Clinical Trials /

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

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 (metastatic). 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 Adenocarcinoma
Recruiting Status:

Suspended

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in Treating Patients With Deficient DNA Mismatch Repair Metastatic Colorectal Cancer
  • Official Title: Colorectal Cancer Metastatic dMMR 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 Deficient DNA Mismatch Repair (dMMR) 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
  • Mismatch Repair Deficiency
  • Stage IV Colorectal Cancer AJCC v7
  • Stage IVA Colorectal Cancer AJCC v7
  • Stage IVB Colorectal Cancer AJCC v7

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 CBT 124, Bevacizumab Biosimilar FKB238, Bevacizumab Biosimilar HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar SCT501, HD204, 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-VEGF, SCT501Arm I (bevacizumab, mFOLFOX6)
Fluorouracil5 Fluorouracil, 5 Fluorouracilum, 5 FU, 5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, 5FU, 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 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.

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. II. To compare the objective response rates (ORR) per
      Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

      III. To determine the safety profiles of the combination of mFOLFOX6/bevacizumab/atezolizumab
      and atezolizumab monotherapy in patients with mismatch-repair deficient (dMMR) metastatic
      colorectal cancer (mCRC).

      IV. To compare the surgical conversion rate. V. To determine the duration of response and
      stable disease. VI. To determine the progression-free survival (PFS) by retrospective central
      independent scan review.

      EXPLORATORY OBJECTIVES:

      I. To compare the health-related quality of life and patient-reported symptoms.

      TRANSLATIONAL OBJECTIVES:

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

      II. To compare disease control rate (complete response [CR] + partial response [PR] + stable
      disease [SD]) at 12 months.

      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 cycles 1-10, leucovorin calcium IV over 2 hours on
      day 1, and fluorouracil IV over 46-48 hours on days 1 and 2. Treatment with oxaliplatin
      repeats every 2 weeks for up to 10 cycles in the absence of disease progression or
      unacceptable toxicity. Cycles of bevacizumab, leucovorin calcium, and fluorouracil 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 cycles in the absence of disease progression or unacceptable toxicity.

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

      After completion of study treatment, patients are followed up every 8 weeks for 18 months,
      and then every 12 weeks for up to 5 years.
    

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 cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1 and 2. Treatment with oxaliplatin repeats every 2 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Cycles of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
  • Bevacizumab
  • 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 cycles 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. Treatment repeats every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive bevacizumab IV over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on day 1. Treatment with oxaliplatin repeats every 2 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Cycles of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Bevacizumab
  • 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) by Clinical Laboratory
             Improvement Act (CLIA)-certified immunohistochemical (IHC) assay with a panel of all
             four IHC markers, including MLH1, MSH2, PMS2, and MSH6; Note: microsatellite
             instability high (MSI-H) diagnosed by microsatellite instability (MSI) testing (either
             Bethesda markers or Pentaplex panel) or by next-generation sequencing (NGS) is not
             eligible unless dMMR is confirmed by CLIA-certified immunohistochemical (IHC) assay
             with a panel of all four IHC markers including MLH1, MSH2, PMS2 and MSH6

          -  An adequate amount of archived tumor tissue, either from primary colorectal cancer
             site or metastatic lesions, for central confirmation of dMMR status:

               -  Either whole or part of the formalin-fixed paraffin-embedded (FFPE) block
                  containing tumor tissue; or

               -  At least 9 unstained slides containing tumor sections

          -  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 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 (obtained within 28 days prior
             randomization)

          -  Platelet count must be >= 100,000/mm^3 (obtained within 28 days prior randomization)

          -  Hemoglobin must be >= 8 g/dL (obtained within 28 days prior randomization)

          -  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 (obtained within 28 days
             prior randomization); and

          -  Alkaline phosphatase must be =< 2.5 x ULN for the lab with the following exception:
             patients with documented liver metastases or bone involvement - alkaline phosphatase
             must be =< 5 x ULN (obtained within 28 days prior randomization); and

          -  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 (obtained within 28 days prior
             randomization)

          -  Serum creatinine =< 1.5 x ULN for the lab or measured or calculated creatinine
             clearance >= 30 mL/min (obtained within 28 days prior randomization)

          -  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 =< 1.5 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; administration of atezolizumab and/or mFOLFOX6/bevacizumab
             may have an adverse effect on pregnancy and poses a risk to the human fetus, including
             embryo-lethality; 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

          -  Women of child-bearing potential 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 (150 days) after the last dose of atezolizumab,
             6 months after the last dose of bevacizumab, and 6 months after the last dose of
             mFOLFOX6; men with female partners of child-bearing potential must 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 mFOLFOX6

        Exclusion Criteria:

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

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

                    -  Evaluable or measurable disease outside the CNS

                    -  No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within
                       10 mm of the optic apparatus (optic nerves and chiasm)

                    -  No history of intracranial hemorrhage or spinal cord hemorrhage

                    -  No ongoing requirement for dexamethasone for CNS disease; patients on a
                       stable dose of anticonvulsants are permitted.

                    -  No neurosurgical resection or brain biopsy within 28 days prior to
                       randomization

               -  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
                       randomization

                    -  Screening CNS radiographic study >= 28 days from completion of radiotherapy
                       and >= 14 days 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) > 150 mmHg or
             diastolic BP 90 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 are excluded unless the patient has completed therapy for the
             malignancy >= 12 months prior to randomization and is considered disease-free;
             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] 5.0) in patients with no prior oxaliplatin therapy

          -  Prior treatment with oxaliplatin chemotherapy within 6 months prior to randomization

          -  Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or
             pathway-targeting agents; patients who have received prior treatment with anti-CTLA-4
             may be enrolled provided the following requirements are met:

               -  Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the
                  last dose to randomization

               -  No history of severe immune-related adverse effects (CTCAE Grade 3 and 4) from
                  anti-CTLA-4

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events (other than alopecia) due to agents administered more
             than 4 weeks earlier are excluded; however, the following therapies are allowed:

               -  Hormone-replacement therapy or oral contraception

               -  Herbal therapy > 7 days prior to randomization (herbal therapy intended as
                  anticancer therapy must be discontinued at least 1 week prior to randomization)

               -  Palliative radiotherapy for bone metastases > 14 days prior to randomization

          -  Treatment with systemic immunostimulatory medications (including, but not limited to
             interferon [IFN]-alpha or interleukin [IL]-2 within 42 days prior to randomization

          -  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

          -  Patients taking bisphosphonate therapy for symptomatic hypercalcemia; use of
             bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is
             allowed

          -  Patients requiring treatment with a receptor activator of nuclear factor kappa-B
             ligand (RANKL) inhibitor (e.g., denosumab) who cannot discontinue it before treatment
             with atezolizumab

          -  Treatment with any other investigational agent within 4 weeks prior to randomization

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited 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

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  Patients with known active tuberculosis (TB) are excluded

          -  Severe infections within 28 days prior to randomization, including but not limited to,
             hospitalization for complications of infection, bacteremia, or severe pneumonia

          -  Signs or symptoms of infection within 14 days prior to randomization

          -  Received oral or intravenous (IV) antibiotics within 14 days prior to randomization;
             patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
             infection or chronic obstructive pulmonary disease) are eligible

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to randomization or anticipation of need for a major surgical procedure during
             the course of the study

          -  Administration of a live, attenuated vaccine within 28 days prior to randomization or
             anticipation that such a live, attenuated vaccine will be required during the study
             and up to 5 months after the last dose of atezolizumab; Note: influenza vaccination
             should be given during influenza season only (approximately October to March);
             patients must not receive live, attenuated influenza vaccine within 28 days prior to
             randomization or at any time during the study

          -  Psychiatric illness/social situations that would limit compliance with study
             requirements

          -  Pregnant women are excluded from this study because atezolizumab is an agent with the
             potential for teratogenic or abortifacient effects; because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with atezolizumab, breastfeeding should be discontinued if the mother is
             treated with atezolizumab; these potential risks may also apply to other agents used
             in this study; (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

          -  Patients with prior allogeneic bone marrow transplantation or prior solid organ
             transplantation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (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:Overall survival (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:Objective response rate (ORR) (complete response [CR] or partial response [PR])
Time Frame:Up to 5 years
Safety Issue:
Description:Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. 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:Incidence of adverse events
Time Frame:Up to 30 days after last course
Safety Issue:
Description:Defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Measure:Surgical conversion rate
Time Frame:Up to 5 years
Safety Issue:
Description:Defined as the proportion of patients that have surgery with curative intent. 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:Disease control rate (CR + PR + stable disease [SD])
Time Frame:At 12 months
Safety Issue:
Description:Assessed by RECIST 1.1. 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)
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:Assessed by RECIST 1.1. 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:PFS
Time Frame:From randomization until first progression by retrospective central independent scan review or death from any cause, assessed up to 5 years
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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