Clinical Trials /

Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in Treating Patients With Deficient DNA Mismatch Repair Metastatic Colorectal Cancer

NCT02997228

Description:

This randomized phase III trial studies how well combination chemotherapy, bevacizumab, and/or atezolizumab work in treating patients with deficient deoxyribonucleic acid (DNA) mismatch repair 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. Immunotherapy with monoclonal antibodies, such as bevacizumab and atezolizumab, may help the body's immune system attack the cancer, and 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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in Treating Patients With Microsatellite Instability-High Metastatic Colorectal Cancer
  • 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 Monotherapy in the First-Line Treatment of Patients With Microsatellite Instability-High (MSI-H) Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01961
  • SECONDARY ID: NCI-2016-01961
  • SECONDARY ID: NRG-GI004/S1610
  • SECONDARY ID: NRG-GI004
  • SECONDARY ID: NRG-GI004
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT02997228

Conditions

  • Colorectal Adenocarcinoma
  • High-Frequency Microsatellite Instability
  • Stage IV Colorectal Cancer
  • Stage IVA Colorectal Cancer
  • Stage IVB Colorectal Cancer

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm II (atezolizumab)
BevacizumabAnti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar FKB238, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGFArm I (bevacizumab, mFOLFOX6)
Fluorouracil5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Arm I (bevacizumab, mFOLFOX6)
Leucovorin CalciumAdinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, Citrovorum Factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, WellcovorinArm I (bevacizumab, mFOLFOX6)
Oxaliplatin1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669Arm I (bevacizumab, mFOLFOX6)

Purpose

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 Description

      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 receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats
      every 2 weeks for up to 48 courses in the absence of disease progression or unacceptable
      toxicity.

      ARM III: Patients receive atezolizumab IV over 30-60 minutes on day 1. Courses with repeat
      every 2 weeks for up to 48 courses in the absence of disease progression or unacceptable
      toxicity. Patients also received bevacizumab IV over 30-90 minutes on day 1, oxaliplatin IV
      over 2 hours on day 1 courses 1-10, leucovorin calcium IV over 2 hours on day 1, and
      fluorouracil IV over 46-48 hours on day 1. Courses repeat every in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (bevacizumab, mFOLFOX6)Active ComparatorPatients receive bevacizumab 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.
  • Fluorouracil
  • Leucovorin Calcium
  • Oxaliplatin
Arm II (atezolizumab)ExperimentalPatients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats every 2 weeks for up to 48 courses in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
Arm III (atezolizumab, bevacizumab, mFOLFOX6)ExperimentalPatients receive atezolizumab IV over 30-60 minutes on day 1. Courses with repeat every 2 weeks for up to 48 courses in the absence of disease progression or unacceptable toxicity. Patients also received bevacizumab IV over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 courses 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on day 1. Courses repeat every in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Fluorouracil
  • Leucovorin Calcium
  • Oxaliplatin

Eligibility Criteria

        Inclusion Criteria:

          -  The patient must have signed and dated an Institutional Review Board (IRB)-approved
             consent form that conforms to federal and institutional guidelines

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

          -  Diagnosis of metastatic adenocarcinoma of colon or rectum without previous
             chemotherapy or any other systemic therapy for metastatic colorectal cancer

          -  Tumor determined to be mismatch-repair deficient (dMMR) or hMSI-H by Clinical
             Laboratory Improvement Act (CLIA)-certified assay

          -  Documentation by positron emission tomography(PET)/computed tomography (CT) scan, CT
             scan, or magnetic resonance imaging (MRI) that the patient has untreated measurable
             metastatic disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

          -  No immediate need for surgical intervention for the primary tumor or palliative
             diversion/bypass

          -  Absolute neutrophil count (ANC) must be >= 1500/mm^3

          -  Platelet count must be >= 100,000/mm^3

          -  Hemoglobin must be >= 10 g/dL

          -  Total bilirubin must be =< 1.5 x ULN (upper limit of normal) for the lab unless the
             patient has a bilirubin elevation > 1.5 x ULN to 3 x ULN due to Gilbert's disease or
             similar syndrome involving slow conjugation of bilirubin

          -  Alkaline phosphatase must be =< 3 x ULN for the lab with the following exception:
             patients with documented liver metastases or bone involvement - alkaline phosphatase
             must be =< 5 x ULN

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 3 x
             ULN for the lab with the following exception: for patients with documented liver
             metastases, AST and ALT must be =< 5 x ULN

          -  Serum creatinine =< 1.5 x ULN for the lab or measured or calculated creatinine
             clearance >= 30 mL/min

          -  A urine sample tested for proteinuria by the dipstick method must indicate 0 -1+
             protein; if dipstick reading is >= 2+, a 24-hour urine specimen must demonstrate <
             1.0 g of protein per 24 hours

          -  International normalized ratio of prothrombin time (INR) and prothrombin time (PT)
             must be =< 3 x ULN for the lab within 28 days before randomization; patients who are
             therapeutically treated with an agent such as warfarin may participate if they are on
             a stable dose and no underlying abnormality in coagulation parameters exists per
             medical history

          -  Pregnancy test done within 14 days prior randomization must be negative (for women of
             childbearing potential only); pregnancy testing should be performed according to
             institutional standards

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for
             the duration of study participation, and for 5 months after the last dose of
             atezolizumab; 6 months after the last dose of bevacizumab; and 6 months after the
             last dose of FOLFOX; should a woman become pregnant or suspect she is pregnant while
             she or her partner is participating in this study, she should inform her treating
             physician immediately; men treated or enrolled on this protocol must also agree to
             use adequate contraception prior to the study, for the duration of study
             participation, and for 6 months after the last dose of bevacizumab and 6 months after
             the last dose of FOLFOX

        Exclusion Criteria:

          -  Patients with central nervous system (CNS) metastases are excluded, with the
             following exception:

               -  Patients with asymptomatic treated CNS metastases may be enrolled, provided all
                  eligibility criteria are met, as well as the following:

                    -  Radiographic demonstration of improvement upon the completion of
                       CNS-directed therapy and no evidence of interim progression between the
                       completion of CNS-directed therapy and the screening radiographic study

                    -  No stereotactic radiation or whole-brain radiation within 28 days prior to
                       cycle 1, day 1

                    -  Screening CNS radiographic study >= 4 weeks from completion of radiotherapy
                       and >= 2 weeks from discontinuation of corticosteroids

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies, fluoropyrimidines, folic acid derivatives or oxaliplatin

          -  Uncontrolled high blood pressure defined as systolic blood pressure (BP) > 160 mmHg
             or diastolic BP 100 mmHg with or without anti-hypertensive medication; patients with
             initial BP elevations are eligible if initiation or adjustment of BP medication
             lowers pressure to meet entry criteria

          -  Any of the following cardiac conditions:

               -  Documented New York Heart Association (NYHA) class III or IV congestive heart
                  failure

               -  Myocardial infarction within 6 months prior to randomization

               -  Unstable angina within 6 months prior to randomization

               -  Symptomatic arrhythmia

          -  Serious or non-healing wound, skin ulcer, or bone fracture

          -  History of transient ischemic attack (TIA), cerebrovascular accident (CVA),
             gastrointestinal (GI) perforation or arterial thrombotic event within 6 months prior
             to randomization or symptomatic peripheral ischemia

          -  Other malignancies unless the patient is considered to be disease-free and has
             completed therapy for the malignancy >= 12 months prior to randomization; patients
             with the following cancers are eligible if diagnosed and treated within the past 12
             months: in situ carcinomas or basal cell and squamous cell carcinoma of the skin

          -  Known DPD (dihydro pyrimidine dehydrogenase) deficiency

          -  Symptomatic peripheral sensory neuropathy >= grade 2 (Common Terminology Criteria for
             Adverse Events [CTCAE] version [v] 4.0) in patients with no prior oxaliplatin therapy

          -  Prior treatment with oxaliplatin chemotherapy within 6 months prior to randomization
             and any prior treatment with an anti-PD-1 or anti-PD-L1 therapeutic antibody

          -  Treatment with systemic immunosuppressive medications (including, but not limited to,
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor [anti-TNF] agents) within 14 days prior to randomization; however,

               -  Patients who have received acute, low dose, systemic immunosuppressant
                  medications (e.g., a one-time dose of dexamethasone for nausea; or chronic daily
                  treatment with corticosteroids with a dose of =< 10 mg/day methylprednisolone
                  equivalent) may be enrolled

               -  The use of inhaled corticosteroids and mineralocorticoids (e.g.,
                  fludrocortisone) for patients with orthostatic hypotension or adrenocortical
                  insufficiency is allowed

          -  Known clinically significant liver disease; however,

               -  Patients with past or resolved hepatitis B infection (defined as having a
                  negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
                  [antibody to hepatitis B core antigen] antibody test) are eligible

               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

          -  History or risk of autoimmune disease, including, but not limited to, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
             syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
             thyroid disease, vasculitis, or glomerulonephritis; however,

               -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
                  replacement hormone may be eligible

               -  Patients with controlled type 1 diabetes mellitus on a stable insulin regimen
                  may be eligible

               -  Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis would
                  be excluded) are permitted provided that they meet the following conditions:

                    -  Patients with psoriasis must have a baseline ophthalmologic exam to rule
                       out ocular manifestations

                    -  Rash must cover less than 10% of body surface area (BSA)

                    -  Disease is well controlled at baseline and only requiring low potency
                       topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
                       fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

                    -  No acute exacerbations of underlying condition within the last 12 months
                       (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
                       retinoids, biologic agents, oral calcineurin inhibitors; high potency or
                       oral steroids)

          -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan; history of radiation pneumonitis in the radiation field
             (fibrosis) is permitted

          -  Patients with known active tuberculosis (TB) are excluded

          -  Severe infections requiring oral or intravenous (IV) antibiotics within 14 days prior
             to randomization

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to randomization

          -  Administration of a live, attenuated vaccine within 28 days prior to randomization

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with atezolizumab; (Note: Pregnancy testing should be performed
             within 14 days prior to randomization according to institutional standards for women
             of childbearing potential)

          -  Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this
             study, but HIV-positive patients must have:

               -  A stable regimen of highly active anti-retroviral therapy (HAART); and

               -  No requirement for concurrent antibiotics or antifungal agents for the
                  prevention of opportunistic infections; and

               -  A CD4 count above 250 cells/uL and an undetectable HIV viral load on standard
                  PCR-based tests
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:PFS
Time Frame:From the time from randomization until first confirmed progression or death from any cause, assessed up to 5 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Disease control rate (CR + PR + SD) assessed by RECIST 1.1
Time Frame:At 12 months
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Incidence of adverse events as defined by CTCAE version 4
Time Frame:Up to 30 days after last course
Safety Issue:
Description:
Measure:ORR (CR or PR) assessed by RECIST 1.1
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:OS
Time Frame:The time from randomization to death from any cause, assessed up to 5 years
Safety Issue:
Description: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.
Measure:Physical functioning, as measured by the PROMIS physical function short form 6a questionnaire
Time Frame:At 16 weeks
Safety Issue:
Description: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.
Measure:Severity and frequency of quality of life (QOL) and patient-reported outcomes (PRO)
Time Frame:Up to 5 years
Safety Issue:
Description: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
Measure:Severity of fatigue, as measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire
Time Frame:At 16 weeks
Safety Issue:
Description: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.
Measure:Surgical conversion rate defined as the proportion of patients that have surgery with curative intent
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 18, 2017