Vactosertib in Combination With Pembrolizumab in Metastatic Colorectal or Gastric Cancer

Study Overview
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Brief Summary
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This is an open-label, multicenter study to assess the safety, tolerability, pharmacokinetics, and antitumor activity of vactosertib in combination with pembrolizumab in patients with metastatic or locally advanced colorectal or gastric/gastroesophageal junction adenocarcinoma

Detailed Description
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This is phase 1b/2a, open label, multi-center study to assess safety, tolerability, pharmacokinetics and anti-tumor activity of vactosertib in combination with pembrolizumab in patients with mCRC including CMS4 or diffuse GC/GEJC with two phases (Dose Finding Phase and Dose Expansion Phase). At screening, CMS4 will be classified by an experienced pathologist in the central lab that will examine the histology of primary surgical tissues. Approximately, 67 total patients are expected to be enrolled in this study. The first phase of the study, the Dose Finding Phase, will determine the MTD of the combination regimen. The second phase, the Dose Expansion Phase, will further evaluate the combination regimen to confirm RP2D.

Official Title
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A Phase 1b/2a Study to Assess the Safety, Tolerability, PK, and Antitumor Activity of Vactosertib in Combination With Pembrolizumab in Patients With Metastatic Colorectal or Gastric Gastroesophageal Junction Adenocarcinoma

Conditions
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Metastatic Colorectal Cancer, Gastric Cancer, Gastroesophageal Junction Adenocarcinoma

Intervention / Treatment
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* Drug: TEW-7197


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: WHO / ECOG /PS of 0 or 1 at enrollment Must have a life expectancy of at least 12 weeks Patients with histologically or cytologically confirmed advanced or metastatic colorectal cancer who have disease progression after treatment with all available therapies including fluoropyrimidine and oxaliplatin or irinotecan for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment. Histologically- or cytologically- confirmed, advanced or metastatic diffuse-type adenocarcinoma of the stomach or gastroesophageal (GE) junction who have had disease progression after at least two previous courses of chemotherapy for metastatic disease, which should include fluoropyrimidine and platinum. Confirmation of measurable disease based on RECIST 1.1 ICI-naïve patients Adequate organ and marrow function as defined below: Bilirubin≤1.5 ×ULN ,AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for patients with liver metastases) ,INR OR PT ≤1.5 × ULN , ANC ≥1500/µL , Platelets ≥100 000/µL, Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L1, Creatinine ≤1.5 × ULN Exclusion Criteria: Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor Has received prior radiotherapy within 2 weeks of start of study treatment. Has received a live vaccine within 30 days prior to the first dose of study drug Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Has known CNS metastases and/or leptomeningeal involvement Judgement by the investigator that the patient should not participate in the study .

Ages Eligible for Study
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Minimum Age: 19 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: Dose Escalation of TEW-7197<br>TEW-7197 will be administered orally for 5 days per week (5D/W) and Pembrolizumab will be administered as a dose of 200 mg every 3weeks. | Drug: TEW-7197<br>* TEW-7197 will be administered orally for 5 days per week (5D/W) at the same time in the morning and evening (BID) approximately 12 hours apart.Pembrolizumab will be administered as a dose of 200 mg every 3weeks.<br>* Other names: vactosertib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | To define the MTD | 3weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events assessed by NCI CTCAE v 5.0 | To evaluate safety profile of TEW-7197 with regards to frequency, type,grade and seriousness and causality of treatment-related clinical and laboratory adverse events. | From screening through study completion (up to 28 days after the last dose of Investigational Drug) | 
| Efficacy of TEW-7197+Pembrolizumab | Objective Response Rate(%) | through study completion, an average of 2 years | 
| Pharmacokinetics (PK) of TEW-7197 | Peak Plasma Concentration of TEW-7197 | At cycle 1(each cycle is 21days) | 
| Pharmacodynamics of TEW-7197 | pSMAD in peripheral blood mononuclear cell determined by immunohistochemistry | At cycle 1 ,3 (each cycle is 21days) |