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

  • STATUS
    Recruiting
  • End date
    Dec 12, 2021
  • participants needed
    700
  • sponsor
    National Cancer Institute (NCI)
Updated on 15 April 2021
platelet count
antibiotics
cancer
corticosteroids
calcium
hysterectomy
immunosuppressive
absolute neutrophil count
monoclonal antibodies
hiv viral load
fluorouracil
combination chemotherapy
pulmonary disease
metastasis
oxaliplatin
tumor cells
leucovorin
colon cancer
monoclonal antibody therapy
stage iii colon cancer
adenocarcinoma
antifungal agents
atezolizumab
investigational agent
anaphylactic reactions
mmr protein

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. 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.

Description

PRIMARY OBJECTIVE:

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 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.

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.

Details
Condition Colorectal Cancer, Lynch Syndrome, Hereditary Neoplastic Syndrome, Deficiency of DNA repair, NOS, Colon Cancer Screening, Colon cancer; rectal cancer, Stage III Colon Cancer AJCC v7, Stage IIIA Colon Cancer AJCC v7, Stage IIIB Colon Cancer AJCC v7, Stage IIIC Colon Cancer AJCC v7, Adenocarcinoma of the Colon, Colon Adenocarcinoma, Hereditary Cancer Syndromes, adenocarcinoma of colon, hnpcc
Treatment fluorouracil, laboratory biomarker analysis, Leucovorin calcium, quality-of-life assessment, Oxaliplatin, Atezolizumab
Clinical Study IdentifierNCT02912559
SponsorNational Cancer Institute (NCI)
Last Modified on15 April 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Do you have any of these conditions: Adenocarcinoma of the Colon or hnpcc or Deficiency of DNA repair, NOS or Colon Adenocarcinoma or Colon Cancer Screening or Stage IIIB Colon Cancer AJC...?
Do you have any of these conditions: Adenocarcinoma of the Colon or Stage III Colon Cancer AJCC v7 or Deficiency of DNA repair, NOS or Colon cancer; rectal cancer or Stage IIIB Colon Canc...?
Do you have any of these conditions: Stage IIIC Colon Cancer AJCC v7 or Colon Cancer Screening or hnpcc or Adenocarcinoma of the Colon or Hereditary Cancer Syndromes or Lynch Syndrome or ...?
Do you have any of these conditions: Stage III Colon Cancer AJCC v7 or Hereditary Cancer Syndromes or Colorectal Cancer or Adenocarcinoma of the Colon or Stage IIIA Colon Cancer AJCC v7 o...?
Do you have any of these conditions: Adenocarcinoma of the Colon or Colon Cancer Screening or Stage IIIC Colon Cancer AJCC v7 or adenocarcinoma of colon or Stage IIIB Colon Cancer AJCC v7...?
Do you have any of these conditions: Hereditary Cancer Syndromes or hnpcc or Stage IIIC Colon Cancer AJCC v7 or Deficiency of DNA repair, NOS or Adenocarcinoma of the Colon or Colon cance...?
Do you have any of these conditions: Colon Cancer Screening or hnpcc or Adenocarcinoma of the Colon or Colon Adenocarcinoma or Stage IIIA Colon Cancer AJCC v7 or Deficiency of DNA repair,...?
Do you have any of these conditions: Deficiency of DNA repair, NOS or Colon Cancer Screening or Colorectal Cancer or Stage IIIB Colon Cancer AJCC v7 or Stage IIIC Colon Cancer AJCC v7 or ...?
Do you have any of these conditions: Stage III Colon Cancer AJCC v7 or Stage IIIC Colon Cancer AJCC v7 or Lynch Syndrome or Hereditary Cancer Syndromes or Stage IIIB Colon Cancer AJCC v7 ...?
Do you have any of these conditions: Stage IIIB Colon Cancer AJCC v7 or Hereditary Neoplastic Syndrome or Colon cancer; rectal cancer or Hereditary Cancer Syndromes or adenocarcinoma of c...?
Do you have any of these conditions: hnpcc or Hereditary Neoplastic Syndrome or Colorectal Cancer or Lynch Syndrome or Stage IIIC Colon Cancer AJCC v7 or Hereditary Cancer Syndromes or Co...?
Do you have any of these conditions: Adenocarcinoma of the Colon or Stage IIIC Colon Cancer AJCC v7 or hnpcc or Deficiency of DNA repair, NOS or Colon Cancer Screening or Colon Adenocarci...?
Do you have any of these conditions: hnpcc or Stage IIIA Colon Cancer AJCC v7 or Colon Cancer Screening or adenocarcinoma of colon or Deficiency of DNA repair, NOS or Colon Adenocarcinoma...?
Do you have any of these conditions: Hereditary Cancer Syndromes or Stage IIIC Colon Cancer AJCC v7 or Hereditary Neoplastic Syndrome or Colorectal Cancer or Stage IIIA Colon Cancer AJCC ...?
Do you have any of these conditions: Adenocarcinoma of the Colon or Deficiency of DNA repair, NOS or Stage IIIA Colon Cancer AJCC v7 or Stage III Colon Cancer AJCC v7 or Stage IIIB Colon ...?
Do you have any of these conditions: adenocarcinoma of colon or Stage III Colon Cancer AJCC v7 or Colon Cancer Screening or Lynch Syndrome or Adenocarcinoma of the Colon or hnpcc or Color...?
Do you have any of these conditions: Stage IIIA Colon Cancer AJCC v7 or Colorectal Cancer or Deficiency of DNA repair, NOS or Colon cancer; rectal cancer or Colon Adenocarcinoma or adenoc...?
Do you have any of these conditions: Stage IIIB Colon Cancer AJCC v7 or Hereditary Neoplastic Syndrome or adenocarcinoma of colon or Colorectal Cancer or Stage IIIC Colon Cancer AJCC v7 o...?
Do you have any of these conditions: adenocarcinoma of colon or Colon cancer; rectal cancer or Colon Adenocarcinoma or Lynch Syndrome or Colon Cancer Screening or Hereditary Cancer Syndro...?
Do you have any of these conditions: Deficiency of DNA repair, NOS or Colon cancer; rectal cancer or Stage IIIA Colon Cancer AJCC v7 or Stage IIIB Colon Cancer AJCC v7 or Adenocarcinoma o...?
Do you have any of these conditions: Hereditary Cancer Syndromes or Hereditary Neoplastic Syndrome or Colon Cancer Screening or Adenocarcinoma of the Colon or Stage IIIB Colon Cancer AJCC...?
Gender: Male or Female
Do you have any of these conditions: Stage III Colon Cancer AJCC v7 or Hereditary Cancer Syndromes or Hereditary Neoplastic Syndrome or Stage IIIA Colon Cancer AJCC v7 or Colorectal Cance...?
Do you have any of these conditions: Stage IIIB Colon Cancer AJCC v7 or Colon Adenocarcinoma or Stage IIIC Colon Cancer AJCC v7 or Stage III Colon Cancer AJCC v7 or hnpcc or Colon cancer;...?
Do you have any of these conditions: Hereditary Cancer Syndromes or Hereditary Neoplastic Syndrome or Deficiency of DNA repair, NOS or adenocarcinoma of colon or Colorectal Cancer or Stag...?
Do you have any of these conditions: Stage IIIC Colon Cancer AJCC v7 or hnpcc or Stage IIIA Colon Cancer AJCC v7 or Colorectal Cancer or Stage IIIB Colon Cancer AJCC v7 or Adenocarcinoma ...?
Do you have any of these conditions: hnpcc or Lynch Syndrome or Hereditary Neoplastic Syndrome or Colorectal Cancer or Stage IIIC Colon Cancer AJCC v7 or Hereditary Cancer Syndromes or St...?
Do you have any of these conditions: hnpcc or Hereditary Neoplastic Syndrome or Adenocarcinoma of the Colon or Colon Cancer Screening or adenocarcinoma of colon or Deficiency of DNA repai...?
Do you have any of these conditions: Hereditary Neoplastic Syndrome or Colon Cancer Screening or Deficiency of DNA repair, NOS or Stage IIIC Colon Cancer AJCC v7 or Stage III Colon Cancer...?
Do you have any of these conditions: Stage IIIA Colon Cancer AJCC v7 or Hereditary Neoplastic Syndrome or hnpcc or Hereditary Cancer Syndromes or adenocarcinoma of colon or Colorectal Can...?
Is your age greater than or equal to 18 yrs?
Do you have any of these conditions: hnpcc or Lynch Syndrome or Hereditary Neoplastic Syndrome or Stage IIIB Colon Cancer AJCC v7 or Colon cancer; rectal cancer or adenocarcinoma of colon...?
Do you have any of these conditions: Hereditary Neoplastic Syndrome or Colon Cancer Screening or Hereditary Cancer Syndromes or Lynch Syndrome or Stage IIIC Colon Cancer AJCC v7 or Adenoc...?
Do you have any of these conditions: Colon Adenocarcinoma or Stage IIIC Colon Cancer AJCC v7 or Stage III Colon Cancer AJCC v7 or Colon cancer; rectal cancer or Hereditary Cancer Syndrome...?
Do you have any of these conditions: Lynch Syndrome or hnpcc or Colon cancer; rectal cancer or Colon Adenocarcinoma or Adenocarcinoma of the Colon or Stage IIIC Colon Cancer AJCC v7 or Co...?
Do you have any of these conditions: Colorectal Cancer or Stage IIIA Colon Cancer AJCC v7 or Adenocarcinoma of the Colon or Hereditary Cancer Syndromes or Colon cancer; rectal cancer or S...?
Do you have any of these conditions: Colon cancer; rectal cancer or Stage IIIB Colon Cancer AJCC v7 or hnpcc or Colorectal Cancer or Colon Adenocarcinoma or Hereditary Neoplastic Syndrome...?
Do you have any of these conditions: Colorectal Cancer or Stage IIIB Colon Cancer AJCC v7 or Stage IIIA Colon Cancer AJCC v7 or Colon Adenocarcinoma or hnpcc or Colon Cancer Screening or ...?
Do you have any of these conditions: Deficiency of DNA repair, NOS or Stage III Colon Cancer AJCC v7 or Stage IIIA Colon Cancer AJCC v7 or Colon Adenocarcinoma or Colon cancer; rectal can...?
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; 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
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
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