Study of AMG 199 in Subjects With MUC17-Positive Solid Tumors Including Gastric, Gastroesophageal Junction, Colorectal, and Pancreatic Cancers

Study Overview
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Brief Summary
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To evaluate the safety and tolerability of AMG 199 in adult subjects and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D).

Detailed Description
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AMG 199 is a novel half-life extended (HLE) bispecific T cell engager (BiTE®) molecule designed to direct T cells towards MUC17-expressing cells. This is a first-in-human study in adult subjects with MUC17-positive solid tumors including gastric cancer, gastroesophageal junction (GEJ), colorectal, and pancreatic cancers, collectively referred to as solid tumors in this clinical investigation to assess AMG 199 safety, tolerability, pharmacokinetics (PK), and anti-tumor activity, with additional exploratory objectives to assess pharmacodynamics (PD), correlative biomarker analysis, and immunogenicity. The primary end point is to evaluate the safety and tolerability of AMG 199 in adult subjects, and determine the MTD and RP2D. The secondary end point is characterize the PK and anti-tumor activity of AMG 199.

Official Title
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A Global Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of the Half-life Extended Bispecific T-cell Engager AMG 199 in Subjects With MUC17-Positive Solid Tumors Including Gastric, Gastroesophageal Junction, Colorectal, and Pancreatic Cancers

Conditions
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MUC17-positive Solid Tumors

Intervention / Treatment
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* Drug: AMG 199


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Key Inclusion Criteria: • Subjects with histologically or cytologically confirmed metastatic or locally advanced unresectable gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma positive for MUC17. Subjects should have been refractory to or have relapsed after two or more prior lines of standard systemic therapy that included a platinum, a fluoropyrimidine, nivolumab (in combination with a platinum and a fluoropyrimidine), either a taxane or irinotecan, and an approved vascular endothelial growth factor receptor (VEGFR) antibody/tyrosine kinase inhibitor (TKI). OR • Subjects with histologically or cytologically confirmed metastatic or locally advanced unresectable colorectal cancer positive for MUC17. Subjects should have been refractory to or have relapsed after at least two and up to five prior lines of standard systemic therapy. Therapy should have included an approved vascular endothelial growth factor (VEGF) antibody (if clinically appropriate) and epidermal growth factor receptor (EGFR) antibody (if kirsten rat sarcoma [KRAS]/ neuroblastoma RAS viral oncogene homolog [NRAS]/ v-Raf murine sarcoma viral oncogene homolog B1 [BRAF] wild type tumor). OR Subjects with histologically or cytologically confirmed unresectable or metastatic pancreatic ductal adenocarcinoma positive for MUC17. Subjects should have been refractory to or have relapsed after at least one and up to three prior lines of standard systemic therapy. Gastric adenocarcinoma and GEJ adenocarcinoma: Subjects eligible for human epidermal growth factor receptor 2 (HER2) directed therapy, prior systemic therapy should have an approved HER2 targeting antibody approved for treatment of gastric cancer. For subjects with microsatellite instability high (MSI H) or mismatch repair deficient (dMMR) tumors a prior line of treatment should have included an approved programmed cell death protein-1 (PD-1) blocking antibody. OR Colorectal cancer: For subjects with MSI H or dMMR tumors a prior line of treatment should have included an approved PD-1-blocking antibody. For subjects with BRAF V600E mutation positive tumors a prior line of treatment should have included a BRAF inhibitor. Subjects may also be included if the aforementioned therapeutic options were medically not appropriate for them. In these cases, the reason(s) why required prior therapies for solid tumors were medically not appropriate should be documented in the subject's electronic case report form (eCRF). Subjects may also be included if the aforementioned therapeutic options have not been available or accessible for them. For dose expansion only: Subjects with at least one measurable lesion ≥ 10mm which has not undergone biopsy within 3 months of screening scan. This lesion cannot be biopsied at any time during the study. Exclusion Criteria: Key Exclusion Criteria: Any anticancer therapy or immunotherapy within 4 weeks of start of first dose. Central nervous system (CNS) metastases, leptomeningeal, or spinal cord compression. Autoimmune disorders requiring chronic systemic steroid therapy or any other form of immunosuppressive therapy. Subjects may be included if the treatment is discontinued more than 3 months prior to the first dose of AMG 199, there is a low likelihood of relapse from the autoimmune disorder, AND there is agreement between the investigator and the Amgen Medical Monitor.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Dose-exploration phase<br>The dose-exploration phase of the study will estimate the MTD (Maximum Tolerated Dose) of AMG 199 using a Bayesian logistic regression model (BLRM). A RP2D (Recommended Phase 2 Dose) may be identified based on emerging safety, efficacy, and PD (Pharmacodynamics) data prior to reaching an MTD. Alternative dosing schedule(s) may be explored based on emerging PK (Pharmacokinetics) and safety data. | Drug: AMG 199<br>* AMG 199 is a BiTE® molecule designed to direct T cells towards MUC17-expressing cells.<br>|
| Experimental: Dose-expansion phase<br>The dose-expansion phase will be conducted to confirm safety, PK, and PD at the MTD or RP2D and to obtain further safety and efficacy data and enable correlative biomarker analysis. | Drug: AMG 199<br>* AMG 199 is a BiTE® molecule designed to direct T cells towards MUC17-expressing cells.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose-limiting toxicities (DLT) | To evaluate the safety and tolerability of AMG 199 in adult subjects and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). | 3 years | 
| Incidence of Treatment-emergent adverse events (TEAEs) | To evaluate the safety and tolerability of AMG 199 in adult subjects and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). | 3 years | 
| Incidence of Treatment-related adverse events (TRAEs) | To evaluate the safety and tolerability of AMG 199 in adult subjects and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). | 3 years | 
| Number of subjects with changes in vital signs | To evaluate the safety and tolerability of AMG 199 in adult subjects and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). | 3 years | 
| Number of subjects with changes in clinical laboratory tests | To evaluate the safety and tolerability of AMG 199 in adult subjects and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). | 3 years | 
| Number of subjects with changes in electrocardiogram (ECG) | To evaluate the safety and tolerability of AMG 199 in adult subjects and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum serum concentration (Cmax) of AMG 199 | To characterize the PK (Pharmacokinetics) of AMG 199. | 3 years | 
| Minimum serum concentration (Cmin) of AMG 199 | To characterize the PK (Pharmacokinetics) of AMG 199. | 3 years | 
| Area under the concentration-time curve (AUC) of AMG 199 | To characterize the PK (Pharmacokinetics) of AMG 199. | 3 years | 
| Accumulation following multiple dosing of AMG 199 | To characterize the PK (Pharmacokinetics) of AMG 199. | 3 years | 
| Half-life (t1/2) of AMG 199 | To characterize the PK (Pharmacokinetics) of AMG 199. | 3 years | 
| Objective response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and iRECIST. | To evaluate preliminary anti-tumor activity of AMG 199 | 3 years | 
| Duration of response (DOR). | To evaluate preliminary anti-tumor activity of AMG 199 | 3 years | 
| Time to progression (TTP) | To evaluate preliminary anti-tumor activity of AMG 199 | 3 years | 
| Progression-free survival (PFS), 6-month PFS | To evaluate preliminary anti-tumor activity of AMG 199 | 6 months | 
| Progression-free survival (PFS), 1-year PFS | To evaluate preliminary anti-tumor activity of AMG 199 | 1 year | 
| Overall survival (OS), 1-year OS. | To evaluate preliminary anti-tumor activity of AMG 199 | 1 year | 
| Overall survival (OS), 2-year OS | To evaluate preliminary anti-tumor activity of AMG 199 | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric Cancer, Gastroesophageal Junction Cancer, Colorectal Cancer, Pancreatic Cancer