Perioperative/Adjuvant atezolizumab in patients with MSI-high or MMR-deficient stage III colorectal cancer ineligible for oxaliplatin-based chemotherapy– a Phase II study

Phase 1

• Conditions: Patients with MSI-high or MMR-deficient stage III colorectal cancer who are ineligible for or who refuse oxaliplatin-based chemotherapy after R0 tumor resection (main study) or planned resection (sub-study); MedDRA version: 21.0Level: PTClassification code 10009955Term: Colon cancer stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10009966Term: Colon carcinoma stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 22.0Level: PTClassification code 10078672Term: DNA mismatch repair protein gene mutationSystem Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 21.0Level: LLTClassification code 10080676Term: Microsatellite instabilitySystem Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 20.0Level: PTClassification code 10001167Term: Adenocarcinoma of colonSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10001171Term: Adenocarcinoma of colon stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: PTClassification code 10061451Term: Colorectal cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: PTClassification code 10010034Term: Colorectal cancer stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: PTClassification code 10052360Term: Colorectal adenocarcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

• Registration Number: EUCTR2020-002715-21-DE
• Lead Sponsor: AIO-Studien-gGmbH

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-02-26
• Last Update Posted: 26 August 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

1. Written informed consent including participation in translational research and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
2. Male or female = 18 years of age
3. Histologically confirmed adenocarcinoma of the colon or rectum
4. For the main study: Pathological stage II high risk or Stage III disease. For the perioperative sub-study: Clinical staged T3-4 and/or nodal positive colorectal cancer without distant metastases
5. For the main study: R0 or R1-resected primary tumor For the perioperative sub-study: Resectable primary tumor; R0 resection anticipated (R1-resected patients can remain on study.)
6. Tumor is MSI-high (MSI-H) or MMR-deficient (dMMR) For the main study: assessed from biopsy or from resected tumor tissue For the perioperative sub-study: assessed from biopsy
7. ECOG status 0 – 2
8. Ineligible for oxaliplatin-based adjuvant chemotherapy or patient’s refusal of oxaliplatin-based adjuvant chemotherapy
9. Adequate blood count, liver enzymes, and renal function – re-testing can be undergone once in case of initial results near cutoff
- White blood cell count = 3.5 x 10^6/mL (Inclusion is also possible if White blood cell = 2,5 x 10^6/mL, in which case the neutrophils must be = 1.5 x 10^9/ml and the lymphocytes = 0.5 x 10^9/ml)
- Platelet count = 100 x 10^9/L (>100,000 per mm3)
- Hemoglobin = 9 g/dL (blood transfusion > 2 weeks before testing is permitted)
- AST (SGOT)/ALT (SGPT) = 5 x institutional upper limit of normal
- Serum Creatinine = 1.5 x institutional ULN or a calculated glomerular filtration rate = 30 mL per minute
10. Patients not receiving therapeutic anticoagulation must have an INR < 1.5 ULN and PTT < 1.5 ULN within 7 days prior to registration. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of registration
11. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
12. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly-effective contraception (i.e., one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for up to 6 months after the last dose of study drug.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 40
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 40

Exclusion Criteria

1. Severe infection within 4 weeks prior to registration e.g. hospitalization for complications of infection, bacteremia, known active pulmonary disease with hypoxia, or severe pneumonia or any active infection requiring systemic therapy within 4 weeks prior to registration. Patients with positive test result for SARS-CoV2 should be managed as per local institutional guidelines
2.For the main study: Distant metastases or residual disease/For the perioperative sub-study: Distant metastases or macroscopic residual disease (R2 resection status)
3. Neoadjuvant radiotherapy or radio-chemotherapy (rectal cancer patients without prior radio- or radio-chemotherapy allowed); prior neoadjuvant radio-chemotherapy or radiotherapy for rectal cancer is allowed if >5 years and secondary colorectal cancer
4. Prior adjuvant chemotherapy for colorectal cancer; allowed if >5 years and secondary colorectal cancer
5. Prior treatment with atezolizumab or any other checkpoint inhibitor
6. Treatment with systemic immunosuppressive medication within 2 weeks prior to treatment start, or anticipation of need for systemic immunosuppressive medication during study treatment
7. Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrollment.
8. History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins.
9. Known hypersensitivity to CHO cell products or any component of the atezolizumab formulation.
10. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. If any of these lung diseases is suspected based on the patient’s history or the integrated evaluation of clinical and radiological records, an additional spirometry should be conducted.
11. Active HBV infection (chronic or acute), defined as having a positive HBsAg test at screening. Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total HBcAb test at screening followed by a negative HBV DNA test, are eligible for the study. The HBV DNA test will be performed only for patients who have a positive total HBcAb test. Patients are also eligible if HBV DNA < 500 IU/mL obtained within 28 days prior to initiation of study treatment, AND anti-HBV treatment for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study
12. Anti-viral therapy against HCV during the trial (allowed prior to trial)
13. Positive HIV test. As an exception, known HIV+ patients may be included if they have: A stable regimen of 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
14. a) Treatment with a live, attenuated vaccine within 4 weeks prior to first dose of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the last dose of study treatment. b) Treatment with any vaccine during screening and the first cycle of treatment.
15. Active tuberculosis
16. Active or history of autoimmune disease or immune deficiency e.g. myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified