Clinical Trial: Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in Treating Patients With Microsatellite Instability-High Metastatic Colorectal Cancer

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: Colorectal Cancer Metastatic MSI-High Immuno-Therapy (COMMIT) Study: A Randomized Phase III Study of mFOLFOX6/Bevacizumab Combination Chemotherapy With or Without Atezolizumab or Atezolizumab Monother

Brief Summary: This randomized phase III trial studies how well combination chemotherapy, bevacizumab, and/or atezolizumab work in treating patients with microsatellite instability-high colorectal cancer that has spread to other places in the body. Drugs used in chemotherapy, such as fluorouracil, oxaliplatin, and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab and atezolizumab, may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy, bevacizumab, and atezolizumab may work better in treating patients with colorectal cancer.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To determine the efficacy, based on progression-free survival (PFS), of fluorouracil, oxaliplatin, and leucovorin calcium (mFOLFOX6)/bevacizumab plus atezolizumab (combination) and atezolizumab (single agent) as compared to mFOLFOX6/bevacizumab (control).

SECONDARY OBJECTIVES:

I. To compare the overall survival (OS). II. To compare the objective response rates (ORR) per RECIST 1.1. III. To determine the safety profiles of the combination of mFOLFOX6/bevacizumab/atezolizumab and atezolizumab monotherapy in patients with microsatellite instability-high metastatic colorectal cancer (MSI-H mCRC).

IV. To compare the surgical conversion rate. V. To compare disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) at 12 months.

VI. To determine the duration of response and stable disease. VII. To compare the health-related quality of life and symptom burden.

TERTIARY OBJECTIVES:

I. To bank tissue and blood samples for other future correlative studies from patients enrolled on the study.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 of courses 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1 and 2. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receiv
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome: PFS [ Time Frame: From the time from randomization until first confirmed progression or death from any cause, assessed up to 5 years ]

The experimental arms will be compared to the control arm by the log-rank test stratified by BRAF status, metastatic disease: (liver-only, extra-hepatic), and prior adjuvant therapy for colon cancer (yes, no). Hazard ratios and associated confidence intervals from a stratified Cox regression model will also be reported along with estimates of the distributions of time to PFS event by the method of Kaplan and Meier.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Disease control rate (CR + PR + SD) assessed by RECIST 1.1 [ Time Frame: At 12 months ]
    Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemo). Observed proportions along with confidence intervals will be presented by treatment.
  • Duration of overall response (CR or PR) as assessed by RECIST 1.1 [ Time Frame: From the time of first response to first confirmed progression by the study investigator or death from any cause, assessed up to 5 years ]
    Will be analyzed using the stratified log rank test. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.
  • Incidence of adverse events as defined by CTCAE version 4 [ Time Frame: Up to 30 days after last course ]
  • ORR (CR or PR) assessed by RECIST 1.1 [ Time Frame: Up to 5 years ]
    Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemo). Observed proportions along with confidence intervals will be presented by treatment.
  • OS [ Time Frame: The time from randomization to death from any cause, assessed up to 5 years ]
    Will be analyzed using the stratified log rank test. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.
  • Physical functioning, as measured by the PROMIS physical function short form 6a questionnaire [ Time Frame: At 16 weeks ]
    Will be compared between the control arm (Chemo-Bev) and the atezolizumab monotherapy arm by means of ordinal logistic regression with adjustment for the corresponding baseline measurement and stratification variables. The comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.
  • Severity and frequency of quality of life (QOL) and patient-reported outcomes (PRO) [ Time Frame: Up to 5 years ]
    The corresponding item (PRO-CTCAE severity, PRO-CTCAE frequency, or QOL scale) will be compared between the control arm (Chemo-Bev) and each experimental arm in turn (atezolizumab monotherapy and Chemo-Bev plus atezolizumab combination therapy) using a mixed regression model for repeated measures with the response being ordinal for the PRO-CTCAE items and linear for QOL scales. The model will also include the corresponding baseline measurement, time, and stratification variables. Presence of treatment-by-time interaction will be investigated for each model. Each comparison will be performed at
  • Severity of fatigue, as measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire [ Time Frame: At 16 weeks ]
    Will be compared between the control arm (Chemo-Bev) and the atezolizumab monotherapy arm by means of ordinal logistic regression with adjustment for the corresponding baseline measurement and stratification variables. The comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.
  • Surgical conversion rate defined as the proportion of patients that have surgery with curative intent [ Time Frame: Up to 5 years ]
    Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemo). Observed proportions along with confidence intervals will be presented by treatment.


Original Secondary Outcome: Same as current

Information By: National Cancer Institute (NCI)

Dates:
Date Received: December 19, 2016
Date Started: November 7, 2017
Date Completion: April 30, 2022
Last Updated: April 23, 2017
Last Verified: April 2017