapy including complementary,
 alternative, herbal or nutritional supplement based treatments whose purpose is for
 anti cancer effect
 - 3.Severe or active symptomatic cardiopulmonary diseases, including unstable angina,
 congestive heart failure, or peripheral vascular disease within 12 months prior to
 study drug administration; and/or chronic obstructive pulmonary disease exacerbation
 or other respiratory illness requiring hospitalization within 4 weeks prior to study
 drug administration. Subjects with effectively treated conditions (eg, stenting for
 coronary artery disease) are eligible if stable for at least 4 weeks prior to study
 drug administration
 - 4.Metastatic disease with active central nervous system (CNS) involvement, defined as
 parenchymal brain involvement. Subjects with cranial nerve or base of skull
 involvement without the above are eligible. Subjects with CNS metastases that are
 stable on imaging at least 1 month following focal treatment with radiation are
 eligible
 - 5.Known history of human immunodeficiency virus (HIV) unless the HIV positive subjects
 has:
 1. A stable regimen of highly active anti retroviral therapy (HAART)
 2. No requirement for concurrent antibiotics or antifungal agents for the prevention
 of opportunistic infections
 3. A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
 PCR based test
 - 6.Serious uncontrolled medical disorder or active infection which would, in the
 opinion of the Investigator, impair the ability of the subject to receive protocol
 therapy or whose control may be jeopardized by the complications of this therapy
 - 7.NPC subjects: Have received a prior organ allograft or allogeneic bone marrow
 transplant.
 - 8.Current non prescription drug or alcohol dependence
 - 9.For all female subjects: pregnancy or breastfeeding
 - 10.All female subjects with reproductive potential must have a negative pregnancy test
 (serum or urine) prior to enrollment
 - 11.Other severe acute or chronic medical or psychiatric condition or laboratory
 abnormality that may increase the risk associated with study participation or study
 drug administration, or may interfere with the interpretation of study results, or in
 the judgment of the investigator would make the subject inappropriate for entry into
 the study
 - 12.Corrected QT by Fridericia's formula (QTcF) of > 470 ms average (mean) on
 triplicate ECG performed during screening


Input:
This is a first in human, multicenter, open label, Phase 1a/b dose escalation and dose
 expansion study to establish the maximum tolerated dose (MTD), recommended Phase 2 dose
 (RP2D), and evaluate the safety and tolerability of QD oral dosing of HC 7366 in a dose
 escalating fashion in subjects with advanced solid tumors. Up to 36 subjects will be enrolled
 into the Phase 1a dose escalation part of the study. Every effort will be made to ensure
 approximately 50% of all subjects enrolled in this study will be subjects with the tumors of
 special interest such as squamous cell carcinoma of the head and neck (SCCHN), colorectal
 cancer (CRC), non-small cell lung cancer (NSCLC), and transitional cell carcinoma of the
 bladder (TCC). Subjects with other solid tumor types are also eligible provided study
 selection criteria are met and they do not exceed 50% of all enrolled subjects. The study
 will be conducted in the United States at approximately 3 to 5 sites. This Phase 1a/b study
 will follow a traditional 3+3 design. The starting dose level will be 10 mg QD, escalating to
 20, 40, 75, 125, and 150 mg QD as safety allows. All doses are to be administered in the
 fasting state with water at least 1 hour before food or at least 2 hours after food. The
 Phase 1b dose expansion part will involve cohort expansion at up to 2 dose levels selected
 from the dose escalation data by the safety monitoring committee (SMC), to obtain additional
 safety and preliminary efficacy information. Each cohort in Phase 1b will enroll 15 subjects.
 The study will be expanded into a Phase 2 study via protocol amendment which will then assess
 the dose and tumor type(s) selected in Phase 1a/b as the most appropriate for further
 clinical development. Subjects will be dosed until unacceptable toxicity, disease progression
 per immune-related Response Evaluation Criteria in Solid Tumors (iRECIST), discontinuation of
 treatment for other protocol allowed reason (eg, subject refusal), any other administrative
 reasons, or after 2 years of treatment, whichever occurs first. For scheduling purposes,
 dosing will occur in 3 week cycles and computed tomography (CT) scans will be conducted once
 every 6 weeks with the first postbaseline scan after 6 weeks of dosing (precycle 3).
 ;
 ;
 Inclusion Criteria:
 1. Have a signed an informed consent form prior to any study specific procedures or
 treatment
 2. Be ≥18 years of age (male or female) at the time of consent
 3. Have 1 of the following tumor types with qualifying characteristics, and have received
 at least 1 and no more than 5 prior lines of therapy:
 1. SCCHN
 2. CRC
 3. NSCLC
 4. TCC
 5. Other solid tumors (eg, carcinoma of unknown primary) with the exception of
 rapidly progressing neoplasms (eg, pancreatic cancer, glioblastoma,
 hepatocellular carcinoma). Note: Subjects do not need to have progressed through
 all possible available therapies with known clinical benefit for their respective
 cancers to participate in this study. Note: Subjects with SCCHN, CRC, NSCLC, and
 TCC are a priority and should constitute as a whole, at least 50% of the enrolled
 population. Enrollment of all others will be capped when reaching a combined 50%,
 in order to maintain 18 slots for subjects with SCCHN, CRC, NSCLC, and TCC.
 4. Have at least 1 radiologically measurable lesion as per Response Evaluation Criteria
 in Solid Tumors (RECIST) v 1.1 defined as a lesion that is at least 10 mm in longest
 diameter or lymph node that is at least 15 mm in short axis imaged by CT scan or
 magnetic resonance imaging and obtained by imaging within 28 days prior to study
 treatment. Tumor lesions situated in a previously irradiated area are considered
 measurable if progression has been demonstrated in such lesions
 5. Have resolution of all previous treatment related toxicities to Grade 1 severity or
 lower, except for stable sensory neuropathy (≤Grade 2) and alopecia. If the subject
 received major surgery or radiation therapy of >30 Gy, they must have recovered from
 the toxicity and/or complications from the intervention
 6. If subjects were previously treated with immune checkpoint inhibitors, at least 4
 weeks must have elapsed since the last dose, and toxicities resolved as above
 7. Subjects must have at least one biopsiable lesion at baseline. Biopsies in this
 clinical study will conform to American Society of Clinical Oncology's Ethical
 Framework for Including Research Biopsies in Oncology Clinical Trials. Provided there
 are suitable and accessible lesions, no biopsy contraindications, minimal risk of
 complications and a positive informed decision, subjects are willing to provide fresh
 tissue for biomarker analysis, and, based on the adequacy of the tissue sample
 quality, for assessment of biomarker status. Two biopsies will be necessary: at
 baseline (within 15 days prior to study Day 1) and at the time of the first response
 assessment CT scan at Cycle 3/Day 1 (+7 days). Newly obtained biopsy specimens are
 preferred to archived samples and formalin fixed, paraffin embedded block specimens
 are preferred to slides
 8. Have Eastern Cooperative Oncology Group performance status of 0 or 1 and sustained
 between screening and initiation of dosing on Day 1
 9. Have no swallowing difficulties that would prevent compliance with oral dosing
 10. Have not experienced >10% body weight loss in the previous 4 weeks
 11. Have a serum albumin level >3 g/dL
 12. Have life expectancy of 3 months or greater as determined by the treating physician
 13. Have adequate organ function on Day 1, as defined by meeting all of the following
 criteria:
 1. Total bilirubin ≤1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ULN for
 subjects with total bilirubin levels >1.5 x ULN
 2. Aspartate aminotransferase and alanine aminotransferase ≤2.5 × ULN or ≤5 × ULN
 for subjects with known hepatic metastases
 14. Have adequate renal function on Day 1, as defined by creatinine ≤1.5 × ULN and
 creatinine clearance ≥60 mL/min, as per the below Cockcroft Gault formula
 15. Have adequate hematologic function on Day 1, as defined by meeting all of the
 following criteria:
 1. Hemoglobin ≥9 g/dL (uncorrected by red blood cell transfusion or erythropoietin
 support)
 2. Absolute neutrophil count ≥1.5 × 109/L
 3. Platelet count ≥100 × 109/L
 16. Have adequate coagulation function on Day 1, as defined by either of the following
 criteria:
 1. International normalized ratio (INR) <1.5 × ULN OR for subjects receiving
 warfarin or low molecular weight heparin, the subject must, in the investigator's
 opinion, be clinically stable with no evidence of active bleeding while receiving
 anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is
 the goal of anticoagulant therapy
 2. Activated partial thromboplastin time <1.5 × ULN unless subject is receiving
 anticoagulant therapy, provided prothrombin time or partial thromboplastin time
 is within therapeutic range of intended use of anticoagulants
 17. Have normal or adequately controlled pan-endocrine function (pituitary, adrenal,
 thyroid, pancreatic, gonadal). Subjects on hormonal supplementation must be stable at
 their treatment doses
 18. Female subjects of childbearing potential must have a negative urine or serum
 pregnancy test within 72 hours prior to receiving the first dose of study medication.
 If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
 test will be required
 19. Female subjects of childbearing potential must be willing to use an adequate form of
 contraception from the signing of the ICF until 90 days after the last dose of study
 medication
 20. Female subjects must agree not to breastfeed and not to donate ova starting at
 screening and throughout the study treatment, and for 90 days after the final
 administration of study drug
 21. Male subjects with a pregnant or breastfeeding partner(s) must agree to remain
 abstinent or use a condom for the duration of the pregnancy or for the time their
 partner is breastfeeding throughout the study treatment and for 90 days after the
 final administration of study drug
 22. Male subjects must not donate sperm during the treatment period and for at least 90
 days after the final administration of the study drug
 23. Male subjects with female partner(s) of child bearing potential must agree to use a
 condom with spermicide during the treatment period and for at least 90 days after the
 final administration of the study drug
 24. Be willing and have the ability to comply with scheduled visits (including
 geographical proximity), treatment plans, laboratory tests, and other study
 procedures.
 Exclusion Criteria:
 1. Had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
 weeks prior to the first dose of study treatment or who has not recovered from adverse
 reactions due to a previously administered agent or major surgery
 2. Is currently participating and receiving study therapy or has participated in a study
 of an investigational agent and received study therapy or used an investigational
 device within 4 weeks of the first dose of treatment
 3. Has a diagnosis of immunodeficiency or receiving systemic steroid therapy or any other
 form of immunosuppressive therapy within 7 days prior to the first dose of study
 treatment. The use of physiologic doses of corticosteroids may be approved after
 consultation with the sponsor
 4. Has known history of active tuberculosis
 5. Has known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
 6. Has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C
 (eg, hepatitis C virus ribonucleic acid [RNA] [qualitative]) infection
 7. Has been diagnosed with severe acute respiratory syndrome coronavirus 2 infection
 confirmed by real time polymerase chain reaction (PCR) test as per the local
 guidelines at screening and positive by PCR within 7 days prior to the first dose of
 study treatment
 8. Has a history of clinically severe autoimmune disease, or history of organ transplant
 9. Has a history of retinitis or photosensitive skin disorders including (but not limited
 to) erythema multiforme, atopic eczema, psoriasis, viral exanthemata, pemphigus, and
 dermatitis herpetiformis
 10. Has known additional malignancy that is progressing or required active treatment
 within the previous 5 years. Exceptions include basal cell carcinoma or squamous cell
 carcinoma of the skin that has undergone potentially curative therapy, superficial
 bladder cancer, or in situ cervical cancer. Subjects with other malignancies are
 eligible if they were cured by surgery alone or surgery plus radiotherapy and have
 been continuously disease free for at least 5 years
 11. Has known active central nervous system metastases and/or carcinomatous meningitis.
 Subjects with previously treated brain metastases may participate provided they are
 stable (without evidence of disease progression by imaging for at least 4 weeks prior
 to the first dose of study treatment and any neurologic symptoms have returned to
 baseline), have no evidence of new or enlarging brain metastases, and are not using
 systemic steroids for at least 7 days prior to study treatment. This exception does
 not include carcinomatous meningitis which is excluded regardless of clinical
 stability
 12. Has a history of interstitial lung disease, pneumonitis within 12 months prior to
 screening, or current pneumonitis
 13. Has an active infection requiring systemic therapy
 14. Has a history or current evidence of any condition, therapy, or laboratory abnormality
 that might confound the results of the study, interfere with the subject's
 participation for the full duration of the study, or is not in the best interest of
 the subject to participate, in the opinion of the treating investigator
 15. Has a clinically significant cardiovascular disease such as unstable angina,
 myocardial infarction, or acute coronary syndrome, symptomatic or uncontrolled
 arrhythmia, congestive heart failure, baseline electrocardiogram (ECG) abnormalities,
 including, but not limited to, QTc prolongation to greater than 470 ms, or any Class
 III or IV cardiac disease as defined by the New York Heart Association Functional
 Classification
 16. Has overt or latent disorders of the exocrine pancreas (such as acute or chronic
 pancreatitis of any etiology) or chronic (including autoimmune) gastrointestinal
 disorders such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, lupus,
 scleroderma, Sjogren's syndrome, and polyarteritis nodosa
 17. Has a known psychiatric or substance abuse disorder(s) that would interfere with
 informed consent or cooperation with the requirements of the study
 18. Is pregnant or breastfeeding or expecting to conceive children within the projected
 duration of the study, starting with the screening visit through 90 days after the
 final administration of the study drug
 19. Is a first degree relative of the investigator, staff, or study sponsor.


Input:
Despite improvements in outcomes for patients with localized Ewing sarcoma, patients with
 relapsed metastatic Ewing sarcoma continue to have poor outcomes with current chemotherapy
 options. A large body of preclinical data supports a role for IGF-1R inhibition in the
 treatment of Ewing sarcoma.
 More recently, clinical trials of IGF-1R monoclonal antibodies have demonstrated single-
 agent activity in patients with relapsed Ewing sarcoma. Ganitumab (AMG 479) is a fully human
 monoclonal antibody directed against IGF-1R. We are proposing this single-agent expanded
 access IND to provide our patient the opportunity to benefit from this treatment after having
 developed progressive disease after multiple lines of prior therapy.
 ;
 ;
 Inclusion Criteria:
 Diagnosis: Confirmed translocation-positive Ewing sarcoma
 Organ Function Requirements:
 Serum creatinine < 1.4 Adequate liver function
 - Total bilitubin <1.5x upper limit of normal for age
 - SGPT (ALT) < 5x upper limit of normal for age Adequate cardiac function > 50% by
 echocardiogram Bone Marrow
 - Absolute neutrophil count > 750
 - Platelet count > 75
 Exclusion Criteria:
 - Female patients of childbearing potential are not eligible unless a negative pregnancy
 test result has been obtained. Lactating females are not eligible unless they have
 agreed not to breastfeed their infants for the duration of protocol therapy. Sexually
 active patients of reproductive potential are not eligible unless they have agreed to
 use an effective contraceptive method for the duration of protocol therapy.
 - Patients with known pre-existing diabetes mellitus will be excluded from study.


Input:
Patients entered into the study will receive ASTX727 orally up to 3 to 8 days prior to
 receiving Lutathera treatment to determine whether pre-treatment with ASTX727 results in
 re-expression of somatostatin receptor-2 in patients with metastatic neuroendocrine tumours.
 The study will use [68Ga]-DOTA-TATE PET to image epigenetic modification of the receptor
 locus.
 ;
 ;
 Inclusion criteria
 1. Be willing and able to provide written informed consent for the trial.
 2. Be aged 18 or over at the day of signing consent
 3. Histologic or cytologic confirmed diagnosis of neuroendocrine tumour
 4. Have archival tissue block available or willing to have fresh tissue biopsy if blocks
 not available
 5. Have disease that can be readily biopsied by ultrasound guidance (n=5)
 6. Ki67 < 55% (only patients with well differentiated grade 1-3 NETs will be included in
 the study as patients with poorly differentiated grade 3 NETs have a prognosis of less
 than 6 months)
 7. Progression or intolerance to first line therapy including somatostatin analogues
 8. ECOG Performance status 0 - 2
 9. No tumoural uptake on [68Ga]-DOTA-TATE or uptake less than background liver
 10. Measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated
 area are considered measurable if progression has been demonstrated in such lesions
 11. Adequate organ function as outlined in the protocol
 12. Women of childbearing potential must be willing to use a highly effective method of
 contraception as outlined in the protocol for the course of the study through 6 months
 after the last dose of Investigational Medicinal Product (IMP).
 Note: Abstinence is acceptable if this is the usual lifestyle and preferred
 contraception for the subjects
 13. Sexually active males must agree to use an adequate method of contraception as
 outlined in the protocol starting with the first dose of IMP through 6 months after
 the last dose of study therapy. Note: Abstinence is acceptable if this is the usual
 lifestyle and preferred contraception for the subject
 Exclusion criteria
 1. Previous treatment with either study medication and/or known hypersensitivity to the
 study medication
 2. Serious concurrent medical illness, including serious active infection
 3. History of organ transplant
 4. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is
 required unless mandated by local health authority.
 5. Has a known history of active Bacillus Tuberculosis (TB).
 6. Has known active CNS metastases and/or carcinomatous meningitis. Participants with
 previously treated brain metastases may participate provided they are radiologically
 stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
 (note that the repeat imaging should be performed during study screening), clinically
 stable and without requirement of steroid treatment for at least 14 days prior to
 first dose of study treatment.
 7. Bleeding or thrombotic disorders or subjects at risk for severe haemorrhage
 8. Is currently participating and receiving therapy or has participated or is
 participating in a study of an IMP or used an investigational device within 4 weeks of
 the first dose of IMP.
 9. Has a known additional malignancy that is progressing or requires active treatment.
 Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
 skin that has undergone potentially curative therapy or in situ cervical cancer.
 10. Has a history or current evidence of any condition, therapy, or laboratory abnormality
 that might confound the results of the trial, interfere with the subject's
 participation for the full duration of the trial, or is not in the best interest of
 the subject to participate, in the opinion of the treating Principal Investigator
 (PI).
 11. Has known psychiatric or substance abuse disorders that would interfere with
 cooperation with the requirements of the trial.
 12. Is pregnant or breastfeeding, or expecting to conceive or father children within the
 projected duration of the trial, starting with the screening visit through to 6 months
 after the last dose of IMP.
 13. Has received a live vaccine within 30 days of first dose of ASTX727 administration.
 Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
 and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
 attenuated vaccines, and are not allowed.
 14. Has received prior radiotherapy within 2 weeks of start of study treatment.
 Participants must have recovered from all radiation-related toxicities, not require
 corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
 for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease and
 stereotactic radiotherapy to the CNS
 15. Other clinically significant co-morbidities that could compromise the subject's
 participating in the study


Input:
The purpose of this study is to assess the feasibility, safety and efficacy of GD2/CD70
 bi-specific CAR-T cell therapy in patients with GD2 and/or CD70 positive tumor. Another goal
 of the study is to learn more about the function of the GD2/CD70 bi-specific CAR-T cells and
 their persistency in patients.
 ;
 ;
 Inclusion Criteria:
 1. Patients with tumors received standard first-line therapy and judged to be
 non-resectable, metastatic, progressive or recurrent.
 2. The expression status of GD2 or CD70 antigens in the tumor tissue will be determined
 for eligibility. Positive expression is defined by GD2 and PMSA antibody staining
 results based on immunohistochemistry or flow cytometry analyses.
 3. Body weight greater than or equal to 10 kg.
 4. Age: ≥1 year and ≤ 75 years of age at the time of enrollment.
 5. Life expectancy: at least 8 weeks.
 6. Prior Therapy:
 There is no limit to the number of prior treatment regimens. Any grade 3 or 4
 non-hematologic toxicity of any previous therapy must be resolved to grade 2 or less.
 7. Participant must not have received hematopoietic growth factors for at least 1 week
 prior to mononuclear cells collection.
 8. At least 7 days must have elapsed since the completion of therapy with a biologic
 agent, selected targeted agent or a metronomic non-myelosuppressive regimen.
 9. At least 4 weeks must have elapsed since prior therapy that included a monoclonal
 antibody.
 10. At least 1 week since any radiation therapy at the time of study entry.
 11. Karnofsky/jansky score of 60% or greater.
 12. Cardiac function: Left ventricular ejection fraction greater than or equal to 40/55
 percent.
 13. Pulse Ox greater than or equal to 90% on room air.
 14. Liver function: defined as alanine transaminase (ALT) <3x upper limit of normal (ULN),
 aspartate aminotransferase (AST) <3x ULN; serum bilirubin and alkaline phosphatase <2x
 ULN.
 15. Renal function: Patients must have serum creatinine less than 3 times upper limit of
 normal.
 16. Marrow function: White blood cell count ≥1000/ul, Absolute neutrophil count ≥500/ul,
 Absolute lymphocyte count ≥500/ul, Platelet count ≥25,000/ul (not achieved by
 transfusion).
 17. Patients with known bone marrow metastatic disease will be eligible for study as long
 as they meet hematologic function criteria, and the marrow disease does not have
 hematologic toxicity.
 18. For all patients enrolled in this study, themselves or their parents or legal
 guardians must sign an informed consent and assent.
 Exclusion Criteria:
 1. Existing severe illness (e.g. significant cardiac, pulmonary, hepatic diseases, etc.)
 or major organ dysfunction, or greater than grade 2 hematologic toxicity.
 2. Untreatable central nervous system (CNS) metastasis: Patients with previous CNS tumor
 involvement that has been treated and is stable for at least 6 weeks following
 completion of therapy are eligible.
 3. Previous treatment with other genetically engineered GD2 or CD70-specific CAR T cells.
 4. Active HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) infection or uncontrolled
 infection.
 5. Patients who require systemic corticosteroid or other immunosuppressive therapy.
 6. Evidence of tumor potentially causing airway obstruction.
 7. Inability to comply with protocol requirements.
 8. Insufficient CAR T cells availability.


Input:
This phase I/II trial studies the side effects and best dose of avelumab with M6620 in
 treating patients with deoxyribonucleic acid (DNA) damage repair (DDR) deficient solid tumors
 that have spread to other places in the body (metastatic) or cannot be removed by surgery
 (unresectable). DDR deficiency refers to a decrease in the ability of cells to respond to
 damaged DNA and to repair the damage, which can be caused by genetic mutations. Immunotherapy
 with monoclonal antibodies, such as avelumab, may help the body's immune system attack the
 cancer, and may interfere with the ability of tumor cells to grow and spread. M6620 may stop
 the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving
 avelumab together with M6620 may help to control DDR deficient metastatic or unresectable
 solid tumors.
 ;
 ;
 Inclusion Criteria:
 - Subjects must have histologically confirmed malignancy that is metastatic or
 unresectable and for which standard curative measures do not exist or are no longer
 effective
 - Subjects will be eligible for this study based on the presence of actionable
 aberrations in one or more of the following DNA damage response (DDR) genes: ARID1A,
 ATM, ATR, ATRX, BAP1, BARD1, BRCA1/2, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCD2,
 FANCE, FANCF, FANCM, MRE11A, MSH2, NBN (NBS1), PALB2, RAD51, RAD51C, RAD51D, SMARCB1,
 and VHL, 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. Variant interpretation for
 actionability will be performed by PODS
 - Subjects with germline defects in DDR genes are eligible for this trial
 - The collection of archival tumor tissue (within 1 year prior to study enrollment) will
 be mandatory. Tumor biopsies on cycle 1 day 15 will be mandatory. Subjects will not be
 put at undue risk to obtain the biopsy at cycle 1 day 15 (C1D15). A biopsy at C1D15
 will not be required if it poses a serious/severe complication risk greater than 2%.
 All other biopsy time points are not mandatory but will be strongly encouraged where
 feasible. These include at baseline and at disease progression. Archival and fresh
 tissue requests can be waived in exceptional circumstances with principal investigator
 (PI) approval and only where rationale is documented
 - Subjects must have received at least 1 line of systemic therapy in the
 advanced/metastatic setting. Subjects with diseases without known effective options,
 and subjects who had declined standard of care therapy prior to study introduction are
 also eligible
 - Subjects enrolling in the dose escalation should have progressed on or be intolerant
 to all therapies known to confer a clinical benefit. Subjects must not have refused
 all available therapies
 - Subjects who have received prior therapy with immune checkpoint inhibitors (ICIs) are
 eligible for this trial. Subjects with a standard-of-care option for an immune
 checkpoint inhibitor are eligible
 - Subjects must have measurable disease per Response Evaluation Criteria in Solid Tumors
 (RECIST) version (v) 1.1, or patients may have bone metastatic disease evaluable by
 Prostate Cancer Working Group 3 (PCWG3) for subjects with metastatic
 castration-resistant prostate cancer (CRPC), or according to tumor evaluation criteria
 best suited and accepted for the tumor type to be evaluated
 - Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1
 - Subjects must have a life expectancy >= 12 weeks
 - Absolute neutrophil count >= 1.5 x 10^9/L
 - Platelets >= 100 x 10^9/L
 - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
 - Total bilirubin =< 1.5 X the institutional upper limit of normal (ULN)
 - Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/
 alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) =< 2.5 X
 institutional ULN or =< 5 X institutional ULN in the presence of liver metastases
 - Serum creatinine =< 2 X ULN or estimated creatinine clearance >= 30 mL/min according
 to the Cockcroft-Gault formula
 - Female patients of childbearing potential must have a negative serum or urine
 pregnancy test at screening (and again at baseline just prior to first administration
 of study drugs)
 - Female patients of non-childbearing potential must meet at least 1 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;
 - Have undergone a documented hysterectomy and/or bilateral oophorectomy
 - Have medically confirmed ovarian failure All other female patients (including
 female patients with tubal ligation) are considered to be of childbearing
 potential
 - Women of childbearing potential and fertile men must agree to use adequate
 contraception when sexually active from signing of the informed consent form for the
 full study until at least 6 months after the last study drug administration. Patients
 must agree to utilize 2 reliable and acceptable methods of contraception
 simultaneously. A man is considered fertile after puberty unless permanently sterile
 by bilateral orchiectomy. Men taking part in this study are advised not to father a
 child during and up to 6 months after treatment; prior to treatment, advice should be
 sought for conserving sperm due to the chance of irreversible infertility as a
 consequence of treatment. Female partners of childbearing potential from male study
 patients have to use adequate contraception / birth control between signing of the
 informed consent and 6 months after the last administration of the study drug if the
 male study patient is not sterilized. The investigator or a designated associate is
 requested to advise the patient how to achieve highly effective birth control. Highly
 effective (failure rate of less than 1% per year) contraception methods, when used
 consistently and correctly, include:
 - Combined (estrogen and progestin containing: oral, intravaginal, transdermal) and
 progestin-only (oral, injectable, implantable) hormonal contraception associated
 with inhibition of ovulation
 - Intra-uterine device or intrauterine hormone-releasing system
 - Bilateral tubal occlusion or vasectomized partner (provided that partner is the
 sole sexual partner and has received medical assessment of the surgical success)
 - Sexual abstinence (reliability to be evaluated in relation to the duration of the
 clinical trial and the preferred and usual lifestyle of the patient) Male
 patients with a female partner of reproductive potential must use a condom and
 ensure that an additional form of contraception is also used during treatment and
 until 6 months after last study drug administration. Patients must agree to
 utilize 2 reliable and acceptable methods of contraception simultaneously
 - Evidence of a personally signed and dated informed consent document 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 procedures
 - Human immunodeficiency virus (HIV)-infected (HIV1/2 antibody-positive) patients may
 participate IF they meet all the following eligibility requirements:
 - They must be on an anti-retroviral regimen with evidence of at least two
 undetectable viral loads within the past 6 months on this same regimen; the most
 recent undetectable viral load must be within the past 12 weeks
 - They must have a CD4 count >= 250 cells/mcL over the past 6 months on this same
 anti-retroviral regimen and must not have had a CD4 count < 200 cells/ mcL over
 the past 2 years, unless it was deemed related to the cancer and/or
 chemotherapy-induced bone marrow suppression
 - For patients who have received chemotherapy in the past 6 months, a CD4
 count < 250 cells/mcL during chemotherapy is permitted as long as viral
 loads were undetectable during this same chemotherapy
 - They must have an undetectable viral load and a CD4 count >= 250 cells/mcL within
 7 days of enrolment
 - They must not be currently receiving prophylactic therapy for an opportunistic
 infection and must not have had an opportunistic infection within the past 6
 months
 Exclusion Criteria:
 - Anticancer systemic therapy or radiotherapy within 4 weeks or 5 half-lives, whichever
 is shorter prior to starting the study agents. Prior palliative radiotherapy to
 metastatic lesion(s) is permitted, provided it has been completed 2 weeks prior to
 study enrollment, and no clinically significant toxicities are expected (e.g.,
 mucositis, esophagitis)
 - Known symptomatic brain metastases requiring steroids. Patients with previously
 treated 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 4 weeks and are neurologically stable
 - Current use of immunosuppressive medication at the time of study enrollment, EXCEPT
 for the following permitted steroids:
 - Intranasal, inhaled, topical steroids, eye drops, or local steroid injection
 (e.g., intra-articular injection)
 - Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or
 equivalent
 - Steroids as premedication for hypersensitivity reactions (e.g. computed
 tomography [CT] scan premedication)
 - Subjects who had major surgery within 4 weeks prior to study enrollment
 - Known prior severe hypersensitivity to investigational products or any component in
 their formulations, including known severe hypersensitivity reactions to monoclonal
 antibodies (National Cancer Institute [NCI] Common Terminology Criteria for Adverse
 Events [CTCAE] version [v] 5 grade >= 3)
 - Active infection requiring systemic therapy
 - Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, and
 pulmonary fibrosis
 - Active or prior autoimmune disease that may deteriorate when receiving an
 immunostimulatory agent. Patients with type I diabetes, vitiligo, psoriasis, or hypo-
 or hyperthyroid disease not requiring immunosuppressive treatment are eligible
 - Prior organ transplantation including allogenic stem cell transplantation
 - Diagnosis of myelodysplastic syndrome (MDS)
 - Vaccination within 4 weeks of study enrollment and while on trial is prohibited except
 for the administration of inactivated vaccines
 - Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
 accident/stroke (< 6 month prior to enrollment), myocardial infarction (< 6 months
 prior to enrollment), unstable angina, congestive heart failure (>= New York Heart
 Association Classification class II) or a serious cardiac arrhythmia requiring
 medication
 - Other acute or chronic medical or psychiatric conditions including but not limited to
 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
 - Pregnant female patients, breastfeeding female patients, fertile male patients, and
 female patients of childbearing potential who are unwilling or unable to use 2 highly
 effective methods of contraception as outlined in this protocol for the duration of
 the study, and for at least 6 months after the last dose of study drug administration
 - Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
 HBV surface antigen or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test
 is positive)
 - Known additional malignancy that is active and/or progressive requiring treatment;
 exceptions include basal cell or squamous cell skin cancer, in situ bladder cancer, or
 other cancer for which the patient has been disease-free for >= 2 years
 - Persisting toxicity related to prior therapy (NCI CTCAE v5 grade > 1); however,
 alopecia and sensory neuropathy grade =< 2, or other grade =< 2 AEs not constituting a
 safety risk, based on the investigator's judgement, are acceptable
 - Subjects receiving treatment with strong inhibitors or inducers of CYP3A4 that cannot
 be discontinued before start of investigational treatment and for the duration of
 study
 - Subjects with ongoing toxicity (any grade) and/or resolved ICI toxicity (grade 3 or
 higher only)


Input:
HS-10376 is an oral, highly selective, small molecular inhibitor of EGFR/HER2 Exon 20
 insertion mutation. This study will evaluate the safety, tolerability, pharmacokinetics and
 clinical activity of HS-10376 in Chinese advanced Non-Small Cell Lung Cancer (NSCLC)
 patients.
 ;
 ;
 Inclusion Criteria:
 1. Men or women greater than or equal to 18 years
 2. Locally advanced or metastatic NSCLC patients confirmed by histology or cytology, for
 which standard treatment is invalid, unavailable or intolerable
 3. Pathological, tumor tissue samples can be used to test EGFR/HER2 Exon 20 insertion
 mutation by central laboratory for subjects
 4. At least one measurable lesion in accordance with RECIST 1.1
 5. Eastern Cooperative Oncology Group (ECOG) performance status: 0~1
 6. Estimated life expectancy >12 weeks
 7. Reproductive-age women agree to use adequate contraception and cannot breastfeed while
 participating in this study and for a period of 6 months after the last dose.
 Likewise, men also consent to use adequate contraceptive method within the same time
 limit.
 8. Females must have the evidence of non-childbearing potential
 9. Signed and dated Informed Consent Form
 Exclusion Criteria:
 1. Treatment with any of the following:
 - Previous or current treatment with EGFR Exon 20 insertion inhibitors, HER2 Exon
 20 insertion inhibitors or EGFR/HER2 Exon 20 insertion inhibitors
 - Any cytotoxic chemotherapy, anticancer Chinese medicine and targeted small
 molecule inhibitors within 14 days of the first dose of HS-10376
 - Any investigational agents and large molecule antibodies within 28 days of the
 first dose of HS-10376
 - Local radiotherapy for palliation within 2 weeks of the first dose of HS-10376,
 or patients received more than 30% of the bone marrow irradiation, or large-scale
 radiotherapy within 4 weeks of the first dose of HS-10376
 - Major surgery (including craniotomy, thoracotomy, or laparotomy, etc.) within 4
 weeks of the first dose of HS-10376
 2. Inadequate bone marrow reserve or serious organ dysfunction
 3. Uncontrolled pleural, ascites or pericardial effusion
 4. Untreated, symptomatic or active central nervous system metastases
 5. Severe or poorly controlled hypertension
 6. Immunodeficiency disease and active infectious disease
 7. Refractory nausea, vomiting, or chronic gastrointestinal diseases, or inability to
 swallow oral medications
 8. History of hypersensitivity to any active or inactive ingredient of HS-10376 or to
 drugs with a similar chemical structure or drugs belonging to the same category of
 HS-10376
 9. The subject who is unlikely to comply with study procedures, restrictions, or
 requirements judged by the investigator
 10. The subject whose safety cannot be ensured or study assessments would be interfered
 judged by the investigator
 11. Pregnant women, breastfeeding women or woman who has a child-bearing plan during the
 study
 12. History of neuropathy or mental disorders, including epilepsy and dementia


Input:
Expanded access requests for IFx-Hu2.0 may be considered for the treatment of adult patients
 (greater than or equal to 18 years of age) with stage III through IV cutaneous melanoma,
 advanced Merkel cell carcinoma (MCC), or advanced cutaneous squamous cell carcinoma (cSCC)
 who have failed all available treatment options.
 To request access, use Responsible Party contact information provided in this record..
 ;NA;
 Inclusion Criteria:
 - To request more information use Responsible Party contact information provided in this
 record
 Exclusion Criteria:
 - To request more information use Responsible Party contact information provided in this
 record


Input:
The purpose of this study is to assess the safety and efficacy of alpelisib plus fulvestrant
 in men and postmenopausal women with hormone receptor (HR) positive, human epidermal growth
 factor 2 (HER2)-negative, advanced breast cancer harboring a PIK3CA mutation in Japan, whose
 disease has progressed on or after aromatase inhibitor (AI) treatment regardless of prior
 CDK4/6 inhibitor use.
 ;
 ;
 Inclusion Criteria:
 - Japanese man or postmenopausal woman
 - Participant has adequate tumor tissue for the analysis of PIK3CA mutational status by
 a Novartis designated laboratory.
 - Participant has identified PIK3CA mutation (as determined by a Novartis designated
 laboratory)
 - Participant has a histologically and/or cytologically confirmed diagnosis of ER+
 and/or PgR+ breast cancer by local laboratory
 - Participant has HER2-negative breast cancer defined as a negative in situ
 hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ
 hybridization (FISH, CISH or SISH) test is required by local laboratory testing
 - Participant has measurable disease, i.e., at least one measurable lesion as per RECIST
 1.1
 - Participant has advanced breast cancer
 - Participant has ECOG performance status 0 or 1
 Exclusion Criteria:
 - Participant with symptomatic visceral disease or any disease burden that makes the
 participant ineligible for endocrine therapy per the investigator's best judgment
 - Participant has received prior treatment;
 - with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant, any
 PI3K, mTOR or AKT inhibitor for Cohort 1 and 3
 - with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant, any
 PI3K, mTOR, AKT inhibitor or CDK 4/6 inhibitor for Cohort 2
 - Participant has a known hypersensitivity to alpelisib or fulvestrant, or to any of the
 excipients of alpelisib or fulvestrant
 - Participant with inflammatory breast cancer at screening
 - Participant is concurrently using other anti-cancer therapy
 - Participant has had surgery within 14 days prior to starting study drug or has not
 recovered from major side effects
 - Participant with an established diagnosis at screening of diabetes mellitus type I or
 not controlled type II (based on FPG and HbA1c)
 - Participant has currently documented pneumonitis /interstitial lung disease
 - History of acute pancreatitis within 1 year of screening or past medical history of
 chronic pancreatitis
 - Participant with unresolved osteonecrosis of the jaw
 - Participant has a history of severe cutaneous reactions
 Other protocol-defined inclusion/exclusion criteria may apply

PIK3CA mutation
ER positive
HER2 negative

PIK3CA mutation
PgR positive
HER2 negative


Input:
BioEXALK is a prospective study evaluating the biological characteristics of advanced
 ALK-rearranged NSCLC treated with next generation TKIs in first line, included in the
 national EXPLORE ALK cohort (GFPC 03-2019), a non-interventional, national, multi-center
 cohort of ALK-rearranged NSCLC patients.
 BioExALK study will be proposed to every patient included in the Explore ALK GFPC 03-2019
 study.
 Biological analysis will be performed on tumor tissue at diagnosis and at the time of disease
 progression when available and on circulating tumor DNA (ctDNA).
 For plasma testing, after obtained patient consent, blood samples will be taken and analyzed
 at the Léon Bérard Center (Lyon).
 Biological analysis on tissue obtained at diagnosis and at disease progression will be
 collected and be sent for centralized analysis to the Rouen University Hospital.
 ;
 ;
 Inclusion Criteria:
 - Stage IIIB/IV NSCLC non eligible to locoregional treatment with curative intent
 - ALK rearrangement confirmed by IHC and/or FISH or NGS according to local methods
 - Patient included in the EXPLORE ALK study
 - Age > or = 18 years
 - Patient treated with first-line new generation ALKi
 - Patient agrees to sign an informed consent form and to collect blood samples at
 inclusion, first tumor evaluation and progression and for whom tumor biopsy at
 diagnosis is available
 - Patient enrolled in the french National Health Insurance program or with a third-
 party payer
 Exclusion Criteria:
 - Patients who do not wish to participate in Bioexalk
 - Patients under guardianship


Input:
The MyDRUG study is a type of Precision Medicine trial to treat patients with drugs targeted
 to affect specific genes that are mutated as part of the disease. Mutations in genes can lead
 to uncontrolled cell growth and cancer. Patients with a greater than 25% mutation to any of
 the following genes; CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, IDH2 or T(11;14) can be enrolled
 to one of the treatment arms. These arms have treatments specifically directed to the mutated
 genes. Patients that do not have a greater than 25% mutation to the genes listed can be
 enrolled to a non-actionable treatment arm.
 The genetic sequencing of the patient's tumor is required via enrollment to the MMRF002
 study: Clinical-grade Molecular Profiling of Patients with Multiple Myeloma and Related
 Plasma Cell Malignancies. (NCT02884102).
 ;
 ;
 Inclusion Criteria:
 - Willing to be registered into the pomalidomide (POMALYST®) Risk Evaluation and
 Mitigation Strategy (REMS®) program
 - Enrolled in the MMRF002 Molecular Profiling Protocol (NCT02884102) with report less
 than 120 days old
 - Disease free of prior malignancies for ≥ 3 years with exception of currently treated
 basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or
 breast, or prostate cancer not requiring therapy
 - High risk patients with relapsed refractory multiple myeloma (RRMM), who have:
 - received at least one prior but no more than 3 prior therapies
 - exposed to both a PI and an IMiD
 - had early relapse after initial treatment Early relapse as defined by at least
 one of the following: (Relapse is defined as the IMWG uniform response)
 1. Relapse within 3 years of initiation of induction chemo therapy for post
 autologous stem cell transplantation (ASCT) followed by maintenance, or 18
 months if unmaintained after ASCT
 2. Within 18 months of initial non-ASCT based therapy
 - Patients must have progressed after their most recent treatment and require therapy
 for myeloma
 - Females of reproductive potential must have a negative pregnancy test at baseline, be
 non-lactating, and willing to adhere to scheduled pregnancy testing
 - Females of reproductive potential and males must practice and acceptable method of
 birth control
 - Laboratory values obtained ≤ 14 days prior to registration:
 - Absolute neutrophil count (ANC) ≥ 1000/ul
 - Hemoglobin (Hgb) ≥ 8 g/dl
 - Platelet (PLT) ≥ 75,000/ul
 - Total bilirubin <1.5 x upper limit of normal (ULN) or if total bilirubin is >1.5
 x ULN, the direct bilirubin must be ≤ 2.0 mg/dL
 - Aspartate aminotransferase (AST) <3 x ULN
 - Creatinine Clearance ≥ 30 mL/min
 Measurable disease of Multiple Myeloma (MM) as defined by at least one of the following:
 - Serum monoclonal protein ≥ 0.5 g by protein electrophoresis
 - ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
 - Serum immunoglobulin free light chain (FLC) ≥10 mg/dL AND abnormal serum
 immunoglobulin kappa to lambda FLC ratio
 - Monoclonal bone marrow plasmacytosis ≥30% (evaluable disease)
 - Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2
 - Ability to take aspirin, warfarin, or low molecular weight heparin
 Sub-Protocol Inclusion Criteria:
 Refer to each respective Sub Protocol for additional inclusion criteria.
 Exclusion Criteria:
 Patients will be ineligible for this study if they meet any one of the following criteria:
 - Aggressive multiple myeloma requiring immediate treatment as defined by:
 - Lactate dehydrogenase (LDH) > 2 times ULN
 - Presence of symptomatic extramedullary disease or central nervous system
 involvement
 - Hypercalcemia >11.5 mg/dl
 - Acute worsening of renal function (CrCl < 30 ml/min) directly related to myeloma
 relapse
 - Any neurological emergency related to myeloma
 - Clinical symptoms of hyperviscosity related to monoclonal protein
 - Involved serum free light chain > 100 mg/dL (1000 mg/L) in the setting of prior
 diagnosis of cast nephropathy
 - Infection requiring systemic antibiotic therapy or other serious infection within 14
 days of enrolment
 - Known hypersensitivity or development of erythema nodosum if characterized by a
 desquamating rash while taking thalidomide, lenalidomide, pomalidomide or similar
 drug. Known allergy to any of the study medications, their analogues, or excipients in
 the various formulations of the agents
 - Prior Ixazomib/Pomalidomide/Dexamethasone combination therapy
 - Pregnant or breast-feeding females
 - Serious medical or psychiatric illness, active alcoholism, or drug addiction that may
 hinder or confuse compliance, interfere in the completion of treatment per protocol,
 or follow-up evaluation
 - Active hepatitis A, B or C viral infection or known human immunodeficiency virus (HIV)
 infection
 - Concurrent symptomatic amyloidosis or plasma cell leukemia
 - POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly,
 endocrinopathy, monoclonal protein (M-protein) and skin changes]
 - Residual side effects to previous therapy > Grade 1 prior to initiation of therapy
 (Alopecia any grade and/or neuropathy Grade 2 without pain are permitted)
 - Prior allogeneic or ASCT within 12 weeks of initiation of therapy. Prior allogeneic
 stem cell transplant with active graft-versus-host disease (GVHD)
 - Prior experimental therapy within 14 days of protocol treatment or 5 half-lives of the
 investigational drug, whichever is longer
 - Prior anticancer therapy within 14 days of initiation of protocol therapy
 (Dexamethasone/ 40mg/day) for a maximum of 4 days before screening is allowed
 - Prior major surgical procedure or radiation therapy within 4 weeks of the initiation
 of therapy (this does not include limited course of radiation used for management of
 bone pain within 7 days of initiation of therapy).
 - Known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that
 limit the ingestion or Gastro Intestinal (GI) absorption of drugs administered orally
 - Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
 hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
 unstable angina, or myocardial infarction within the past 6 months
 - Other co-morbidity, which would interfere with patient's ability to participate in
 trial or that confounds the ability to interpret data from the study
 Sub-Protocol Exclusion Criteria:
 Refer to each respective Sub Protocol for additional exclusion criteria.


Input:
This phase II trial studies the effect of larotrectinib in treating patients with NTRK gene
 amplification positive solid tumors that have spread to nearby tissues or lymph nodes
 (locally advanced) or other places in the body (metastatic). Larotrectinib may stop the
 growth of tumor cells by blocking some of the enzymes needed for cell growth.
 ;
 ;
 Inclusion Criteria:
 - At least 16 years of age
 - Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene
 amplification identified through molecular assays (such as IHC and any next-generation
 sequencing [NGS] platform, reference lab NGS, or in house NGS platform) as routinely
 performed at The University of Texas MD Anderson Cancer Center or other
 similarly-certified laboratories. The minimum level of amplification is 7 copies. This
 rationale of amplification level is based on data from MOCLIA at The University of
 Texas MD Anderson Cancer Center
 - Must have received prior standard therapy appropriate for tumor type and stage of
 disease, or, in the opinion of the investigator, is unlikely to tolerate or derive
 clinically meaningful benefit from appropriate standard of care therapy
 - Must have at least one measurable lesion as defined by RECIST v1.1. Subjects with
 primary CNS tumors should meet the following criteria:
 - Must have received prior treatment including radiation and/or chemotherapy, with
 radiation completed > 12 weeks prior to cycle 1 day 1 (C1D1) of therapy, as
 recommended or appropriate for the tumor type
 - Must have >= 1 site of bi-dimensionally measurable disease (confirmed by magnetic
 resonance imaging [MRI] and evaluable by RANO), with the size of at least one of
 the measurable lesions >= 1 cm in each dimension
 - Must have imaging study within 28 days before enrollment. If on steroid therapy,
 the dose must be stable for at least five days immediately before and during the
 imaging study
 - Eastern Cooperative Oncology Group (ECOG) score =< 3. If enrolled with primary CNS
 tumor to be assessed by RANO, Karnofsky performance score (KPS) >= 70 %
 - Archived tumor tissue. If archival tissue is unavailable, an on-study tumor biopsy
 should be attempted if it can be safely performed
 - Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) < 2.5
 x upper limit of normal (ULN) or < 5 x ULN if liver function abnormalities are due to
 underlying malignancy
 - Total bilirubin < 2.5 x ULN, except in cases of biliary obstruction. Subjects with a
 known history of Gilberts disease and an isolated elevation of indirect bilirubin are
 eligible
 - Serum creatinine < 2.0 x ULN or estimated glomerular filtration rate >= 30 mL/minute
 using the Cockcroft-Gault formula
 - Ability to comply with outpatient treatment, laboratory monitoring, and required
 clinic visits for the duration of study participation
 - Willingness of men and women of reproductive potential to use two effective birth
 control methods, one used by the subject and another by his/her partner, for the
 duration of treatment and for 3 months following study completion
 Exclusion Criteria:
 - Investigational agent or anticancer therapy within 2 weeks prior to the planned start
 of larotrectinib or five half-lives, whichever is shorter, and without clinically
 significant toxicities from that therapy
 - Prior progression while receiving approved or investigational tyrosine kinase
 inhibitors targeting TRK. However, subjects who received less than 28 days of such
 treatment and discontinued because of intolerance or toxicity are eligible
 - Symptomatic or unstable brain metastases that needs corticosteroid usage. Subjects
 with asymptomatic brain metastases or primary CNS tumors are eligible
 - Uncontrolled concurrent malignancy that would limit assessment of efficacy. Allowed
 diseases may include, but are not limited to in situ cancers of cervix, breast, or
 skin, superficial bladder cancer, limited-stage prostate cancer, and basal or squamous
 cancers of the skin
 - Active uncontrolled systemic bacterial, viral, or fungal infection, unstable
 cardiovascular disease or other systemic disease that would limit compliance with
 study procedures. Unstable cardiovascular disease is defined as:
 - Persistently uncontrolled hypertension defined as systolic blood pressure (BP) >
 150 mmHg and/or diastolic BP > 100 mmHg despite antihypertensive therapy
 - Myocardial infarction within 3 months of screening
 - Stroke within 3 months of screening
 - Inability to discontinue treatment with a strong cytochrome P450 (CYP450), 3A4
 (CYP3A4) inhibitor or inducer prior to start of treatment
 - Pregnancy or lactation


Input:
In this study, the purpose of this study is to investigate whether prophylactic medical
 compression therapy in breast cancer patients receiving docetaxel adjuvant chemotherapy could
 reduce the incidence and severity of lymphedema in the upper limbs that received axillary
 lymph node resection (sentinel lymph node biopsy or axillary lymph node dissection).
 ;NA;
 Inclusion Criteria:
 1. Patients who underwent radical mastectomy and sentinel lymphctomy or axillary
 lymphectomy after diagnosis of unilateral breast cancer
 2. Patients who are scheduled for adjuvant chemotherapy including Docetaxel after surgery
 3. Patients aged 19 to 70
 4. Patients who can understand the contents of this study and obtain consent
 Exclusion Criteria:
 1. Patients with a history of breast-related surgery prior to this breast cancer surgery
 2. Patients with metastases to other organs
 3. Patients who have undergone neoadjuvant chemotherapy or have previously received
 radiation therapy
 4. Patients with systemic diseases that may not be able to conduct clinical research
 5. Patients with skin diseases who cannot receive medical compression treatment


Input:
This is a prospective single arm, multi-center, phase II clinical trial to observe the
 efficacy and safety of VR-CAP (Bortezomib and Rituximab-Cyclophosphamide, Epirubicin and
 Prednisone) in the first-line treatment for patients with marginal zone lymphoma.
 ;
 ;
 Inclusion Criteria:
 1. Age between 18 to 70 years old (including 18 and 70)
 2. Diagnosed as marginal zone lymphoma
 3. No receiving chemotherapy before enrollment
 4. Indications for treatment: 1) symptoms related to tumor; 2) end-organ function damage;
 3) large mass; 4) continuous or rapid progress of disease; 5) patient's willingness
 5. Having at least one measurable lesions
 6. World health organization-Eastern Cooperative Oncology Group Performance tatus (ECOG)
 0-1
 7. Life expectancy no less than 3 months
 8. enough main organ function
 9. Pregnancy test within 7 days must be negative for women of childbearing period, and
 appropriate measures should be taken for contraception for women in childbearing
 period during the study and six months after this study
 10. Agreeing to sign the written informed consents
 Exclusion Criteria:
 1. Diagnosed as central nervous system lymphoma
 2. World health organization-Eastern Cooperative Oncology Group Performance tatus (ECOG)
 ≥2
 3. Other malignant tumor history or active malignant tumor need be treated
 4. Serious surgery and trauma less than two weeks
 5. Systemic therapy for serious acute/chronic infection
 6. Congestive heart failure, uncontrolled coronary heart disease, arrhythmia and heart
 infarction less than 6 months
 7. Active tuberculosis. Patients suspected of active TB need to be examined for chest
 X-ray, sputum and clinical symptoms and signs
 8. HIV-positive, AIDS patients and untreated active hepatitis（HBV/HBV and HCV）
 9. Patients with a history of deep vein thrombosis or pulmonary embolism less than 12
 months
 10. Patients with a history of mental illness
 11. Researchers determine unsuited to participate in this trial


Input:
The study comprises two phases: Phase 1a and Phase 1b. The purpose of the study is to observe
 the safety， tolerability and efficacy of FS-1502.
 ;
 ;
 Inclusion Criteria:
 1. Age ≥18 years at the time of study registration (men and women eligible);
 2. Phase Ia dose-escalation study:
 Patients with HER2-expressing advanced malignant solid tumors who had failed to
 standard therapy(including surgery, chemotherapy, radiation therapy or biotherapy) ,
 or can not receive standard therapy, or no standard therapy is available.
 1. HER2 expression: IHC3+, IHC2+/FISH+
 2. HER2 expression: IHC1+, IHC2+/FISH-
 Phase Ib dose-expanded study:
 Histologically or cytologically confirmed HER2-positive patients with advanced breast
 cancer who had previously received at least 2 line therapy and had failed anti-HER2
 therapy. Details as follows:
 1. HER2 positive (defined as IHC3+ or IHC2+/FISH+);
 2. For patients with advanced breast cancer who had previously failed anti-HER2
 therapy and had received at least 2-line therapy, postoperative adjuvant therapy
 which could be considered as a treatment line number if disease progression
 during treatment and within 12 months after completion of treatment.
 3. Provide evidence of disease progression or intolerable toxicity as confirmed by
 the investigator or medical history recorded prior to enrollment.
 4. The enrollment can be based on written HER2 test report from certified local lab,
 and if patients had no HER2 test report, they should provide sufficient paraffin
 sections or fresh tumor tissue specimens which should be sent to the local lab or
 the central laboratory for testing and confirmation.
 Pivotal clinical study:
 Patients with locally advanced or relapsed metastatic breast cancer who have been
 histologically or cytologically confirmed to be HER2-positive and who have received
 two or more lines of anti-HER2 therapy in the past. Details as follows:
 1. Her2-positive patients: Patients with IHC3+ or IHC2+ and FISH positive patients
 should provide enough tumor tissue samples within 5 years for the central
 laboratory to confirm HER2 status. Patients with HER2-positive patients are
 considered to be eligible for inclusion in this study; If the specimens provided
 are undetectable or are not available, a positive HER2 test from a local
 laboratory approved by the NMPA may be reported for entrainment.
 2. Previous treatment with two or more lines of anti-HER2 therapy, neoadjuvant
 therapy or adjuvant therapy can be used as a treatment line number if the disease
 progresses during or within 12 months after treatment.
 3. Evidence of investigator-confirmed or documented disease progression or
 intolerance of toxicity prior to enrollment.
 3. The ECOG performance status must be 0 or 1.
 4. Expected survival for at least 12 weeks.
 5. Has adequate organ and bone marrow function: absolute neutrophil count (ANC) ≥
 1.0x1E9/L(without colony stimulating factor within 7 days); hemoglobin ≥ 90g/L
 (without red blood cell infusion within 14 days); platelet count ≥ 100x1E9/L(without
 thrombopoietin or thrombopoietin receptor agonists within 7 days nor platelet infusion
 within 14 days); Total bilirubin ≤ 1.5x upper limit normal (ULN), or ≤ 3x ULN if with
 Gilbert syndrome; aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
 ≤ 2.5x ULN; AST and ALT ≤ 5x ULN if liver metastasis; Serum creatinine < 1.5x ULN and
 creatinine clearance ≥ 50mL/min (Cockroft-Gault formula calculation); Serum potassium
 ≥3.5 mmol/L；albumin ≥ 3g/dL; left ventricular ejection fraction (LVEF) >50%；urinary
 protein ≤1+ or 24-hour urinary protein dose < 1.0g.
 6. Has at least one non-intracranial measurable lesion by RECIST version 1.1.
 7. Male or female patients with fertility must agree to use effective contraceptive
 methods during the study period and within 3 months of the last dose of study therapy,
 such as dual barrier contraceptive methods, condoms, oral or injectable
 contraceptives, and intrauterine devices.
 8. Ability to understand and voluntarily sign written informed consent.
 Exclusion Criteria:
 1. Patients who received chemotherapy, targeted therapy, radiotherapy, etc., 14 days or
 within 5 half-lives periods, whichever is shorter, prior to the start of dosing.
 Patients who received major surgery, tumor immunotherapy, or monoclonal antitumor
 therapy within 4 weeks prior to the start of dosing.
 2. Patients who have participated in other clinical trials 4 weeks before the start of
 study drug administration or within 5 half-lives periods, whichever is shorter.
 3. Patients previously treated with anti-HER2 ADC drugs.
 4. Patients with central nervous system metastasis.
 5. Clinically uncontrolled mass pleural effusion, pericardial effusion, or abdominal
 effusion (2 weeks before first administration).
 6. Non-recovery of toxic effects from previous antitumor therapy (> NCI-CTCAE 5.0 grade
 1) alopecia, neurotoxicity, or other toxicity that had become chronic as assessed by
 the investigator and did not affect the safety of the investigational medication was
 admitted to NCI-CTCAE 5.0 grade 2 or below.
 7. Patients with corneal epitheliopathy (other than mild punctiform keratopathy or
 existing eye diseases affecting the evaluation of ocular toxicity after trial
 administration) or who were unwilling to stop wearing contact lenses during the study.
 8. Patients take medications that prolong the QTc interval (mainly Ia, Ic, Class III
 antiarrhythmic drugs) or have risk factors that prolong the QTc interval, such as
 uncorrectable hypokalemia, hereditary long QT syndrome;
 9. Cardiac function and disease conform to one of the following conditions:
 1. Three 12-lead electrocardiogram (ECG) measurements were performed at the research
 center during the screening period, and three mean values were calculated
 according to the QTc formula adopted by the instrument, QTc > 470 ms;
 2. New York Heart Association (NYHA)Grade ≥ 2 for congestive heart failure;
 3. arrhythmia of clinical significance grade ≥ 2.
 4. History of myocardial infarction or severe arteriovenous thrombosis within 6
 months.
 10. Pregnant or lactating women;
 11. Known allergy to any excipients of FS-1502;
 12. Active infections requiring systemic treatment;
 13. Persons with active hepatitis B (HBV surface antigen positive with HBV DNA exceeding
 1000 IU/ml or meeting the research Center criteria for diagnosis of active hepatitis B
 infection) or hepatitis C (HCV RNA positive), human immunodeficiency virus infection
 (HIV positive);
 14. Had been diagnosed with any other malignancies within the 5 years prior to study
 participation, other than early malignancies that have undergone radical treatment
 (carcinoma in situ), such as adequately treated basal or squamous cell skin cancers or
 carcinoma in situ of the cervix;
 15. Any other clinically significant disease or condition that the investigator believes
 may affect protocol compliance or affect the patient's signing of the ICF.


Input:
This is an open-label, multicenter, dose-escalation and parallel-group expansion Phase II
 clinical trial to evaluate the efficacy, safety and tolerability of KN026 in combination with
 palbociclib and fulvestrant in women or male with HER2-positive metastatic breast cancer .The
 subjects will receive 20 mg/kg IV Q2W+ palbociclib 100/125 mg/day orally+/-Fulvestrant 500 mg
 IM until progressive disease, unacceptable toxicity or death.
 ;
 ;
 Inclusion Criteria:
 - Male or female subject >= 18 years;
 - Histologically or cytologically confirmed, metastatic or locally advanced unresectable
 HER2-positive;
 - Adequate organ function assessed within 7 days prior to first trial treatment
 - ECOG score 0 or 1;
 - Left ventricular ejection fraction (LVEF) ≥ 50% at baseline;
 - Life expectancy >3 months
 Exclusion Criteria:
 - Untreated active CNS metastasis or leptomeningeal metastasis;
 - Uncontrolled tumor-related pain;
 - Has received other anti-tumor treatment or an investigational drug within 28 days or
 within 5 times of half-life (whichever is shorter, and no less than 2 weeks) prior to
 the first trial treatment;
 - Major surgery for any reason within 28 days;
 - Curative radiation within 3 months of the first dose of trial treatment;
 - History of uncontrolled intercurrent illness;
 - Other medical conditions that at the discretion of investigator interfere with the
 requirements of the trial in terms of safety or efficacy evaluation, or treatment
 compliance


Input:
The purpose of this study is to determine the Predictive value of a SNP signature and liquid
 biopsy in patients with natural killer T-cell lymphoma.
 ;NA;
 Inclusion Criteria:
 - biopsy proved Natural Killer T-cell Lymphoma
 - newly diagnosed patients
 Exclusion Criteria:
 - patients with biopsy samples unavailable


Input:
Talazoparib has shown clinical efficacy in breast cancer patients with germline BRCA1 or
 BRCA2 mutations. Beyond BRCA1 and BRCA2 mutations, it is plausible that talazoparib may have
 activity in patients with homologous recombination defects (HRD).
 ;
 ;
 Inclusion Criteria:
 1. Adults ≥19 years old.
 2. Pathologically documented breast cancer that is unresectable or metastatic
 3. Tumor with homologous recombination deficiency (HRD) defined by
 - Germline or Somatic BRCA1/2 mutation
 - Homologous recombination repair (HRR) genes mutation
 - HRD detected through RAD51 foci formation functional assay
 - HRR genes: ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B,
 RAD51C, RAD51D, and RAD54L
 4. Previously treated with a taxane, unless this treatment was contraindicated (whether
 in recurrent/metastatic setting or in neoadjuvant/adjuvant setting).
 5. Previous treatment with platinum therapy in the advanced or metastatic setting is
 permitted, provided the patient did not have a progression during the platinum
 treatment. If the patient was treated with neoadjuvant or adjuvant platinum therapy,
 at least 6 months of disease-free interval is required after the last dose.
 6. Documented radiologic progression (during or after most recent treatment or within 6
 months after completing adjuvant therapy).
 - If the patients had relapsed within 6 months after adjuvant therapy, this will be
 counted as a systemic chemotherapy for advanced or metastatic disease.
 7. At least 3 weeks has passed since last chemotherapy treatment
 8. At least 2 weeks has passed since last hormone therapy or radiation therapy (including
 palliative radiation).
 9. Eastern Cooperative Oncology Group (ECOG) performance status of 0, or 1
 10. At least one measurable lesion that can be accurately assessed at baseline by computed
 tomography (CT) (magnetic resonance imaging [MRI] where CT is not feasible) and is
 suitable for repeated assessment as per RECIST v.1.1.
 11. Male and female subjects of reproductive/childbearing potential must agree to use a
 highly effective form of contraception or avoid intercourse during and upon completion
 of the study and for at least 7.0 months after the last dose of study treatment.
 - This study recommend "Copper T intrauterine device" as a highly effective methods of
 contraception (<1% failure rate)
 12. Adequate normal organ and marrow function measured within 28 days prior to
 administration of study treatment
 - Hemoglobin ≥9.0 g/dL
 - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
 - Platelet count ≥ 75 x 109/L
 - Serum bilirubin ≤ 2.0mg/dL [This will not apply to patients with confirmed
 Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is
 predominantly unconjugated in the absence of hemolysis or hepatic pathology), who
 will be allowed only in consultation with their physician.]
 - AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver
 metastases are present, in which case it must be ≤5x ULN
 - Adequate renal function: Serum creatinine ≤1.5mg/dL or estimated creatinine
 clearance >60 mL/min
 13. Negative urine pregnancy test within 7 days prior to registration in premenopausal
 patients.
 14. Ability to understand and comply with protocol during study period
 15. Patients should sign a written informed consent before study entry
 Exclusion Criteria:
 1. Prior treatment PARP inhibitor
 2. However, if the patient participated in a clinical trial evaluating adjuvant PARP
 inhibitor, patient is allowed to be included in the present study if the patient
 recurred 6 months after completing PARP inhibitor. No more than three line of previous
 systemic chemotherapy, excluding neo-adjuvant and adjuvant chemotherapy. (No
 limitation on hormone therapy. Hormone therapy is not counted as previous line)
 3. If there is a standard treatment available for metastatic breast cancer.
 4. History of another primary malignancy except for
 - Malignancy treated with curative intent and with no known active disease ≥3 years
 - contralateral breast cancer
 - Adequately treated non-melanoma skin cancer or lentigo malignancy without
 evidence of disease
 - Adequately treated carcinoma in situ without evidence of disease
 5. Patients with GI tract disease resulting in an inability to take oral medication,
 malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures
 affecting absorption, uncontrolled GI disease (e.g., Crohn's disease, ulcerative
 colitis)
 6. History of leptomeningeal carcinomatosis
 7. Brain metastases or spinal cord compression.
 - Patients with symptomatic uncontrolled brain metastases. A scan to confirm the
 absence of brain metastases is not required. The patient can receive a stable dose of
 corticosteroids before and during the study as long as these were started at least 4
 weeks prior to treatment. Patients with spinal cord compression unless considered to
 have received definitive treatment for this and evidence of clinically stable disease
 for 28 days
 8. active infection or immunocompromised patients including tuberculosis (clinical
 evaluation that includes clinical history, physical examination and radiographic
 findings, and TB testing in line with local practice), hepatitis B , hepatitis C, or
 human immunodeficiency virus (positive HIV 1/2 antibodies).
 - Subjects with simple HBV carrier, a past or resolved HBV infection (defined as the
 presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.
 Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
 reaction is negative for HCV RNA.
 9. Patients who have a known immediate or delayed hypersensitivity reaction or
 idiosyncrasy to drugs chemically related to any of the study agents or their
 excipients.
 10. Female patients who are pregnant or breastfeeding.
 11. Judgment by the investigator that the patient is unsuitable to participate in the
 study and the patient is unlikely to comply with study procedures, restrictions and
 requirements.


Input:
This phase II trial studies how well olaparib works in treating patients with bladder cancer
 and other genitourinary tumors with deoxyribonucleic acid (DNA)-repair defects that has
 spread to other places in the body (advanced or metastatic) and usually cannot be cured or
 controlled with treatment. PARPs are proteins that help repair DNA mutations. PARP
 inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair
 themselves, and they may stop growing.
 ;
 ;
 Inclusion Criteria:
 - Patients must have a histologically confirmed diagnosis non-prostate GU cancer
 - Patients must have Clinical Laboratory Improvement Act (CLIA) testing and fit one of
 the following groups:
 - Confirmed presence of a cancer-associated alteration considered pathogenic/likely
 pathogenic by FM and/or the Genetics Review Panel in one or more of the following
 genes: BRCA1, BRCA2, ATM, BAP1, MSH2, PALB2, and BRIP1 or in one or more of the
 DNA-repair genes tested in the FoundationOne FoundationOneCDx (F1CDx) panel
 including the following genes (Foundation One mutation analysis results performed
 prior to enrollment on this study may be accepted for eligibility review and in
 the event that a patient cannot undergo a biopsy and tumor is not available,
 Foundation Medicine liquid biopsy may be performed): ABL1, ATR, ATRX, BARD1,
 BRD4, CCND1, CHEK1, CHEK2, DOT1L, FANCC, FANCE, FANCG, FANCL, IKBKE, MEN1, MLH1,
 MSH2, MSH6, MUTYH, NPM1, PMS2, POLD1, POLE, RAD51, SMARCB1, STK11, TP53
 - Note: FoundationOneCDx (F1CDx) is a next generation sequencing based in
 vitro diagnostic device for detection of substitutions, insertion and
 deletion alterations (indels), and copy number alterations (CNAs) in 324
 genes and select gene rearrangements, as well as genomic signatures
 including microsatellite instability (MSI) and tumor mutational burden (TMB)
 using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue
 specimens
 - Patients with benign or variants of unknown significance as determined by
 FoundationOne FoundationOneCDx (F1CDx) panel and Genetics Review Panel review
 will be included to be followed for survival
 - Patients must have measurable disease, defined as at least one lesion that can be
 accurately measured in at least one dimension (longest diameter to be recorded for
 non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
 x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
 imaging (MRI), or calipers by clinical exam
 - Evidence of disease progression as defined by Response Evaluation Criteria in Solid
 Tumors (RECIST) (version 1.1) during treatment or after the most recent dose of
 therapy with at least one platinum-based regimen of chemotherapy and/or an
 immune-checkpoint inhibitor (atezolizumab, pembrolizumab, nivolumab, avelumab or
 durvalumab) (2-week washout from chemotherapy and 4-weeks washout from monoclonal
 antibodies is required)
 - Age >= 18 years. Because no dosing or adverse event data are currently available on
 the use of olaparib in patients < 18 years of age, children are excluded from this
 study, but will be eligible for future pediatric trials
 - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (or Karnofsky >=
 70%)
 - Leukocytes >= 3,000/mcL
 - Absolute neutrophil count >= 1,500/mcL
 - Platelets >= 100,000/mcL
 - Total bilirubin =< 1.5 x upper limit of normal (ULN) (for subjects with documented
 Gilbert's disease total bilirubin =< 3.0 mg/dL)
 - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 2.5 x institutional upper limit of normal (for subjects with liver metastasis
 AST/ALT =< 5 x ULN)
 - Creatinine clearance >= 50 mL/min/1.73 m^2
 - Hemoglobin >= 10 g/dL; transfusions are allowed
 - Prothrombin time (PT)/international normalized ratio (INR) and activated partial
 thromboplastin time (aPTT) within 1.25 x ULN institutional limits, except where a
 lupus anti-coagulant has been confirmed or the patient is on direct oral anticoagulant
 (DOA)
 - Patients must be able to tolerate oral medications and not have gastrointestinal
 illnesses that would preclude absorption of olaparib
 - Pre-clinical data indicate that olaparib adversely affects embryofetal survival and
 development. Therefore, women of child-bearing potential and their partners should
 agree to use two (2) highly effective forms of contraception throughout study
 participation and for at least one (1) month after the last dose of olaparib. Male
 study participants should avoid fathering a child or donating sperm during the study
 and for three (3) months after the last dose of olaparib.
 - Note: Olaparib is a PARP inhibitor with the potential for teratogenic or
 abortifacient effects. Because there is a potential risk for adverse events in
 nursing infants secondary to treatment of the mother with olaparib, breastfeeding
 should be discontinued if the mother is treated with olaparib
 - Ability to understand and the willingness to sign a written informed consent document
 or patients with impaired decision making capacity (IDMC) if they are represented by a
 legally authorized representative (LAR)
 - Patients must provide archival tumor sample for mutation analysis or be willing to
 undergo mandatory screening biopsy. In the event that the patient cannot undergo
 biopsy and tumor is not available, Foundation Medicine liquid biopsy will be performed
 - Postmenopausal or evidence of non-childbearing status for women of childbearing
 potential: negative urine or serum pregnancy test within 28 days of study treatment
 and confirmed prior to treatment on day 1. Postmenopausal is defined as:
 - Amenorrheic for 1 year or more following cessation of exogenous hormonal
 treatments
 - Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the
 post menopausal range for women under 50
 - Radiation-induced oophorectomy with last menses > 1 year ago
 - Chemotherapy-induced menopause with > 1 year interval since last menses
 - Surgical sterilization (bilateral oophorectomy or hysterectomy)
 - Patients is willing and able to comply with the protocol for the duration of the study
 including undergoing treatment and scheduled visits and examinations
 Exclusion Criteria:
 - Patients who have had prior treatment with olaparib or any other PARP inhibitor
 (PARPi)
 - Patients with myelodysplastic syndrome/acute myeloid leukemia; or baseline features
 suggestive of myelodysplastic syndrome or acute myelogenous leukemia on peripheral
 blood smear or bone marrow biopsy, if clinically indicated
 - Persistent toxicities (>= Common Terminology Criteria for Adverse Events [CTCAE] grade
 2) with the exception of alopecia, caused by previous cancer therapy
 - Patients who are receiving any other investigational agents. Patients may be on other
 clinical trials or treatment during screening to determine eligibility
 - Patients with known brain metastases should be excluded from this clinical trial
 because of their poor prognosis and because they often develop progressive neurologic
 dysfunction that would confound the evaluation of neurologic and other adverse events.
 A scan to confirm the absence of brain metastases is not required. Patients with
 spinal cord compression unless considered to have received definitive treatment for
 this and evidence of clinically stable disease for 28 days
 - History of allergic reactions attributed to compounds of similar chemical or biologic
 composition of olaparib
 - Patients receiving any medications or substances that are inhibitors or inducers of
 CYP3A are ineligible. A washout period prior to starting olaparib for patients on
 CYP3A inhibitors is 2 weeks; and the required washout period for CYP3A inducers is 5
 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
 - Because the lists of these agents are constantly changing, it is important to
 regularly consult a frequently-updated medical reference texts such as the
 Physicians' Desk Reference. As part of the enrollment/informed consent
 procedures, the patient will be counseled on the risk of interactions with other
 agents, and what to do if new medications need to be prescribed or if the patient
 is considering a new over-the-counter medicine or herbal product
 - Pregnant women are excluded from this study because olaparib is a PARP inhibitor agent
 with the potential for teratogenic or abortifacient effects
 - Any chronic or concurrent acute liver disease
 - History of stroke, transient ischemic attack (TIA), or myocardial infarction, within 6
 months prior to enrollment
 - Uncontrolled concurrent disease or illness including but not limited to:
 - Ongoing or active infection
 - Symptomatic congestive heart failure, unstable angina pectoris, clinically
 significant cardiac arrhythmia
 - Unstable or untreated cardiac conditions or ejection fraction of < 50% as
 determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)
 - Uncontrolled diabetes mellitus
 - Psychiatric illness/social situations that would limit compliance with study
 requirements
 - Other severe, acute, or chronic medical or psychiatric condition or laboratory
 abnormality that may increase the risk associated with study participation or study
 drug administration or that may interfere with the interpretation of study results
 and, in the judgment of the investigator, would make the patient inappropriate for the
 study
 - Immunocompromised patients, e.g., patients who are known to be serologically positive
 for human immunodeficiency virus (HIV)
 - Patients with known active hepatitis (i.e., hepatitis B or C) due to risk of
 transmitting the infection through blood or other body fluids
 - Other malignancy within the last 5 years except: adequately treated non-melanoma skin
 cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ
 (DCIS), stage 1, grade 1 endometrial carcinoma, or other solid tumors including
 lymphomas (without bone marrow involvement) curatively treated with no evidence of
 disease for >= 5 years. Patients with a history of localized triple negative breast
 cancer or localized resected prostate cancer may be eligible, provided they completed
 their adjuvant chemotherapy more than three years prior to registration, and that the
 patient remains free of recurrent or metastatic disease
 - Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec on 2 or more time
 points within a 24 hour period or family history of long QT syndrome
 - Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
 reasons) within 2 weeks prior to study treatment
 - Major surgery within 2 weeks of starting study treatment and patients must have
 recovered from any effects of any major surgery
 - Previous allogenic bone marrow transplant or double umbilical cord blood
 transplantation (dUCBT)


Input:
This is a multicenter, global, Phase 2, open-label, 2-part, first-line study to investigate
 the safety, tolerability, and anti-tumor activity of ZW25 (zanidatamab) plus standard
 first-line combination chemotherapy regimens for selected gastrointestinal (GI) cancers.
 Eligible patients include those with unresectable, locally advanced, recurrent or metastatic
 HER2-expressing gastroesophageal adenocarcinoma (GEA), biliary tract cancer (BTC), or
 colorectal cancer (CRC).
 ;
 ;
 Inclusion:
 - Disease diagnosis:
 - Part 1:
 - GEA: Unresectable, locally advanced, recurrent or metastatic HER2-expressing GEA
 (IHC 3+ or 2+ with or without gene amplification based upon local assessment or
 central assessment)
 - BTC: Unresectable, locally advanced, recurrent or metastatic HER2-expressing BTC
 (including intrahepatic cholangiocarcinoma [ICC], extrahepatic cholangiocarcinoma
 [ECC], or gallbladder cancer [GBC]) (IHC 3+ with or without gene amplification;
 or IHC 0, 1+ or 2+ with gene amplification, based upon central assessment)
 - CRC: Unresectable, locally advanced, recurrent or metastatic HER2-expressing CRC
 (IHC 3+ with or without gene amplification; or IHC 0, 1+ or 2+ with gene
 amplification, based upon central assessment). Patients will be required to be
 extended RAS (KRAS and NRAS) and BRAF wild-type based upon central assessment.
 - Part 2:
 - GEA: Unresectable, locally advanced, recurrent or metastatic HER2-expressing GEA
 (IHC 3+, or IHC 2+ and FISH+ by central assessment)
 - BTC: Same as Part 1
 - CRC: Same as Part 1
 - Tumor measurements as per Response Evaluation Criteria in Solid Tumors (RECIST)
 version 1.1:
 - Part 1: Measurable or non-measurable disease
 - Part 2: Measurable disease
 - An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
 - Adequate organ function
 - Adequate cardiac left ventricular function, as defined by a LVEF >/= institutional
 standard of normal
 Exclusion:
 - Prior treatment with a HER2-targeted agent
 - Prior systemic anti-cancer therapy (including investigational products) except prior
 adjuvant/neoadjuvant therapy, which must be completed at least 6 months prior to first
 study treatment dosing. For subjects with BTC and CRC the following additional
 exceptions apply:
 - BTC: patients may have started therapy for advanced disease but may not have
 received more than one cycle of any standard gemcitabine-based chemotherapy
 regimen.
 - CRC: patients may have started therapy for advanced disease but may not have
 received more than one cycle of 5-FU-based chemotherapy (< 1 month of therapy).
 - Patients with certain contraindications to bevacizumab cannot be enrolled on the
 mFOLFOX6-2 with bevacizumab arm.
 - Palliative radiotherapy is allowed if completed at least 2 weeks prior to first study
 treatment dosing
 - Untreated known brain metastases (patients with treated brain metastases who are off
 steroids, off antiseizure medications, and stable for at least 1 month at the time of
 screening are eligible)
 - Clinically significant cardiac disease, such as ventricular arrhythmia requiring
 therapy, uncontrolled hypertension or any history of symptomatic congestive heart
 failure (CHF). Patients with known myocardial infarction or unstable angina within 6
 months prior to randomization are also excluded.
 - QTc Fridericia (QTcF) > 470 ms. For patients with longer QTcF on initial
 electrocardiogram (ECG), follow-up ECG may be performed in triplicate to determine
 eligibility
 - Peripheral neuropathy > Grade 1 per NCI-CTCAE v5.0
 - Clinically significant interstitial lung disease
 - Prior or concurrent malignancy whose natural history or treatment has the potential to
 interfere with the safety or efficacy assessment of the investigational regimen
 - Active hepatitis B or hepatitis C infection or infection with Human Immunodeficiency
 Virus (HIV)-1 or HIV-2 (Exception: patients with well controlled HIV [e.g., CD4 >
 350/mm3 and undetectable viral load] are eligible)

HER2 expression
KRAS wildtype
NRAS wildtype
BRAF wildtype


Input:
The main objective of this trial is to explore the activity of chlorambucil, an alkylating
 agent commonly used in chronic lymphocytic leukemia treatment, in metastatic patients, gBRCA,
 including VUS, or DDR mutated, previously treated with a platinum-containing chemotherapy.
 ;
 ;
 Inclusion Criteria:
 1. Pathologically confirmed pancreatic adenocarcinoma
 2. Age ≥ 18 years
 3. ECOG PS 0-2
 4. Stage IV disease
 5. Identified genetic aberrations that are associated with homologous recombination
 deficiency (HRD)
 1. Cohort A: Documented mutation in gBRCA1 or gBRCA2 that is predicted to be
 deleterious or suspected deleterious
 2. Cohort B: BRCA1 or BRCA2 mutations that are considered to be of uncertain/unknown
 significance (VUS)
 3. Cohort C: Patients with other identified genetic aberrations that are associated
 with HRD
 6. Adequate PFS during previous platinum-based chemotherapy for at least 4 months before
 progression
 7. Screening laboratory values:
 Leukocytes > 3000/mmc Thrombocytes > 150000/mmc Hemoglobin > 10 g/dl Creatinine <2.0
 times upper normal limit (unless normal creatinine clearance). Total bilirubin < 2.0
 times upper normal limit (unless due to Gilbert's syndrome).
 Alanine aminotransferase (ALT) < 3.0 times upper normal limit.
 8. Able to take oral medication
 9. Progression during or after platinum-based chemotherapy
 10. Other prior chemotherapy apart from first-line treatment for pancreatic cancer, are
 allowed, including maintenance treatment with PARP inhibitors
 11. More than 2 weeks since prior chemotherapy end
 12. Signed written informed consent
 13. QTc <450 msec or QTc <480 msec for patients with bundle branch block
 Exclusion Criteria:
 1. Clinically significant cardiac disease including unstable angina, acute myocardial
 infarction within 6 months prior to screening, congestive heart failure, and
 arrhythmia requiring therapy, with the exception of extra systoles or minor conduction
 abnormalities
 2. Active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic
 therapy
 3. Vaccination with vaccines called "live", since this treatment causes a drop of
 immunity defenses and a serious infection could result fatal.
 4. History of seizure, head trauma and treatment with anti-epileptogenic drugs
 5. Hypersensitivity to chlorambucil or to any excipients, in particular lactose
 6. Recent radiotherapy (at least 4 weeks) or previous treatment with other cytotoxic
 agents
 7. BRCA-mutated advanced pancreatic cancer who did not undergo maintenance with olaparib
 after platinum-based chemotherapy
 8. Mismatch repair (MMR)/high levels of microsatellite instability (MSI-H), or high
 levels of tumor mutational burden (TMB) pancreatic cancer who did not undergo
 immunotherapy with pembrolizumab monotherapy or any other anti-PD1 agent
 9. Concomitant PARP inhibitors therapy
 10. Life expectancy less than 3 months, in the opinion of the investigator
 11. Other past or current malignancy. Subjects who have been free of malignancy for at
 least 5 years, or have a history of completely resected non-melanoma skin cancer, or
 successfully treated in situ carcinoma are eligible
 12. Symptomatic duodenal stenosis
 13. CT contrast medium allergy and claustrophobia to RM investigation
 14. Any significant medical condition laboratory abnormality, or psychiatric illness that
 would prevent the subject from participating in the study
 15. Any condition including the presence of laboratory abnormalities, which places the
 subject at unacceptable risk if he/she were to participate in the study
 16. Any condition that confounds the ability to interpret data from the study
 17. Any familiar, sociologic or geographic conditions that can potentially interfere with
 the adhesion to the protocol or to the follow-up
 18. Pregnant or nursing. Adequate contraception is defined as oral hormonal birth control,
 intrauterine device, and male partner sterilization (if male partner is sole partner
 for that subject) and the double barrier method (condom or occlusive cap plus
 spermicidal agent).
 19. Concurrent treatment with other experimental drugs