Study of NGM438 as Monotherapy and in Combination With Pembrolizumab in Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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Study of NGM438 as Monotherapy and in Combination with Pembrolizumab in Advanced or Metastatic Solid Tumors

Official Title
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A Phase 1/1b Dose Escalation/Expansion Study of NGM438 as Monotherapy and in Combination With Pembrolizumab in Advanced or Metastatic Solid Tumors

Conditions
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Pancreatic Cancer, Breast Cancer, Gastric Cancer, Non Small Cell Lung Cancer, Cervical Cancer, Endocervical Cancer, Squamous Cell Carcinoma of Head and Neck, Bladder Urothelial Cancer, Colorectal Cancer, Esophageal Cancer, Ovarian Cancer, Renal Cell Carcinoma, Prostate Cancer, Melanoma, Mesothelioma, Cholangiocarcinoma

Intervention / Treatment
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* Drug: NGM438
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented locally advanced or metastatic solid tumor malignancy. Progressed or was intolerant to all available therapies known to confer clinical benefit appropriate for their tumor type for which the patient was eligible and willing to receive. Adequate bone marrow, kidney and liver function Performance status of 0 or 1. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1 except for AEs not constituting a safety risk by Investigator judgement. Exclusion Criteria: • Prior treatment targeting LAIR1

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NGM438 Monotherapy Dose Escalation<br>Part 1a Single Agent Dose Escalation | Drug: NGM438<br>* NGM438 is given intravenously (IV) every 3 weeks in a 21 day cycle. Multiple dose levels will be evaluated.<br>|
| Experimental: NGM438 Combination Dose Finding with Pembrolizumab<br>Part 1b NGM438 plus pembrolizumab | Drug: NGM438<br>* NGM438 is given intravenously (IV) every 3 weeks in a 21 day cycle. Multiple dose levels will be evaluated.<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered intravenously (IV) every 3 weeks in a 21 day cycle.<br>|
| Experimental: Biopsy Cohort with NGM438 Monotherapy Lead-in Followed by Combination Therapy with Pembrolizumab<br>Part 1C NGM438 followed by NGM438 plus pembrolizumab | Drug: NGM438<br>* NGM438 is given intravenously (IV) every 3 weeks in a 21 day cycle. Multiple dose levels will be evaluated.<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered intravenously (IV) every 3 weeks in a 21 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients with Dose-limiting Toxicities | A DLT is defined as an AE that meets at least one of the criteria listed in protocol, according to National Cancer Institute (NCI) common terminology criteria for AE (CTCAE) version 5.0, and is considered by the Investigator to be clinically relevant and attributed to the study treatment during the first 21 days after the first dose of study treatment. | Baseline up to 21 Days | 
| Number of Patients with Adverse Events | Number of patients with adverse events (AEs) according to severity, seriousness, and relationship to study drug. An AE is defined as any untoward medical occurrence in a patient, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of patients who experience at least one AE will be presented. | Approximately 24 months | 
| Number of Patients with Clinically Significant Laboratory Abnormalities | Number of patients with clinically significant change from baseline in laboratory abnormalities as characterized by type, frequency, severity (graded by CTCAE version 5.0) and timing. | Approximately 24 months | 
| Changes in potential pharmacodynamic biomarker CD163 in paired tumor tissue in Patients in the Biopsy Cohort Summary of baseline, post baseline and changes from baseline in CD163 |  | Baseline up to 15 days | 
| Changes in potential pharmacodynamic biomarker MMP9 in paired tumor tissue in Patients in the Biopsy Cohort Summary of baseline, post baseline and changes from baseline in MMP9 |  | Baseline up to 15 days | 
| Changes in potential pharmacodynamic biomarker CD8 in paired tumor tissue in Patients in the Biopsy Cohort Summary of baseline, post baseline and changes from baseline in CD8 |  | Baseline up to 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration (Cmax) of NGM438 | Cmax is defined as the observed maximum serum concentration post drug administration. Will be measured on Day 1, 2, 4, 8 and 15 of Cycles 1 and 3, Day 1 of Cycle 2 and Day 1 of Cycles 4-6 and every third cycle thereafter | Approximately 24 months. Each Cycle is 21 days. | 
| Area Under the Curve (AUC) of Serum NGM438 | Area under the curve from time zero extrapolated to the last time point prior to the next dose. Will be measured on Day 1, 2, 4, 8 and 15 of Cycles 1 and 3, Day 1 of Cycle 2 and Day 1 of Cycles 4-6 and every third cycle thereafter | Approximately 24 months. Each Cycle is 21 days. | 
| Time to Maximum (Tmax) Observed Serum Concentration of NGM438 | Tmax is defined as the time to reach the observed maximum serum concentration (Cmax). Will be measured on Day 1, 2, 4, 8 and 15 of Cycles 1 and 3, Day 1 of Cycle 2 and Day 1 of Cycles 4-6 and every third cycle thereafter | Approximately 24 months. Each Cycle is 21 days. | 
| Half-life (t1/2) of NGM438 in Serum | Time measured for the serum concentration to decrease by one half during the terminal phase. Will be measured on Day 1, 2, 4, 8 and 15 of Cycles 1 and 3, Day 1 of Cycle 2 and Day 1 of Cycles 4-6 and every third cycle thereafter | Approximately 24 months. Each Cycle is 21 days. | 
| Systemic Clearance (CL) of NGM438 | CL is defined as systemic clearance. Will be measured on Day 1, 2, 4, 8 and 15 of Cycles 1 and 3, Day 1 of Cycle 2 and Day 1 of Cycles 4-6 and every third cycle thereafter | Approximately 24 months. Each Cycle is 21 days. | 
| Volume of Distribution (Vss) of NGM438 at Steady State | Vss is defined as the volume of distribution at steady state. Will be measured on Day 1, 2, 4, 8 and 15 of Cycles 1 and 3, Day 1 of Cycle 2 and Day 1 of Cycles 4-6 and every third cycle thereafter | Approximately 24 months. Each Cycle is 21 days. | 
| Anti-drug Antibodies (ADA) Against NGM438 | Incidence and titers of anti-drug antibodies (ADA) against NGM438. Will be measured on Day 1 of each cycle through Cycle 6 and every third cycle thereafter. | Approximately 24 months. Each Cycle is 21 days. | 
| Number of Patients in Dose Escalation and Dose Finding Cohorts with Objective Responses | Objective Response Rate is defined as the proportion of patients who achieve a confirmed complete response (CR) or partial response (PR) divided by the total number of evaluable patients per RECIST v1.1 | Approximately 24 months | 
| Trough Concentrations of NGM438 in Patients in the Biopsy Cohort | Trough Concentration refers to the serum concentration of NGM438 observed just before treatment administration. Will be measured on Day 1, 2, 4, 8 and 15 of Cycles 1 and 3, Day 1 of Cycle 2 and Day 1 of Cycle 4 and each cycle thereafter. | Approximately 24 months. Each Cycle is 21 days. |