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 (ATOMIC)
- Conditions
- stage III colon adenocarcinoma with deficient MMR
- Interventions
- Procedure: Biospecimen CollectionProcedure: Computed TomographyProcedure: Magnetic Resonance ImagingOther: Quality-of-Life Assessment
- Registration Number
- 2024-517269-18-00
- Lead Sponsor
- National Cancer Institute, AIO-Studien gGmbH
- Brief Summary
To determine whether atezolizumab combined with FOLFOX and its continuation as monotherapy can significantly improve DFS compared to FOLFOX alone in patients with stage III colon cancers and dMMR.
- 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.
Recruitment & Eligibility
- Status
- Authorised, recruitment pending
- Sex
- Not specified
- Target Recruitment
- 28
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)
Platelet count ≥ 100,000/mm³; platelets ≥ 75,000/mm³ 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
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. Note: loss of MLH1 and PMS2 commonly occur together. 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. Note that patients who 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).
Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue for subsequent retrospective central confirmation of dMMR status.
Tumor(s) 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 in the colon (rectal involvement is an exclusion). [Note: 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.
Age ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Not pregnant and not nursing. For women of childbearing potential (WOCBP) only, a negative pregnancy test done ≤ 7 days prior to registration is required. A WOCBP is a sexually mature female who: 1) is not naturally postmenopausal (defined as at least 12 consecutive months with no menses without an alternative medical cause); OR 2) has not had a hysterectomy and/or bilateral oophorectomy (Note: Women with tubal ligation are still considered of child-bearing potential according to CTFG Guidance). Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial.
Absolute neutrophil count (ANC) ≥ 1500/mm³
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.
Known history of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins
Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation
Contraindications against any of the chemotherapeutic agents of the mFOLFOX6 regimen including but not limited to known allergy to 5-fluorouracil, oxaliplatin, or folinic acid
Inability to provide consent because the patient does not understand the nature, significance, and/or implications of the clinical trial and therefore cannot form a rational intention in the light of the facts (e.g. patients with psychiatric illness).
Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
A “currently active” second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Guidance: a. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for ≥ 3 years, had a gastric or bowel carcinoid < 1 cm, or DCIS/LCIS of the breast without invasive cancer, or endometrial dysplasia/carcinoma in situ. b. Patients are not considered to have a “currently active” malignancy if they had a sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, sebaceous adenocarcinoma, keratoacanthoma, and squamous cell carcinoma) that was noninvasive.
Prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for the current colon cancer, except for one cycle of mFOLFOX6. Cycle 1 of mFOLFOX6 must have been administered per Appendix III of the main protocol.
Active known autoimmune disease, including colitis, inflammatory bowel disease (i.e. ulcerative colitis or Crohn's disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency
Known active hepatitis B or C a. Active hepatitis B can be defined as: i. Hepatitis B virus surface antigen (HBsAg) detectable for > 6 months; ii. 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; iii. Persistent or intermittent elevation in ALT/AST levels; iv. Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation. b. Active hepatitis C can be defined as: i. Hepatitis C antibody (AB) positive, AND ii. Presence of hepatitis C virus (HCV) RNA
Known active pulmonary disease with hypoxia defined as: a. Oxygen saturation < 85% on room air, or b. Oxygen saturation < 88% despite supplemental oxygen
Grade ≥ 2 peripheral motor or sensory neuropathy
HIV-positivity, unless all of the following are met: a. A stable regimen of highly active anti-retroviral therapy (HAART) b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections c. A CD4 count above 250 cells/μL, and an undetectable HIV viral load on standard PCR-based tests
Other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study
Systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm I (combination chemotherapy, atezolizumab) Biospecimen Collection 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. Arm I (combination chemotherapy, atezolizumab) Magnetic Resonance Imaging 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. Arm I (combination chemotherapy, atezolizumab) Computed Tomography 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. Arm I (combination chemotherapy, atezolizumab) Quality-of-Life Assessment 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. Arm II (combination chemotherapy) Computed Tomography 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. Arm II (combination chemotherapy) Magnetic Resonance Imaging 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. Arm I (combination chemotherapy, atezolizumab) Leucovorin Calcium 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. Arm II (combination chemotherapy) Biospecimen Collection 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. Arm II (combination chemotherapy) Quality-of-Life Assessment 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. Arm II (combination chemotherapy) Leucovorin Calcium 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. Arm II (combination chemotherapy) Oxaliplatin 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. Arm I (combination chemotherapy, atezolizumab) Atezolizumab 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. Arm I (combination chemotherapy, atezolizumab) Fluorouracil 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. Arm I (combination chemotherapy, atezolizumab) Oxaliplatin 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. Arm II (combination chemotherapy) Fluorouracil 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.
- Primary Outcome Measures
Name Time Method Disease-free survival (DFS), defined as the time from randomization to first documentation of disease recurrence (primary tumor relapse) or death. Disease-free survival (DFS), defined as the time from randomization to first documentation of disease recurrence (primary tumor relapse) or death.
- Secondary Outcome Measures
Name Time Method Overall survival From the time from randomization to death, from any cause, assessed up to 5 years 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.
Incidence of adverse events Up to 30 days after last treatment 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).
Trial Locations
- Locations (9)
Universitätsklinikum Leipzig AöR
🇩🇪Leipzig, Germany
Universitaetsklinikum Mannheim GmbH
🇩🇪Mannheim, Germany
Universitaetsklinikum Wuerzburg AöR
🇩🇪Wuerzburg, Germany
Universitaetsklinikum Carl Gustav Carus Dresden an der Technischen Universitaet Dresden AöR
🇩🇪Dresden, Germany
Universitaetsklinikum Ulm AöR
🇩🇪Ulm, Germany
St. Josef-Hospital
🇩🇪Bochum, Germany
Facharztzentrum Eppendorf
🇩🇪Hamburg, Germany
Klinikum der Universitaet Muenchen AöR
🇩🇪Munich, Germany
Charite Universitaetsmedizin Berlin KöR
🇩🇪Berlin, Germany
Universitätsklinikum Leipzig AöR🇩🇪Leipzig, GermanyUlrich HackerSite contact03419712574ulrich.hacker@medizin.uni-leipzig.de