Phase 1/2 Open-label Study of Combination Therapy With the MEK Inhibitor, Cobimetinib, Immune Checkpoint Blockade, Atezolizumab, and the AUTOphagy Inhibitor, Hydroxychloroquine in KRAS-mutated Advanced Malignancies
Overview
- Phase
- Phase 1
- Intervention
- Cobimetinib
- Conditions
- Gastrointestinal Cancer
- Sponsor
- Columbia University
- Enrollment
- 27
- Locations
- 2
- Primary Endpoint
- Phase 1: Estimated Maximum Tolerated Dose (MTD) Hydroxychloroquine (HCQ)
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This research study is for patients with an advanced cancer that carries a mutation in a gene called KRAS. Genes are parts of our DNA which carry instructions for a cell (the smallest component of an body part). In many cancers, the KRAS gene contains errors (mutations) which allows the tumors to grow. The purpose of this study is to determine if combination treatment with atezolizumab, cobimetinib, and hydroxychloroquine is safe, and if it will decrease the size of the tumor and prolong life in patients whose tumors contain this mutation. Cobimetinib and atezolizumab are both approved by the FDA for use in other cancers, but not in some cancer types being studied in this trial. Hydroxychloroquine is FDA approved to treat malaria and other conditions, but has also not been approved for these cancer types. Preliminary results have shown that this combination of drugs is effective at killing cancer cells and shrinking tumors in several KRAS-mutated cancers in animals.
Detailed Description
The overall objective of this study is to investigate the safety and preliminary efficacy of combination therapy with cobimetinib and hydroxychloroquine, with or without atezolizumab in patients with KRAS-mutated advanced malignancies. Given that the pre-clinical and clinical benefit from this combination is from within poorly differentiated endocrine carcinoma (PDAC) animal models and human subjects with PDAC and duodenal cancer, we will include at least 12 of the 18 evaluable subjects from PDAC and/or colorectal malignancies. The phase 2 portion of the study will be amended after preliminary safety and efficacy results from phase 1 and other ongoing clinical trials have been analyzed and a summary incorporated within the protocol as an amendment including a rationale of the cohorts to be tested.
Investigators
Gulam Manji
Assistant Professor of Medicine Division of Hematology/Oncology
Columbia University
Eligibility Criteria
Inclusion Criteria
- •Histological or pathological confirmation of malignancy with a KRAS-activating mutation.
- •Extent of disease Advanced disease for which no curable options are available. Subjects who are not deemed candidates for these curative therapies will be eligible if they meet other criteria.
- •Prior treatments
- •Pancreatic adenocarcinoma Subjects must have progressed on or be intolerant of combination therapy containing either 5-Fluorouracil/Capecitabine- and/or gemcitabine-based therapy. Subjects who experienced disease recurrence while receiving adjuvant chemotherapy or within three months of completing adjuvant chemotherapy are eligible.
- •Colorectal adenocarcinoma Subjects must have progressed on or be intolerant of combination therapy containing 5-Fluorouracil/Capecitabine, and must have received Oxaliplatin and Irinotecan.
- •MSI-H/dMMR or NTRK-fusion positive tumors Subjects must have received prior treatment with approved drugs for tumors harboring these aberrations.
- •Histology agnostic cancers other than pancreatic and colorectal adenocarcinoma (see above; Phase 1 and 2) Subjects must have progressed on or be intolerant of all standard of care therapies that result in a median progression free survival benefit of ≥ 8 weeks, or overall response rate of \>5%.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Age ≥18 years
- •Adequate hematological and end-organ function (test results from within 14 days prior to initiation of study treatment):
Exclusion Criteria
- •Prior treatment with investigational therapy. Participants may not have had any treatments with investigational therapy within the 28 days prior to initiation of study treatment.
- •Prior radiation therapy Participants may not have had radiation therapy within 2 weeks prior to initiation of study treatment. Participants may not have had previous radiotherapy to 25% or more of the bone marrow.
- •Prior Therapy Participants may not have had systemic chemotherapy within 14 days or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.
- •In addition, the following prior treatment is not allowed during Phase 1 of the study:
- •Receptor tyrosine kinase inhibitors targeting MAP kinase pathway;
- •Any pharmacological agents inhibiting the autophagy pathway.
- •In addition, the following prior treatment is not allowed during Phase 2 of the study:
- •T-cell co-stimulating agents or immune checkpoint blockade therapies
- •Receptor tyrosine kinase inhibitors targeting Mitogen-Activated Protein (MAP) kinase pathway;
- •Any pharmacological agents inhibiting the autophagy pathway.
Arms & Interventions
Phase 2: Cohort 3
Histology Agnostic Adenocarcinoma (N = 23-56) subjects will receive study treatment based on the MTD determined from Phase 1
Intervention: Cobimetinib
Phase 1: Maximum Tolerated Dose (MTD)
Subjects will be treated with combination therapy at the designated dose levels: Dose 1 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, no Atezolizumab Dose 2 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, Atezolizumab 840mg Dose 3 - Hydroxychloroquine 600mg twice per day, Cobimetinib 60mg, Atezolizumab 840mg
Intervention: Cobimetinib
Phase 1: Maximum Tolerated Dose (MTD)
Subjects will be treated with combination therapy at the designated dose levels: Dose 1 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, no Atezolizumab Dose 2 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, Atezolizumab 840mg Dose 3 - Hydroxychloroquine 600mg twice per day, Cobimetinib 60mg, Atezolizumab 840mg
Intervention: Hydroxychloroquine
Phase 1: Maximum Tolerated Dose (MTD)
Subjects will be treated with combination therapy at the designated dose levels: Dose 1 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, no Atezolizumab Dose 2 - Hydroxychloroquine 600mg twice per day, Cobimetinib 40mg, Atezolizumab 840mg Dose 3 - Hydroxychloroquine 600mg twice per day, Cobimetinib 60mg, Atezolizumab 840mg
Intervention: Atezolizumab
Phase 2: Cohort 1
Advanced Pancreatic Adenocarcinoma (N = 23-67) subjects will receive study treatment based on the MTD determined from Phase 1
Intervention: Cobimetinib
Phase 2: Cohort 1
Advanced Pancreatic Adenocarcinoma (N = 23-67) subjects will receive study treatment based on the MTD determined from Phase 1
Intervention: Hydroxychloroquine
Phase 2: Cohort 1
Advanced Pancreatic Adenocarcinoma (N = 23-67) subjects will receive study treatment based on the MTD determined from Phase 1
Intervention: Atezolizumab
Phase 2: Cohort 2
Advanced Colorectal Adenocarcinoma (N = 20-34) subjects will receive study treatment based on the MTD determined from Phase 1
Intervention: Cobimetinib
Phase 2: Cohort 2
Advanced Colorectal Adenocarcinoma (N = 20-34) subjects will receive study treatment based on the MTD determined from Phase 1
Intervention: Hydroxychloroquine
Phase 2: Cohort 2
Advanced Colorectal Adenocarcinoma (N = 20-34) subjects will receive study treatment based on the MTD determined from Phase 1
Intervention: Atezolizumab
Phase 2: Cohort 3
Histology Agnostic Adenocarcinoma (N = 23-56) subjects will receive study treatment based on the MTD determined from Phase 1
Intervention: Hydroxychloroquine
Phase 2: Cohort 3
Histology Agnostic Adenocarcinoma (N = 23-56) subjects will receive study treatment based on the MTD determined from Phase 1
Intervention: Atezolizumab
Outcomes
Primary Outcomes
Phase 1: Estimated Maximum Tolerated Dose (MTD) Hydroxychloroquine (HCQ)
Time Frame: 28 days
The MTD is defined as the dose combination at which 30% of the patients experience a dose-limiting toxicity (DLT) by the end of Cycle 2
Phase 1: Estimated Maximum Tolerated Dose (MTD) Cobimetinib
Time Frame: 28 days
The MTD is defined as the dose combination at which 30% of the patients experience a dose-limiting toxicity (DLT) by the end of Cycle 2
Secondary Outcomes
- Phase 1: Number of Participants With Treatment-Emergent Adverse Events(Up to 20 weeks)