Clinical Trials /

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
  • Official Title: Randomized Trial of Standard Chemotherapy Alone or Combined With Atezolizumab as Adjuvant Therapy for Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair

Clinical Trial IDs

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

Conditions

  • Colon Adenocarcinoma
  • DNA Repair Disorder
  • Lynch Syndrome
  • Stage III Colon Cancer AJCC v7
  • Stage IIIA Colon Cancer AJCC v7
  • Stage IIIB Colon Cancer AJCC v7
  • Stage IIIC Colon Cancer AJCC v7

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm I (combination chemotherapy, atezolizumab)
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 (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 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.

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 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 dMMR.

      II. To assess the adverse events (AE) profile and safety of each treatment arm, using the
      Common Terminology Criteria for Adverse Events (CTCAE) and patient related outcomes
      (PRO)-CTCAE.

      QUALITY OF LIFE OBJECTIVES:

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

      POTENTIAL CORRELATIVE SCIENCE OBJECTIVES:

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

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

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

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

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

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

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

      VIII. 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.

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

      X. 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 cycles in the absence of
      disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over
      30-60 minutes starting on day 1 of cycle 1 or 2. Treatment repeats every 14 days for up to 25
      cycles 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 cycles in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for recurrence every 6 months
      for 2 years, then annually for 3 years. Patients are also followed up for survival every 6
      months for up to 8 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 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes starting on day 1 of cycle 1 or 2. Treatment repeats every 14 days for up to 25 cycles 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 cycles 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 [Tx, T1, T2, T3, or T4],
             N1-2M0; includes N1C); tumors must be deemed to originate in the colon including
             tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve)

          -  Presence of deficient (d) DNA mismatch repair (dMMR); MMR status must be assessed by
             immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where
             loss of one or more proteins indicates dMMR; dMMR may be determined either locally or
             by site-selected reference lab; Note: loss of MLH1 and PMS2 commonly occur together;
             formalin-fixed paraffin-embedded (FFPE) tumor tissue is required for subsequent
             retrospective central confirmation of dMMR status

          -  Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to
             participate; patients whose tumors show MSI-H by polymerase chain reaction (PCR)-based
             assay are not eligible to participate unless they also have MMR testing by IHC and are
             found to have dMMR (i.e. loss of one or more MMR proteins)

          -  Patients who are known to have Lynch syndrome and have been found to carry a specific
             germline 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 in the operative report or
             otherwise confirmed by the surgeon; near or positive radial margins are acceptable so
             long as en bloc resection was performed; proximal or distal margin positivity is not
             permitted

          -  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

          -  Based upon the operative report and other source documentation, the location of the
             primary tumor will be categorized as proximal or distal to the splenic flexure (distal
             includes), and further categorization will be as follows: cecum/ascending, descending,
             sigmoid colon, or rectosigmoid colon

          -  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 the current colon cancer except for one cycle of mFOLFOX6

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

          -  This study involves: 1) an investigational agent whose genotoxic, mutagenic and
             teratogenic effects on the developing fetus and newborn are unknown; and 2) an agent
             that has known genotoxic, mutagenic, and teratogenic effects; therefore, 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: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 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 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

          -  Patients positive for human immunodeficiency virus (HIV) are eligible only if they
             meet all of the following:

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

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

               -  A CD4 count above 250 cells/mcL, and an undetectable HIV viral load on standard
                  PCR-based tests

          -  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:Disease free survival (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:Overall survival
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.
Measure:Incidence of adverse events
Time Frame:Up to 30 days after last treatment
Safety Issue:
Description:Assessed by Common Terminology Criteria for Adverse Events version 4.0. 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).

Details

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

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