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NCT02912559 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
ACTIVE NOT RECRUITING
Registry last update
2026-10-01

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 (dMMR). 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 dMMR colon cancer.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Disease Free Survival (DFS)

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outcome · POSTED

Overall Survival

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outcome · POSTED

Number of Patients Experiencing Adverse Events

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
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 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, have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), and have been shown to be dMMR by IHC 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; patients with more than one primary colon adenocarcinoma are eligible if the qualifying stage III tumor is confined to the colon, and not rectum, and the other cancers of lower stage are removed in the en bloc R0 resection * 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 (included with distal), and further categorization will be as follows: cecum/ascending, transverse, 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 * Age \>= 12 years * Performance Status: * Patients \< 16 years of age: Lansky \>= 50% * Patients 16 to \< 18 years of age: Karnofsky \>= 50% * Patients \>= 18 years of age: 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 * Alternatively, for patients \< 18 years of age, maximum serum creatinine =\< the below age-gender-specific norms: * 12 years: 1.2 (male and female) * 13 to \< 16 years: 1.5 (male), 1.4 (female) * 16 to \< 18 years: 1.7 (male), 1.4 (female) * 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 polymerase chain reaction (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
healthy Volunteers
false
minimum Age
12 Years
sex
ALL
std Ages
  1. CHILD
  2. ADULT
  3. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    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 of each cycle. 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 on day 1 of each cycle, beginning in cycle 1 or 2. Treatment repeats every 14 days for up to 25 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI every 6 months for the first 2 years, then for years 3-5 or until evidence of relapse, whichever comes first. Patients may also undergo blood sample collection throughout the trial.
    intervention Names
    1. Drug: Atezolizumab
    2. Procedure: Biospecimen Collection
    3. Procedure: Computed Tomography
    4. Drug: Fluorouracil
    5. Drug: Leucovorin Calcium
    6. Procedure: Magnetic Resonance Imaging
    7. Drug: Oxaliplatin
    8. Other: Quality-of-Life Assessment
    label
    Arm I (combination chemotherapy, atezolizumab)
    type
    EXPERIMENTAL
  2. description
    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 of each cycle. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI every 6 months for the first 2 years, then for years 3-5 or until evidence of relapse, whichever comes first. Patients may also undergo blood sample collection throughout the trial.
    intervention Names
    1. Procedure: Biospecimen Collection
    2. Procedure: Computed Tomography
    3. Drug: Fluorouracil
    4. Drug: Leucovorin Calcium
    5. Procedure: Magnetic Resonance Imaging
    6. Drug: Oxaliplatin
    7. Other: Quality-of-Life Assessment
    label
    Arm II (combination chemotherapy)
    type
    ACTIVE_COMPARATOR
interventions
  1. arm Group Labels
    1. Arm I (combination chemotherapy, atezolizumab)
    description
    Given IV
    name
    Atezolizumab
    other Names
    1. MPDL 3280A
    2. MPDL 328OA
    3. MPDL-3280A
    4. MPDL3280A
    5. MPDL328OA
    6. RG 7446
    7. RG-7446
    8. RG7446
    9. RO 5541267
    10. RO-5541267
    11. RO5541267
    12. Tecentriq
    type
    DRUG
  2. arm Group Labels
    1. Arm I (combination chemotherapy, atezolizumab)
    2. Arm II (combination chemotherapy)
    description
    Undergo blood sample collection
    name
    Biospecimen Collection
    other Names
    1. Biological Sample Collection
    2. Biospecimen Collected
    3. Sample Collection
    4. Specimen Collection
    type
    PROCEDURE
  3. arm Group Labels
    1. Arm I (combination chemotherapy, atezolizumab)
    2. Arm II (combination chemotherapy)
    description
    Undergo CT
    name
    Computed Tomography
    other Names
    1. CAT
    2. CAT Scan
    3. Computed Axial Tomography
    4. Computerized Axial Tomography
    5. Computerized axial tomography (procedure)
    6. Computerized Tomography
    7. Computerized Tomography (CT) scan
    8. CT
    9. CT Scan
    10. Diagnostic CAT Scan
    11. Diagnostic CAT Scan Service Type
    12. tomography
    type
    PROCEDURE
  4. arm Group Labels
    1. Arm I (combination chemotherapy, atezolizumab)
    2. Arm II (combination chemotherapy)
    description
    Given IV
    name
    Fluorouracil
    other Names
    1. 5 Fluorouracil
    2. 5 Fluorouracilum
    3. 5 FU
    4. 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
    5. 5-Fluorouracil
    6. 5-Fluracil
    7. 5-Fu
    8. 5FU
    9. AccuSite
    10. Carac
    11. Fluoro Uracil
    12. Fluouracil
    type
    DRUG
  5. arm Group Labels
    1. Arm I (combination chemotherapy, atezolizumab)
    2. Arm II (combination chemotherapy)
    description
    Given IV
    name
    Leucovorin Calcium
    other Names
    1. Adinepar
    2. Calcifolin
    3. Calcium (6S)-Folinate
    4. Calcium Folinate
    5. Calcium Leucovorin
    6. Calfolex
    7. Calinat
    8. Cehafolin
    9. Citofolin
    10. Citrec
    11. Citrovorum Factor
    12. Cromatonbic Folinico
    type
    DRUG
  6. arm Group Labels
    1. Arm I (combination chemotherapy, atezolizumab)
    2. Arm II (combination chemotherapy)
    description
    Undergo MRI
    name
    Magnetic Resonance Imaging
    other Names
    1. Magnetic Resonance
    2. Magnetic Resonance Imaging (MRI)
    3. Magnetic resonance imaging (procedure)
    4. Magnetic Resonance Imaging Scan
    5. Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    6. MR
    7. MR Imaging
    8. MRI
    9. MRI Scan
    10. MRIs
    11. NMR Imaging
    12. NMRI
    type
    PROCEDURE
  7. arm Group Labels
    1. Arm I (combination chemotherapy, atezolizumab)
    2. Arm II (combination chemotherapy)
    description
    Given IV
    name
    Oxaliplatin
    other Names
    1. 1-OHP
    2. Ai Heng
    3. Aiheng
    4. Dacotin
    5. Dacplat
    6. Diaminocyclohexane Oxalatoplatinum
    7. Eloxatin
    8. Eloxatine
    9. Elplat
    10. JM 83
    11. JM-83
    12. JM83
    type
    DRUG
  8. arm Group Labels
    1. Arm I (combination chemotherapy, atezolizumab)
    2. Arm II (combination chemotherapy)
    description
    Ancillary studies
    name
    Quality-of-Life Assessment
    other Names
    1. Quality of Life Assessment
    type
    OTHER
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
712
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    DFS will be compared between treatment arms using the stratified log rank test at one-sided level 0.025. If zero DFS events are observed in a certain stratum at an interim analysis and unstratified log-rank is used, all subsequent analyses for DFS will use unstratified log-rank test. The hazard ratio (HR) for DFS will be estimated using a stratified Cox proportional hazards model and the 95 percent 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 percent CI for the median DFS for each treatment arm.
    measure
    Disease Free Survival (DFS)
    time Frame
    3 years
secondary Outcomes
  1. 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, only if DFS is statistically significant. The HR for OS will be estimated using a Cox proportional hazards model and the 95 percent CI for the HR will be provided. If a stratified log-rank test is used, stratified HR will be considered, and if an unstratified log-rank test is used, unstratified HR will be considered.
    measure
    Overall Survival
    time Frame
    5 years
  2. description
    Assessed by Common Terminology Criteria for Adverse Events version 4.0. The number of patients experiencing a grade 3 or greater adverse event (AE) regardless of attribution will be reported.
    measure
    Number of Patients Experiencing Adverse Events
    time Frame
    5 years
Full study description
brief Summary
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 (dMMR). 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 dMMR colon cancer.
detailed Description
PRIMARY OBJECTIVE: I. To determine whether atezolizumab combined with 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 (among patients aged \>= 18 years). QUALITY OF LIFE OBJECTIVE: 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. II. To access the efficacy of atezolizumab adjusting for baseline QOL and fatigue measurements. 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. XI. To determine changes in growth patterns compared to baseline (relative to age-specific standards for height and weight). (Patients aged 12 to \< 18 years to evaluate the impact of atezolizumab on growth and development patterns in this population) XII. To determine changes in development patterns compared to baseline (relative to onset of menarche \[for females\] and pubertal changes). (Patients aged 12 to \< 18 years to evaluate the impact of atezolizumab on growth and development patterns in this population) 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. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) every 6 months for the first 2 years, then for years 3-5 or until evidence of relapse, whichever comes first. Patients may also undergo blood sample collection throughout the trial. 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. Patients undergo CT or MRI every 6 months for the first 2 years, then for years 3-5 or until evidence of relapse, whichever comes first. Patients may also undergo blood sample collection throughout the trial. 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.
Source references
references
  1. citation
    Sinicrope FA, Ou FS, Arnold D, Peters WR, Behrens RJ, Lieu CH, Matin K, Cohen DJ, Potter SL, Nixon AB, Kottschade LA, Kathol E, Frankel WL, Shergill A, Hsu D, Reinacher-Schick A, Mehan P, Gold PJ, Khalil MF, Zemla T, Gatten C, O'Reilly EM, Meyerhardt JA. Atezolizumab plus FOLFOX for Stage III Mismatch Repair-Deficient Colon Cancer. N Engl J Med. 2026 Mar 26;394(12):1155-1166. doi: 10.1056/NEJMoa2507874.
    pmid
    41880612
    type
    DERIVED
  2. citation
    Langenfeld SJ, Raman S, Gribovskaja-Rupp I. Selected Abstracts. Dis Colon Rectum. 2025 Oct 1;68(10):1224-1230. doi: 10.1097/DCR.0000000000003879. Epub 2025 Jul 9. No abstract available.
    pmid
    40953502
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        ef="https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm">Drugs@FDA</a> .</p><h2>Efficacy and Safety</h2><p>Efficacy was evaluated in&nbsp;ATOMIC/ML39057 (NCT02912559), a multicenter, randomized, open-label, active-controlled trial in 711 adults and one pediatric patient with Stage III dMMR colon cancer after a complete rese
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      FDA approves atezolizumab in combination with chemotherapy for Stage III mismatch repair deficient colon cancer

    Preserved source evidence · Not medical advice