Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy, Phase 1 Study of CMG901

Study Overview
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Brief Summary
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This is a multi-center, open-label, dose escalation and dose expansion, Phase 1 study to evaluate the safety, tolerability, PK and preliminary anti-tumor activity of CMG901. The dose escalation part (Part A) will determine the MTD of CMG901 in subjects with relapsed and/or refractory advanced solid tumor for which there is no available standard therapy likely to confer clinical benefit, or the subject is not a candidate for such available therapy based on a modified 3+3 dose escalation design (an accelerated dose titration design followed by traditional 3+3 dose escalation design). The dose expansion part (Part B) will evaluate the preliminary anti-tumor activity and safety of CMG901 in subjects with Claudin 18.2 positive gastric cancer (GC), gastroesophageal junction (GEJ) cancer, and pancreatic cancer who have relapsed and/or are refractory to approved therapies.

Official Title
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An Open-Label, Phase 1, Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Antitumor Activities of CMG901 in Subjects With Advanced Unresectable or Metastatic Solid Tumor

Conditions
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Advanced Solid Tumor, Gastric Cancer, Gastroesophageal Junction Adenocarcinoma, Pancreatic Cancer

Intervention / Treatment
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* Drug: CMG901


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Part A: Patient must have histologically or cytologically confirmed advanced and/or metastatic solid tumor malignancies for which standard treatment do not exist, are no longer effective, or are not acceptable to the patient. Part A: Must provide archival tumor tissue specimen or agree to undergo a fresh biopsy if archival specimen is unavailable for retrospective Claudin 18.2 testing prior to enrollment; Claudin 18.2 expression is not required for enrollment. Part A: Measurable or evaluable disease per RECIST v 1.1. Part B: Histologically-confirmed, advanced unresectable or metastatic GC, GEJ adenocarcinoma, or pancreatic cancer which have relapsed and/or are refractory to approved therapies. Part B: CLDN18.2-positive tumor sample assessed by central testing. New biopsies and archival bio-samples are allowed. If archival tissue samples from several points of time are available, the most recent one is preferred. Part B: Measurable disease per RECIST v 1.1. Women of childbearing potential and male subjects must agree to remain abstinent or use contraceptive methods as defined by the protocol. Eastern Cooperative Oncology Group Performance Status 0-1. Side effects of any prior therapy or procedures for any medical condition has recovered to NCI-CTCAE v.5.0 Grade ≤ 1 or stable status by investigator. Key Exclusion Criteria: Received: chemotherapy or any investigational anti-tumor agents within 28 days of the start of CMG901 treatment; molecularly-targeted agents, immunoconjugate, or antibody drug conjugate within 28 days or or 5 half-lives (whichever is shorter) of the start of CMG901 treatment; major surgery within 28 days of the start of CMG901 treatment; radiotherapy within 21 days of the start of CMG901 treatment; potent cytochrome P450 3A4 (CYP3A4) inhibitors within 14 days or or 5 half-lives (whichever is longer) of the start of CMG901 treatment. Diagnosis of immunodeficiency or requiring another form of chronic immunosuppressive therapy. Or is receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone or equivalent) within 7 days prior to the first dose. History of severe hypersensitivity to any component or excipient of CMG901. Ongoing or active infection assessed by investigator. Any severe cardiac dysfunction including left ventricular ejection fraction <50%, congestive heart failure ≥Grade 2 (New York Heart Association), QTc >480 msec, history of acute myocardial infarction, angina pectoris, uncontrolled arrhythmia, acute coronary syndromes, stent placement, stroke, or transient ischemic attack within 6 months of enrollment. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with uncontrolled ascites, pleural effusion, or pericardial effusion by investigator. Preexisting sensory and/or motor neuropathy Grade ≥2. Uncontrolled diabetes mellitus or diabetic neuropathy within 3 months of the first dose of CMG901. Known infection with HIV, or HIV positive; Known active hepatitis B, or HBsAg positive with HBV-DNA positive, or anti-HBc positive with HBV-DNA positive; Known active hepatitis C, or anti-HCV antibody positive with HCV-RNA positive. Any severe and/or uncontrolled systemic disease or other conditions that in the opinion of the Investigator make the subject unsuitable for participation in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part A, Dose Escalation: Modified 3+3 dose escalation design: an accelerated dose titration design followed by traditional 3+3 dose escalation design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, Dose escalation<br>CMG901 will be administered in treatment cycles once every 3 weeks (Q3W). Dose escalation will be carried out according to a modified 3+3 dose-escalation design. Accelerated dose titration design will be used for the first 2 dose levels (0.3mg/kg and 0.6mg/kg), and then traditional 3+3 dose escalation design will be used for the following levels (1.2mg/kg, 1.8mg/kg, 2.2mg/kg, 2.6mg/kg and 3.0mg/kg). | Drug: CMG901<br>* CMG901 will be administered intravenously (IV) on Day 1 of every 21-day cycle. Individual subjects may continue study treatment until there is evidence of disease progression (clinical or radiologic) judged by Investigators, unacceptable toxicity or other reasons for treatment discontinuation.<br>|
| Experimental: Part B, Dose expansion _GC_ MTD level<br>This cohort will comprise subjects with Claudin 18.2 positive GC or GEJ adenocarcinoma with prior failure of, progression on, or intolerance to, standard therapy. The starting dose of CMG901 for Expansion will be derived from the MTD determined during Dose Escalation. | Drug: CMG901<br>* CMG901 will be administered intravenously (IV) on Day 1 of every 21-day cycle. Individual subjects may continue study treatment until there is evidence of disease progression (clinical or radiologic) judged by Investigators, unacceptable toxicity or other reasons for treatment discontinuation.<br>|
| Experimental: Part B, Dose expansion _PC_ MTD level<br>This cohort will comprise subjects with Claudin 18.2 positive pancreatic cancer with prior failure of, progression on, or intolerance to, standard therapy. The starting dose of CMG901 for Expansion will be derived from the MTD determined during Dose Escalation. | Drug: CMG901<br>* CMG901 will be administered intravenously (IV) on Day 1 of every 21-day cycle. Individual subjects may continue study treatment until there is evidence of disease progression (clinical or radiologic) judged by Investigators, unacceptable toxicity or other reasons for treatment discontinuation.<br>|
| Experimental: Part B, Dose expansion _GC_ MTD-1 level<br>This cohort will comprise subjects with Claudin 18.2 positive GC or GEJ adenocarcinoma with prior failure of, progression on, or intolerance to, standard therapy. The starting dose of CMG901 for Expansion will be derived from the MTD-1 level determined during Dose Escalation. | Drug: CMG901<br>* CMG901 will be administered intravenously (IV) on Day 1 of every 21-day cycle. Individual subjects may continue study treatment until there is evidence of disease progression (clinical or radiologic) judged by Investigators, unacceptable toxicity or other reasons for treatment discontinuation.<br>|
| Experimental: Part B, Dose expansion _PC_ MTD-1 level<br>This cohort will comprise subjects with Claudin 18.2 positive pancreatic cancer with prior failure of, progression on, or intolerance to, standard therapy. The starting dose of CMG901 for Expansion will be derived from the MTD-1 level determined during Dose Escalation. | Drug: CMG901<br>* CMG901 will be administered intravenously (IV) on Day 1 of every 21-day cycle. Individual subjects may continue study treatment until there is evidence of disease progression (clinical or radiologic) judged by Investigators, unacceptable toxicity or other reasons for treatment discontinuation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants with a Dose-Limiting Toxicity (DLT) |  | Up to 21 days after the first dose | 
| Part A: Incidence, severity, and outcome of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 |  | Up to 30 days after the last dose of CMG901 or until the start of subsequent anticancer therapy, if earlier | 
| Part B: Objective Response Rate, Assessed According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) |  | Up to 24 months | 
| Part B: Recommended phase II dose |  | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A & Part B: AUC to the last quantifiable concentration [AUC(0-last)], over the dosing interval [AUC(0-tau)], extrapolated to infinity [AUC(0-inf), time to Cmax (tmax), apparent half-life (t1/2), systemic clearance (CL). |  | 21 days after the first dose | 
| Part A & Part B: AUC(0-last), AUC(0-tau), Cmax, tmax, t1/2, systemic clearance (CL), volume of distribution (Vz, Vss), minimum concentration (Cmin), Ctrough, accumulation ratios for Cmax and AUC(0-tau) for multiple doses |  | up to 24 months | 
| Part A & Part B: Incidence of anti-CMG901 |  | up to 24 months | 
| Part A & Part B: Disease Control Rate, Assessed According to RECIST v1.1 |  | up to 24 months | 
| Part A & Part B: Duration of Response, Assessed According to RECIST v1.1 |  | up to 24 months | 
| Part A & Part B: Progression Free Survival, Assessed According to RECIST v1.1 |  | up to 24 months | 
| Part A: Claudin 18.2 expression by retrospective testing in tumor specimens by immunohistochemistry |  | up to 24 months | 
| Part A: ORR, Assessed according to RECIST 1.1 |  | Up to 24 months | 
| Part A & Part B: Overall Survival |  | Up to 24 months | 
| Part B: Incidence, severity, and outcome of TEAEs and SAEs based on NCI CTCAE version 5.0 |  | Up to 24 months |