Study of Combination Therapy With the MEK Inhibitor, Cobimetinib, Immune Checkpoint Blockade, Atezolizumab, and the AUTOphagy Inhibitor, Hydroxychloroquine in KRAS-mutated Advanced Malignancies

NCT04214418 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: AAAS4165ML41472
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 2

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.

Conditions

Gastrointestinal Cancer

Outcome Measures

Primary Outcomes (2)

• Phase 1: Estimated Maximum Tolerated Dose (MTD) Hydroxychloroquine (HCQ)

  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

  28 days

• Phase 1: Estimated Maximum Tolerated Dose (MTD) Cobimetinib

  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

  28 days

Secondary Outcomes (1)

• Phase 1: Number of Participants With Treatment-Emergent Adverse Events

  Up to 20 weeks

Study Arms (4)

Phase 1: Maximum Tolerated Dose (MTD)

EXPERIMENTAL

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

Drug: Cobimetinib; Drug: Hydroxychloroquine; Drug: Atezolizumab

Phase 2: Cohort 1

EXPERIMENTAL

Advanced Pancreatic Adenocarcinoma (N = 23-67) subjects will receive study treatment based on the MTD determined from Phase 1

Drug: Cobimetinib; Drug: Hydroxychloroquine; Drug: Atezolizumab

Phase 2: Cohort 2

EXPERIMENTAL

Advanced Colorectal Adenocarcinoma (N = 20-34) subjects will receive study treatment based on the MTD determined from Phase 1

Drug: Cobimetinib; Drug: Hydroxychloroquine; Drug: Atezolizumab

Phase 2: Cohort 3

EXPERIMENTAL

Histology Agnostic Adenocarcinoma (N = 23-56) subjects will receive study treatment based on the MTD determined from Phase 1

Drug: Cobimetinib; Drug: Hydroxychloroquine; Drug: Atezolizumab

Interventions

Cobimetinib DRUG

(40-60 mg) orally once daily (morning) on days 1-21 of each 28-day selective small molecule inhibitor for MEK1 and MEK2

Phase 1: Maximum Tolerated Dose (MTD); Phase 2: Cohort 1; Phase 2: Cohort 2; Phase 2: Cohort 3

Hydroxychloroquine DRUG

(600mg) orally twice daily on days 1-28 of each 28-day cycle

Phase 1: Maximum Tolerated Dose (MTD); Phase 2: Cohort 1; Phase 2: Cohort 2; Phase 2: Cohort 3

Atezolizumab DRUG

840 mg IV on Days 1 and 15 of each cycle humanized IgG1 monoclonal antibody (MAb)

Also known as: TECENTRIQ, MPDL3280A

Phase 1: Maximum Tolerated Dose (MTD); Phase 2: Cohort 1; Phase 2: Cohort 2; Phase 2: Cohort 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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):
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without granulocyte colony-stimulating factor support
• White blood cell (WBC) count ≥ 2.5 x 109/L
• Lymphocyte count ≥ 0.5 x 109/L
• Platelet count ≥ 100 x 109/L without transfusion
• Hemoglobin (Hgb) \> 9.0 g/dL

You may not qualify if:

• 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.
• Adverse events from prior anti-cancer therapy Participants may not initiate treatment if they have adverse events from prior anti-cancer therapy that have not resolved to Grade ≤ 1 or better, with the exception of Grade ≤ 2 peripheral neuropathy or any grade alopecia.
• Patients currently receiving any other investigational agents
• Concomitant treatment with other anti-neoplastic agents (hormone therapy acceptable)
• Uncontrolled pleural effusion, pericardial effusion, or ascites
• Patients with symptomatic brain metastases Subjects with untreated brain metastasis ≤ 1 cm can be considered eligible if deemed asymptomatic by the investigator upon consultation with the medical monitor, and do not require immediate radiation or steroids. Subjects with brain metastasis that is treated and stable for 1 month may be considered eligible if they are asymptomatic and on stable dose of steroids, or if they do not require steroids following successful local therapy.

Sponsors & Collaborators

• Columbia University: lead
• Genentech, Inc.: collaborator

Study Sites (2)

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

Brown University

Providence, Rhode Island, 02912, United States

Location

MeSH Terms

Conditions

Gastrointestinal Neoplasms

Interventions

cobimetinib; Hydroxychloroquine; atezolizumab

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Gulam Manji, MD, PhD
• Organization: Columbia University

gam2140@cumc.columbia.edu

212-304-6357

Study Officials

• Gulam Manji, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine Division of Hematology/Oncology

Model Details: The phase 1 portion of the study will be conducted using the time-to-event continue reassessment method (TITE-CRM) using four dose levels. The phase 2 portion of the study will use the recommended phase 2 dose for three cohorts with KRAS mutation - 1. Pancreatic adenocarcinoma; 2. Colorectal adenocarcinoma; and 3. Histology agnostic adenocarcinoma.

Study Record Dates

• First Submitted: December 27, 2019
• First Posted: January 2, 2020
• Study Start: February 12, 2020
• Primary Completion: April 11, 2022
• Study Completion: July 1, 2022
• Last Updated: December 18, 2024
• Results First Posted: December 18, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share
• Time Frame: End of study
• Access Criteria: Coded data

Locations

US (2)