Atezolizumab Monotherapy vs Atezolizumab Plus Cobimetinib in Liver Metastases From Colorectal Cancer

NCT03340558 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: Pro00085578
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This study is for patients with metastatic colorectal cancer who are candidates for resection of metastases. This study will be conducted sequentially with 2 cohorts: 1.) Monotherapy Cohort and 2.) Combination Cohort Pre-metastatectomy

• Monotherapy Cohort: The first 10 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 of each 28-day cycle.
• Combination Cohort: The next 15 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 and Cobimetinib 60 mg PO on Days 1-21 of each 28-day cycle. Note: Cobimetinib must be held for the 7 days prior to metastatectomy. All subjects will be treated for 2 cycles (8 weeks) prior to metastatectomy Metastatectomy Subjects will undergo liver metastatectomy within 42 days of completion of Cycle 2 of pre-metastatectomy treatment. No study treatment is administered while the patient is healing after surgery. Post-metastatectomy Once the patient has healed from the surgery, adjuvant treatment may be administered at the discretion of the treating physician. Restaging following standards of care for this setting.

Conditions

Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (2)

• Change in CD4 T cell immune infiltrates

  The change in CD4 T cell tumor infiltrates will be measured as the absolute number of infiltrates per number of high-powered fields. The paired t-test will be used to compare changes in CD4 T cells in pre- and post-treatment.

  Subject tissue will be assessed pre-treatment (baseline) and post-treatment within 42 days after completion of Cycle 2 using metastatectomy tissue.

• Change in CD8 T cell immune infiltrates

  The change in CD8 T cell tumor infiltrates will be measured as the absolute number of infiltrates per number of high-powered fields. The paired t-test will be used to compare changes in CD8 T cells in pre- and post-treatment.

  Subject tissue will be assessed pre-treatment (baseline) and post-treatment within 42 days after completion of Cycle 2 using metastatectomy tissue.

Secondary Outcomes (2)

• Disease-free survival

  Disease-free survival will be measured from study entry up to 5 years.

• Overall Survival

  Overall survival will be measured from study entry up to 5 years

Study Arms (2)

Monotherapy Cohort

EXPERIMENTAL

The first 10 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 of each 28-day cycle. Subjects will be treated for 2 cycles before undergoing metastatectomy within 42 days of completion of Cycle 2. No study treatment is administered while subjects are healing after surgery.

Biological: Atezolizumab

Combination Cohort

EXPERIMENTAL

The next 15 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 and Cobimetinib 60 mg PO on Days 1-21 of each 28-day cycle. Cobimetinib must be held for the 7 days prior to metastatectomy. Subjects will be treated for 2 cycles before undergoing metastatectomy within 42 days of completion of Cycle 2.

Biological: Atezolizumab; Drug: Cobimetinib

Interventions

Atezolizumab BIOLOGICAL

Atezolizumab is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1.

Combination Cohort; Monotherapy Cohort

Cobimetinib DRUG

MEK inhibitor

Combination Cohort

Eligibility Criteria

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

You may qualify if:

• Histologically and/or cytologically confirmed and radiographically measurable per RECIST v1.1 colorectal cancer with liver metastasis. Patients may have other sites of metastatic disease.µlµ
• Liver lesion safely amenable to core needle biopsy.
• Willing to undergo core needle biopsy of liver metastatic site.
• Microsatellite stable disease as determined by IHC and/or PCR.
• Plan for next therapeutic intervention to be surgical resection of metastatic disease.
• Age ≥18 years with ability to understand and willingness to provide informed consent.
• ECOG performance status of 0 or 1.
• Life expectancy of \>3 months.
• For Combination Therapy cohort only: Able to swallow pills.
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to start of study drug and must be willing to use two methods of contraception, one of them being a barrier method during the study and for 3 months (or 6 months for subjects on Combination Therapy cohort) after last study drug administration.
• Adequate organ and marrow function as defined below:
• Absolute neutrophil count (ANC) ≥1500 µl
• WBC counts \> 2500/µl
• Lymphocyte count ≥ 300/µl
• Platelets ≥ 100,000/µl

You may not qualify if:

• Prior therapy with anti-PD-1 or anti-PD-L1 therapeutic antibody or pathway targeting agents.
• a. Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided the following requirements are met: i. Minimum of 12 weeks from the first dose of anti-CTLA-4 and \> 6 weeks from the last dose.
• ii. No history of severe immune-related adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3 and 4)
• For Combination Therapy cohort only: Prior therapy with MEK inhibitors.
• Anticancer therapy, including but not limited to chemotherapy, hormonal therapy, or radiotherapy, within 4 weeks prior to start of study treatment; however, the following are allowed:
• Hormone-replacement therapy or oral contraceptives
• Herbal therapy \> 1 week prior to start of study treatment (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to start of study treatment)
• Palliative radiotherapy for bone metastases \> 2 weeks prior to start of study treatment
• Expected to require any other form of systemic or localized anticancer therapy while on study.
• Adverse events from prior anticancer therapy that have not resolved to Grade ≤ 1 except for alopecia.
• Investigational agent within 4 weeks prior to start of study treatment (or within five half-lives of the investigational product, whichever is longer).
• Major surgical procedure within 28 days prior to start of study treatment or anticipation of need for a major surgical procedure during the course of the study. This does not refer to the planned liver metastatectomy that is part of the study.
• Malignancies other than the disease under study within 5 years prior to start of study treatment, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g. chronic lymphocytic leukemia Rai stage 0, prostate cancer with Gleason score \< 6, and prostate-specific \[PSA\] ≤ 10 mg/mL, etc).
• Diagnosis of acute leukemias, accelerated/blast-phase chronic myelogenous leukemia, chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory myeloma.
• Prior allogenic bone marrow transplantation or prior solid organ transplantation.

Sponsors & Collaborators

• Niharika Mettu: lead
• Roche-Genentech: collaborator

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

atezolizumab; cobimetinib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Niharika Mettu, MD, PhD

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Medical Instructor

Study Record Dates

• First Submitted: November 9, 2017
• First Posted: November 13, 2017
• Study Start: May 1, 2018
• Primary Completion: February 1, 2021
• Study Completion: February 1, 2025
• Last Updated: October 9, 2018

Record last verified: 2018-10

Locations

US (1)