Atezolizumab for Stage III colon adenocarcinoma | Deficient DNA mismatch repair (dMMR)

Inclusion criteria

• {"criterion_text":"- 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)\n- Platelet count ≥ 100,000/mm³; platelets ≥ 75,000/mm³ required for patients who received cycle 1 of mFOLFOX6 prior to registration\n- Creatinine ≤ 1.5 x upper limit of normal (ULN) or Calculated creatinine clearance ≥ 45 mL/min by Cockcroft-Gault equation\n- Total bilirubin ≤ 1.5 x upper limit of normal (ULN), except in the case of Gilbert disease\n- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)\n- 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\n- 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).\n- Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue for subsequent retrospective central confirmation of dMMR status.\n- 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\n- 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.\n- Age ≥ 18 years\n- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2\n- 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.\n- Absolute neutrophil count (ANC) ≥ 1500/mm³"}

Exclusion criteria

• {"criterion_text":"- 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.\n- Known history of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins\n- Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation\n- 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\n- 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).\n- 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.\n- 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.\n- 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.\n- Active known autoimmune disease, including colitis, inflammatory bowel disease (i.e. ulcerative colitis or Crohn's disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency\n- 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\n- Known active pulmonary disease with hypoxia defined as: a. Oxygen saturation < 85% on room air, or b. Oxygen saturation < 88% despite supplemental oxygen\n- Grade ≥ 2 peripheral motor or sensory neuropathy\n- 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\n- Other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study\n- Systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration"}

Primary endpoints

• {"endpoint_text":"- Disease-free survival (DFS), defined as the time from randomization to first documentation of disease recurrence (primary tumor relapse) or death.","definition_or_measurement_approach":"Defined as the time from randomization to first documentation of disease recurrence (primary tumor relapse) or death."}

Germany

Earliest CTIS Part Ii Submission Date

21-08-2024

Latest Decision Or Authorization Date

31-01-2025

Processing Time Days

163

Number Of Sites

9

Number Of Participants

28

Primary sponsor

Full Name

National Cancer Institute

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

United States

Co-sponsors

• AIO-Studien gGmbH