A Study of MRG002 in Patients With HER2-Positive Advanced Solid Tumors and Locally Advanced or Metastatic Gastric/Gastroesophageal Junction (GEJ) Cancer

Study Overview
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Brief Summary
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The objective of this study is to assess the safety, efficacy, and pharmacokinetics of MRG002, as well as the immunogenicity as defined by the incidence of anti-drug antibody (ADA) of MRG002 in patients with HER2-positive advanced solid tumors and locally advanced or metastatic gastric/gastroesophageal junction (GEJ) cancer.

Detailed Description
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This study consists of two parts. In Part A, patients will receive MRG002 as a monotherapy at doses of 2.2 or 2.6 mg/kg intravenously (IV) over 60-90 minute on Day 1 of every 3 weeks (Q3W), to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). In part B, patients will receive a single IV infusion of MRG002 at RP2D on Day 1 of Q3W.

Official Title
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An Open-Label, Multi-center Phase I/II Dose Escalation and Expansion Study to Assess the Safety, Efficacy and Pharmacokinetics of MRG002 in Patients With HER2-Positive Advanced Solid Tumors and Locally Advanced or Metastatic Gastric/Gastroesophageal Junction (GEJ) Cancer

Conditions
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Advanced Solid Tumors, Advanced or Metastatic Gastric Cancer, Advanced or Metastatic Gastroesophageal Junction Cancer

Intervention / Treatment
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* Drug: MRG002


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient must be able to provide written informed consent and follow the requirements specified in protocol. Age: ≥18 years. Life expectancy ≥6 months. Must have histologically or cytologically confirmed HER2-positive metastatic, unresectable cancer and must have had prior disease progression on all standard therapies for their tumor. Available archival tumor tissue (archival or from a new biopsy). At least one non-irradiated measurable tumor lesion according to RECIST v1.1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Acceptable liver, renal, hematologic and coagulation function. Exclusion Criteria: Toxicities (except alopecia & fatigue) due to prior antitumor therapy are higher than CTCAE v5.0 Grade 1. Toxicities due to radiotherapy (higher than grade 1) have not resolved to CTCAE v5.0 Grade ≤1 at least 21 days prior to the screening visit. Prior palliative or therapeutic radiation therapy to any RECIST v1.1 target lesion that defines baseline measurable disease for the study. Untreated or uncontrolled central nervous system (CNS) metastases. Any chemotherapy, biotherapy, immunotherapy, radiotherapy or other anti-tumor therapy within 3 weeks of the first dose of study treatment. Any severe cardiac dysfunction within 6 months of enrollment. Pulmonary embolism or deep vein thrombosis within 3 months prior to the first dose of study drug. Concurrent malignancy within 5 years prior to entry. Uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure > 100 mmHg). History of ventricular tachycardia, or torsade des pointes. History of moderate to severe dyspnea at rest due to advanced malignancies or their complications, severe primary lung disease, current need of continuous oxygen therapy, or clinically active interstitial lung disease (ILD) or pneumonitis. Major surgery within 4 weeks of the first dose of study treatment and not fully recovered. Minor surgery within 2 weeks prior to study treatment. Known allergic reactions to any component or excipient of MRG002 or known allergic reactions to trastuzumab or other prior anti-HER2 or other monoclonal antibody ≥ Grade 3. Patients who have any known liver disease, including chronic hepatitis B, hepatitis C, autoimmune hepatic disorders, primary biliary cirrhosis or sclerosing cholangitis; Patients who have concurrent, serious, uncontrolled infections or known infection with HIV, or have a diagnosed acquired immunodeficiency syndrome (AIDS); or an uncontrolled autoimmune disease, or have undergone organ transplant. Active uncontrolled bacterial, viral, fungal, rickettsial, or parasitic infection. Any severe and/or uncontrolled systemic disease that at the discretion of investigator and sponsor makes it undesirable for the patient to participate in this study. Use of systemic corticosteroids within 4 weeks prior to the first dose of treatment. Use of strong CYP3A4 inhibitors. Pregnancy or breast-feeding.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Solid Tumors<br>Phase I Dose Escalation: MRG002 will be administrated by an IV infusion of escalating doses (starting dose of 2.2 mg/kg, followed by 2.6 mg/kg) on Day 1 of every 3 weeks (21-day cycle). | Drug: MRG002<br>* Administrated intravenously<br>|
| Experimental: Locally Advanced or Metastatic Gastric/GEJ Cancer<br>MRG002 will be administrated by an IV infusion on Day 1 of every 3 weeks (21-day cycle). | Drug: MRG002<br>* Administrated intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The dose level in which (i) less than 2 out of 6 patients in a treatment cohort experiences dose-limiting toxicity (DLT); or (ii) <33% of an evaluable patient treatment cohort experiences DLT. | DLT will be evaluated during the first 21-day treatment cycle (Cycle 1) | 
| Recommended Phase II Dose (RP2D) | Identify the recommended Phase II dose (RP2D) of MRG002 for Phase II clinical study. The RP2D may be the same as the MTD or an evaluable dose level lower than the MTD. | Day 1 to Day 21 of Cycle 1 | 
| Objective Response Rate (ORR) | Objective response rate (ORR) will be assessed by Independent Central Review (ICR) based on RECIST v1.1. Cumulative safety and dosing data will be reviewed by an independent Data Safety Monitoring Board (DSMB). | Baseline to study completion (24 months) | 
| Incidence of Adverse Events (AEs) | AEs will be coded using MedDAR. Descriptive statistics will be used to summarize results to assess the safety and tolerability profile of MRG002. | After signing informed consent until 45 days after the last dose of MRG002 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DoR) | Sensitivity analyses of DoR from the Investigator's assessment will be performed in the final analysis. | Baseline to study completion (24 months) | 
| Disease Control Rate (DCR) | Sensitivity analyses of DCR from the Investigator's assessment will be performed in the final analysis. | Baseline to study completion (24 months) | 
| Progression Free Survival (PFS) | Sensitivity analyses of PFS from the Investigator's assessment will be performed in the final analysis. | Baseline to study completion (24 months) | 
| Pharmacokinetics (PK) parameter for MRG002: Maximum Drug Concentration (Cmax) | Cmax will be derived from the PK blood samples collected and will be summarized with descriptive statistics. | Baseline to study completion (24 months) | 
| PK parameter for MRG002: Area Under the Curve Up to the Last Validated Measurable Plasma Concentration (AUClast) | AUClast will be derived from the PK blood samples collected and will be summarized with descriptive statistics. | Baseline to study completion (24 months) | 
| PK parameter for total antibody (TAb): Cmax | Cmax will be derived from the PK blood samples collected and will be summarized with descriptive statistics. | Baseline to study completion (24 months) | 
| PK parameter for TAb: AUClast | AUClast will be derived from the PK blood samples collected and will be summarized with descriptive statistics. | Baseline to study completion (24 months) | 
| PK parameter for Monomethyl Auristatin E (MMAE): Cmax | Cmax will be derived from the PK blood samples collected and will be summarized with descriptive statistics. | Baseline to study completion (24 months) | 
| PK parameter for MMAE: AUClast | AUClast will be derived from the PK blood samples collected and will be summarized with descriptive statistics. | Baseline to study completion (24 months) | 
| Immunogenicity | 5 mL Blood samples for anti-drug antibody (ADA) analysis will be collected each time according to the pre-defined timepoints. The incidence of ADA will be summarized for all patients who received at least one administration of MRG002. | Baseline to study completion (24 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRG002, Antibody Drug Conjugate (ADC), HER2, Solid tumors, Gastric/GEJ Cancer