To Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetic Profile of ABN401 in Patients With Advanced Solid Tumors Harboring c-MET Dysregulation

Study Overview
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Brief Summary
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ABN401-003 is a Phase 2 clinical study to assess efficacy, safety, tolerability and pharmacokinetic profile of ABN401 in specific populations of advance solid tumors with c-MET alterations as monotherapy.

Detailed Description
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This study will start with one cohort. Two additional cohorts are under consideration and the study will be a parallel cohort expansion study.

Official Title
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A Phase 2 Multicenter, Open-Label, Parallel Cohort Expansion Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetic Profile of ABN401 in Patients With Advanced Solid Tumors Harboring c-Mesenchymal-epithelial Transition Factor (c-MET) Dysregulation

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: ABN401


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 18 years of age or designated age of majority according to the regulatory authorities, whichever is higher. Eastern Cooperative Oncology Group (ECOG) performance status (PS), 0 or 1. Have a life expectancy of at least 3 months. Diagnosis: must have histologically or cytologically confirmed NSCLC, advanced, recurrent, or metastatic, For Cohort 1: MET exon 14 skipping suspected by local or central biomarker assessment. [local testing is accepted for eligibility; all patients will have confirmation by central laboratory, but this result is not necessary for eligibility; local molecular pathology result will suffice]. This testing can be from archival or fresh tissue sample and/or blood specimen; any sample, any test positive subjects are eligible. Treatment experience a. Cohort 1: Anti-tumor treatment naïve subject upon refusal to receive 1st line standard of care, or not tolerated to 1st line standard of care, or progressed after standard of care with no greater than 2 prior treatment regimens (neoadjuvant, adjuvant, and maintenance therapies do not qualify as separate treatment regimens). At least one measurable lesion per response evaluation criteria in solid tumors (RECIST) 1.1, with the exception of bone-only disease (i.e., non-measurable disease per RECIST 1.1) with at least 1 radiological non-target lesion. If not menopausal or surgically sterile, willing to practice at least one of the following highly effective methods of birth control for at least a (partner's) menstrual cycle before and for 3 months after study drug administration: Barrier type devices (examples are condom, diaphragm, and contraceptive sponge) used only in combination with a spermicide Sexual intercourse with vasectomized male/sterilized female partner, Hormonal female contraceptive (oral, parenteral, intravaginal, implantable, or transdermal) for at least 3 consecutive months prior to investigational product administration (when not clinically contraindicated as in breast, ovarian and endometrial cancers), Use of an intrauterine contraceptive device. Note: Abstinence, the rhythm method, and/or contraception by the partner are not acceptable methods of birth control Resolution of prior-therapy-related AEs (including immune-related AEs but excluding alopecia) to ≤ Grade 1 per CTCAE v 5.0, and no treatment for these AEs for at least 2 weeks prior to the time of enrollment. Alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 AEs not constituting a safety risk based on investigator's judgment are acceptable. Adequate organ function as indicated by laboratory values. Tissue and/or blood specimens Willing to undergo a new biopsy or have available archival formalin-fixed, paraffin-embedded tumor tissue specimen. The archival tissue must be: collected after progression from most recent prior systemic anti-cancer treatment, OR tissue samples collected prior to previous lines of treatment, ALL subjects must undergo blood sample for biomarker assessment. Able and willing to comply with the protocol and the restrictions and assessments therein. Exclusion Criteria: Previous severe hypersensitivity reaction to any component of study drug(s). Prior therapy a. Previous treatment with c-MET inhibitors or hepatocyte growth factor (HGF)-targeting therapy. Genetic analysis results: a. Cohort 1: Existing genetic data from the patient's tumor tissue showing known molecular alterations which would make them eligible for targeted therapies (e.g., EGFR mutations, ALK rearrangements, KRAS mutation, ROS1 translocation, BRAF mutation, RET alteration, and NTRK fusion, etc.). Chronic inflammatory liver condition. History or clinical evidence of any significant liver or biliary pathology including cirrhosis, infectious disease, inflammatory conditions, steatosis, or cholangitis (including ascending cholangitis, primary sclerosing cholangitis, obstruction, perforation, fistula of biliary tract, spasm of sphincter of Oddi, biliary cyst or biliary atresia). Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis Impairment of GI function or GI disease that may significantly alter the absorption of ABN401 (e.g., ulcerative diseases, uncontrolled nausea, uncontrolled vomiting, uncontrolled diarrhea, or malabsorption syndrome) Prior organ or stem cell transplant. Known active infection with human immunodeficiency virus (HIV), human T-cell leukemia virus, type (HTLV-1), hepatitis B virus (HBV), or hepatitis C virus (HCV), unless the patients fall into below categories (patients fall into one of the a, b, c category are eligible to participate) a. HIV CD4+ cells ≥ 350 cells/µL No history of AIDS No history of opportunistic infection in the past 12 months b. HCV Undetectable viral load (Participants positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for hepatitis C RNA) c. HBV Concurrent HBV treatment and undetectable viral load (Participants with a past or resolved hepatitis B infection defined as the presence of hepatitis B core antibody [anti-HBc] and absence of hepatitis B surface antigen are eligible) Symptomatic ascites or pleural effusion, unless clinically stable for at least two weeks following treatment for these conditions (including therapeutic thoraco- or paracentesis). Known active central nervous system (CNS) primary tumor or metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to first dose of ABN401, have no evidence of new or enlarging brain metastases and are off steroids for at least 15 days prior to first dose of ABN401. Presence or history of a malignant disease other than disease to be treated in current protocol that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers, indolent malignancies that currently do not require treatment, and completely resected carcinoma in situ of any type. Active infection requiring therapy. However, subject with minor infections requiring oral antibiotics, (e.g., urinary tract infection, Upper respiratory tract infection, etc.) could be eligible based on investigator's judgement. Use of systemic corticosteroids > 10 mg/day prednisone or equivalent within 30 days or other immunosuppressive drugs within 30 days prior to first drug administration. Patients receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of treatment with ABN401 and for the duration of the study Strong and moderate inhibitors/inducers of P-glycoprotein Strong and moderate inhibitors/inducers of CYP3A4 Proton pump inhibitors (PPI) Has received or will receive a live vaccine within 30 days prior to the first administration of study medication. Seasonal flu vaccine that does not contain live vaccine are permitted. Received an investigational product or treated with an investigational device within 30 days prior to first ABN401 administration. Has been receiving: radiotherapy, chemotherapy, or molecularly-targeted agents or tyrosine kinase inhibitors within 2 weeks (4 weeks in case of thoracic radiotherapy to lung fields) or 5 half-lives (whichever is longer) of the start of study treatment; immunotherapy/monoclonal antibodies within 3 weeks of the start of study treatment; nitrosoureas, antibody-drug conjugates, or radioactive isotopes within 6 weeks of the start of study treatment; 7-day washout is permitted for palliative radiation (i.e. limited field, ≤ 14-day course of radiotherapy) to non-CNS lesions. History or clinical evidence of any surgical or medical condition which the investigator judges as likely to interfere with the results of the study or pose an additional risk in participating e.g., rapidly progressive or uncontrolled disease involving a major organ system-vascular, cardiac, pulmonary, gastrointestinal, gynecologic, hematologic, neurologic, neoplastic, renal, endocrine, autoimmune or an immunodeficiency, or clinically significant active psychiatric or abuse disorders. Is a regular user (including recreational use) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol). Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study. Patients with a corrected QT interval (using Fridericia's correction formula) (QTcF) of > 470 msec (females) and > 450 msec (males).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: ABN401<br>Subjects will receive ABN401 800 mg, monotherapy, administered orally once daily in 21-day cycles | Drug: ABN401<br>* Tablets Route of Administration: Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) according to response evaluation criteria in solid tumors (RECIST)1.1 by imaging central review (ICR) | ORR is defined as the proportion of patients who experience a complete response (CR) or partial response (PR) as measured by RECIST 1.1 | Up to 12 months | 
| Incidence of ABN401 adverse events (AEs) | Safety and tolerability will be a comprehensive evaluation of AEs based on: Occurrence of dose-limiting toxicity (DLT) (in case of combination), ≥ Grade 3 toxicity or intolerability Frequency of dose interruption, modifications Recording of AEs by CTCAE V5.0 Results of monitoring vital signs, Occurrence of cumulative AEs, Results of clinical chemistry, liver function tests (LFTs), hematology/coagulation, and urine analysis tests, Electrocardiogram (ECG) results, Changes in physical examination, Need for concomitant medications | Up to 12 months | 
| Pharmacokinetic (PK) parameter from plasma ABN401 concentration - Tmax: Time to reach maximum concentration |  | Cycle 1: Day 1, Day 2, Day 15, and Day 16 (pre-dose). Pre-dose on Day 1 for subsequent cycles starting from cycle 2 Day 1. Each cycle is 21 days. | 
| Pharmacokinetic (PK) parameter from plasma ABN401 concentration - Cmax: Maximum concentration |  | Cycle 1: Day 1, Day 2, Day 15, and Day 16 (pre-dose). Pre-dose on Day 1 for subsequent cycles starting from cycle 2 Day 1. Each cycle is 21 days. | 
| Pharmacokinetic (PK) parameter from plasma ABN401 concentration - Ke: apparent first-order terminal elimination rate constant |  | Cycle 1: Day 1, Day 2, Day 15, and Day 16 (pre-dose). Pre-dose on Day 1 for subsequent cycles starting from cycle 2 Day 1. Each cycle is 21 days. | 
| Pharmacokinetic (PK) parameter from plasma ABN401 concentration - T1/2: apparent first-order terminal elimination half-life |  | Cycle 1: Day 1, Day 2, Day 15, and Day 16 (pre-dose). Pre-dose on Day 1 for subsequent cycles starting from cycle 2 Day 1. Each cycle is 21 days. | 
| Pharmacokinetic (PK) parameter from plasma ABN401 concentration - AUC0-t: area under the concentration-time curve from time zero to the last measurable concentration |  | Cycle 1: Day 1, Day 2, Day 15, and Day 16 (pre-dose). Pre-dose on Day 1 for subsequent cycles starting from cycle 2 Day 1. Each cycle is 21 days. | 
| Pharmacokinetic (PK) parameter from plasma ABN401 concentration - AUC0-12: area under the concentration-time curve from time zero to 12 hr post-dose |  | Cycle 1: Day 1, Day 2, Day 15, and Day 16 (pre-dose). Pre-dose on Day 1 for subsequent cycles starting from cycle 2 Day 1. Each cycle is 21 days. | 
| Pharmacokinetic (PK) parameter from plasma ABN401 concentration - AUC0-24: area under the concentration-time curve from time zero to 24 hr post-dose |  | Cycle 1: Day 1, Day 2, Day 15, and Day 16 (pre-dose). Pre-dose on Day 1 for subsequent cycles starting from cycle 2 Day 1. Each cycle is 21 days. | 
| Pharmacokinetic (PK) parameter from plasma ABN401 concentration - AUC0-∞: area under the concentration-time curve from time zero extrapolated to infinity |  | Cycle 1: Day 1, Day 2, Day 15, and Day 16 (pre-dose). Pre-dose on Day 1 for subsequent cycles starting from cycle 2 Day 1. Each cycle is 21 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) measured by RECIST 1.1 by investigator | ORR is defined as the proportion of patients who experience a CR or PR as measured by RECIST 1.1 | Up to 12 months | 
| Duration of response (DoR) as measured by RECIST 1.1 | DoR as measured by RECIST 1.1 by ICR and investigator will be used. DoR is defined as the time period from documentation of disease response to disease progression. | Up to 12 months | 
| Disease advanced control rate (DCR) as measured per RECIST 1.1 | DCR is defined as the proportion of patients who achieve CR, PR, and stable disease (SD) as measured per RECIST 1.1 by ICR and investigator | Week 12 | 
| Progression-free survival (PFS) according to RECIST 1.1 | PFS defined as the time from first dose of ABN401 until disease progression according to RECIST 1.1 by investigator | Up to 12 months | 
| Overall survival (OS) | OS defined as the time from first dose of study drug until death from any cause | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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c-MET