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Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair

NCT02912559

Description:

This phase III trial studies combination chemotherapy and atezolizumab to see how well it works compared with combination chemotherapy alone in treating patients with stage III colon cancer and deficient deoxyribonucleic acid (DNA) mismatch repair. Drugs used in combination chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, 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 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 with atezolizumab may work better than combination chemotherapy alone in treating patients with colon cancer.

Related Conditions:
  • Colon Adenocarcinoma
  • Lynch Syndrome
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair or Microsatellite Instability
  • Official Title: Randomized Trial of FOLFOX Alone or Combined With Atezolizumab as Adjuvant Therapy for Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair or Microsatellite Instability

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01417
  • SECONDARY ID: NCI-2016-01417
  • SECONDARY ID: A021502
  • SECONDARY ID: A021502
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT02912559

Conditions

  • Colon Adenocarcinoma
  • DNA Repair Disorder
  • Lynch Syndrome
  • Microsatellite Instability
  • Stage IIIA Colon Cancer
  • Stage IIIB Colon Cancer
  • Stage IIIC Colon Cancer

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm I (combination chemotherapy, atezolizumab)
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 (combination chemotherapy, atezolizumab)
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 (combination chemotherapy, atezolizumab)
Oxaliplatin1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669Arm I (combination chemotherapy, atezolizumab)

Purpose

This randomized phase III trial studies combination chemotherapy and atezolizumab to see how well it works compared with combination chemotherapy alone in treating patients with stage III colon cancer and deficient deoxyribonucleic acid (DNA) mismatch repair or microsatellite instability. Drugs used in combination chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, 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 atezolizumab, may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy with atezolizumab may work better than combination chemotherapy alone in treating patients with colon cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine whether atezolizumab combined with oxaliplatin, leucovorin calcium, and fluorouracil (FOLFOX) and its continuation as monotherapy can significantly improve disease-free survival (DFS) compared to FOLFOX alone in patients with stage III colon cancers and high-frequency microsatellite instability (MSI-H) or deficient DNA mismatch repair (dMMR).

SECONDARY OBJECTIVES:

I. To determine whether atezolizumab combined with FOLFOX and its continuation as monotherapy can significantly improve overall survival compared to FOLFOX alone in patients with stage III colon cancers and MSI-H or dMMR.

TERTIARY OBJECTIVES:

I. To determine the impact of the addition of atezolizumab to FOLFOX on patient health-related quality of life (QOL), functional domains of health-related QOL, and disease- and treatment-related symptoms.

II. To determine if the "immunoscore" can predict the efficacy of atezolizumab for disease-free survival among patients with stage III colon cancer.

III. To assess whether circulating immune cell populations can predict the efficacy of atezolizumab as adjuvant therapy for stage III colon cancer.

IV. To explore the associations of genomic alterations identified in cell-free (cf)DNA with DFS in patients treated with FOLFOX with or without atezolizumab.

V. To assess whether soluble markers of systemic inflammation in blood can predict the efficacy of atezolizumab as adjuvant therapy for stage III colon cancer.

VI. To assess the relationship between baseline plasma 25(OH) D level, change in 25(OH)D level, and DFS and overall survival (OS) in patients with stage III colon cancer receiving FOLFOX +/- atezolizumab.

VII. To determine the ability of using fecal microbiota and their metabolic products to predict survival benefit from anti-PD-L1 antibody therapy in dMMR/MSI-H colon cancer patients.

VIII. To determine if hypermutation or hyper-indel status is associated with response to atezolizumab.

IX. To determine if unique messenger ribonucleic acid (mRNA) expression signatures are predictive of disease-free survival among patients receiving adjuvant chemotherapy for stage III colon cancer.

X. To determine if the efficacy of atezolizumab differs among dMMR/MSI cancers due to germline MMR mutation (MLH1, MSH2, MSH6, PMS2) versus those with MLH1 hypermethylation and CIMP in patients with stage III colon cancer.

XI. To identify overall mutational burden and number of putative tumor neoantigens in colon carcinoma specimens.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3. Treatment repeats every 14 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes starting on day 1 of course 1 or 2. Treatment repeats every 14 days for up to 25 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3. Treatment repeats every 14 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month and every 6 months for 5 years.

Trial Arms

NameTypeDescriptionInterventions
Arm I (combination chemotherapy, atezolizumab)ExperimentalPatients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3. Treatment repeats every 14 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes starting on day 1 of course 1 or 2. Treatment repeats every 14 days for up to 25 courses in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Fluorouracil
    • Leucovorin Calcium
    • Oxaliplatin
    Arm II (combination chemotherapy)Active ComparatorPatients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV as a bolus on day 1, then continuously over 46 hours on days 1-3. Treatment repeats every 14 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
      • Fluorouracil
        • Leucovorin Calcium
        • Oxaliplatin

      Eligibility Criteria

      Inclusion Criteria:

      - Histologically proven stage III colon adenocarcinoma (any T, N1-2M0; includes N1C)

      - Presence of microsatellite instability (MSI-H) or deficient (d) DNA mismatch repair (dMMR); MSI can be determined using a polymerase chain reaction (PCR)-based assay or alternatively, dMMR status by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR testing; MSI/dMMR may be determined either locally or by site-selected reference lab; Note: loss of MLH1 and PMS2 commonly occur together

      - Patients with MSI testing that did not show dMMR (loss of MMR protein) or MSI-H are not eligible to participate

      - Patients who are known to have Lynch syndrome and have been found to carry a specific mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2) are eligible to participate

      - Tumors must have been completely resected; in patients with tumor adherent to adjacent structures, en bloc R0 resection must be documented; positive radial margins are not excluded as long as en bloc resection was performed; proximal or distal margin positivity is excluded

      - Entire tumor must be in the colon (rectal involvement is an exclusion); surgeon confirmation that entire tumor was located in the colon is required only in cases where it is important to establish if the tumor is a colon versus (vs) rectal primary

      - No evidence of residual involved lymph node disease or metastatic disease at the time of registration based on clinician assessment of imaging; the treating physician will determine if incidental lesions on imaging require workup to exclude metastatic disease; if based on review of images, the treating physician determines the patient to be stage III, then the patient is eligible

      - No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for colon cancer EXCEPT for 1 cycle of mFOLFOX6

      - Eastern Cooperative Oncology Group (ECOG) performance status =< 2

      - For women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required; a female of childbearing potential is a sexually mature female who:

      - Has not undergone a hysterectomy or bilateral oophorectomy; or

      - Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

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

      - Platelet count >= 100,000/mm^3; platelets >= 75,000 required for patients who received cycle 1 of mFOLFOX6 prior to registration

      - Creatinine =< 1.5 x upper limit of normal (ULN) or

      - Calculated (calc.) creatinine clearance >= 45 mL/min by Cockcroft-Gault equation

      - Total bilirubin =< 1.5 x upper limit of normal (ULN) except in the case of Gilbert disease

      - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)

      - Thyroid-stimulating hormone (TSH) within normal limits (WNL); supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible

      - No active known autoimmune disease, including colitis, inflammatory bowel disease (i.e., ulcerative colitis or Crohn's disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency

      - No known active hepatitis B or C

      - Active hepatitis B can be defined as:

      - Hepatitis B virus surface antigen (HBsAg) detectable for > 6 months;

      - Serum hepatitis B virus (HBV) DNA 20,000 IU/ml (105 copies/ml); lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B

      - Persistent or intermittent elevation in ALT/AST levels

      - Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation

      - Active hepatitis C can be defined as:

      - Hepatitis C antibody (AB) positive AND

      - Presence of hepatitis C virus (HCV) RNA

      - Excluded if known active pulmonary disease with hypoxia defined as:

      - Oxygen saturation < 85% on room air, or

      - Oxygen saturation < 88% despite supplemental oxygen

      - No grade >= 2 peripheral motor or sensory neuropathy

      - No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study

      - No systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration

      - No known history of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins

      - No known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation

      - No known allergy to 5-fluorouracil, oxaliplatin, or leucovorin

      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:DFS
      Time Frame:From the time from randomization to first documentation of disease recurrent or death, assessed up to 5 years
      Safety Issue:
      Description:DFS will be compared between treatment arms using the stratified log rank test at one-sided level 0.025. The hazard ratio (HR) for DFS will be estimated using a stratified Cox proportional hazards model and the 95% confidence interval (CI) for the HR will be provided. Results from an unstratified analysis will also be provided. Kaplan-Meier methodology will be used to estimate the median DFS for each treatment arm, and Kaplan-Meier curves will be produced. Brookmeyer Crowley methodology will be used to construct the 95% CI for the median DFS for each treatment arm.

      Secondary Outcome Measures

      Measure:Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events version 4.0
      Time Frame:Up to 30 days after last treatment
      Safety Issue:
      Description:Frequency tables will be reviewed to determine the patterns. The overall adverse event rates will be compared between treatment arms using Chi-square test (or Fisher's exact test if the data in contingency table is sparse).
      Measure:OS
      Time Frame:From the time from randomization to death, from any cause, assessed up to 5 years
      Safety Issue:
      Description:The distribution of overall survival will be estimated using the method of Kaplan-Meier. Overall survival will be compared between treatment arms using the log-rank test.

      Details

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

      Trial Keywords

        Last Updated

        January 31, 2017