Pilot Study Assessing the Safety and Tolerability of the Neoadjuvant Use of Tremelimumab (Anti-CTLA-4) Plus Durvalumab (MEDI4736) (Anti-PD-L1) in the Treatment of Resectable Colorectal Cancer Liver Metastases
Overview
- Phase
- Phase 1
- Intervention
- Durvalumab
- Conditions
- Metastatic Carcinoma in the Liver
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Post-operative Toxicity
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This phase I trial studies the side effects and how well tremelimumab and durvalumab work in treating patients with colorectal cancer that has spread to the liver and can be removed by surgery. Immunotherapy with monoclonal antibodies, such as tremelimumab and durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Detailed Description
PRIMARY OBJECTIVES: I. Assess the safety and feasibility of adding tremelimumab 75 mg intravenously (IV) plus durvalumab (MEDI4736) 1500 mg administered once pre-operatively and 4 cycles of durvalumab 1500 mg IV every 4 weeks for 4 cycles post-operatively in patients who are candidates for resection for colorectal cancer liver metastases. SECONDARY OBJECTIVES: I. Explore the changes in various immune parameters, including programmed cell death-1 ligand 1 (PD-L1) and programmed cell death1 (PD-1) expression in the tumor, over treatment and correlate with response and survival with goal of biomarker discovery. II. Estimate the relapse-free survival (RFS) in all enrolled subjects. OUTLINE: Patients receive tremelimumab IV over 1 hour and durvalumab IV over 4 hours during week 11. Between weeks 15 and 17, patients undergo liver surgery. Patients then receive durvalumab IV over 1 hour during weeks 21, 25, 29, and 33. After completion of study treatment, patients are followed up twice a year for 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically or cytologically confirmed colorectal cancer with liver metastases deemed resectable by a general or liver surgeon (resectability may involve the use of ablative techniques to some but not all liver metastases); those patients with known disease outside of the liver are not eligible (except for patients with primary lesions in place that are planned for resection or nonspecific lung metastases \< 1 cm)
- •Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 10 mm with spiral computed tomography (CT) scan
- •All lines of prior therapy accepted; subjects with prior hepatic or extra-hepatic resections of metastatic disease will be included
- •Life expectancy of greater than 6 months
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
- •Leukocytes \>= 3,000/mcL
- •Absolute neutrophil count \>= 1,500/mcL
- •Platelets \>= 100,000/mcL
- •Total bilirubin \< 1.5 X institutional normal limits (subjects with known Gilbert syndrome are eligible with total bilirubin \< 3.0 mg/dL)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\]) =\< 3 X institutional upper limit of normal
Exclusion Criteria
- •Prior chemotherapy \< 2 weeks prior to study drug treatment and treatment related adverse events that have not recovered to baseline or grade 1 (alopecia excluded); prior radiation therapy \< 4 weeks prior to study drug treatment
- •Patients may not be receiving any other investigational agents
- •Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]); the following are exceptions to this criterion: a) patients with vitiligo or alopecia; b) patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; c) any chronic skin condition that does not require systemic therapy; d) patients without active disease in the last 5 years may be included but only after consultation with the study physician; d) patients with celiac disease controlled by diet alone
- •Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
- •Prior exposure to T cell checkpoint inhibitor therapies, including durvalumab and tremelimumab
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, interstitial lung disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- •History of active primary immunodeficiency
- •Women who are pregnant, which includes women with a positive pregnancy test at enrollment or prior to the administration of study medication, or breastfeeding are not allowed on study
- •Receipt of a live vaccine within 30 days of study entry
Arms & Interventions
Treatment (tremelimumab, durvalumab)
Patients receive tremelimumab IV over 1 hour and durvalumab IV over 4 hours during week 11. Between weeks 15 and 17, patients undergo liver surgery. Patients then receive durvalumab IV over 1 hour during weeks 21, 25, 29, and 33.
Intervention: Durvalumab
Treatment (tremelimumab, durvalumab)
Patients receive tremelimumab IV over 1 hour and durvalumab IV over 4 hours during week 11. Between weeks 15 and 17, patients undergo liver surgery. Patients then receive durvalumab IV over 1 hour during weeks 21, 25, 29, and 33.
Intervention: Laboratory Biomarker Analysis
Treatment (tremelimumab, durvalumab)
Patients receive tremelimumab IV over 1 hour and durvalumab IV over 4 hours during week 11. Between weeks 15 and 17, patients undergo liver surgery. Patients then receive durvalumab IV over 1 hour during weeks 21, 25, 29, and 33.
Intervention: Therapeutic Conventional Surgery
Treatment (tremelimumab, durvalumab)
Patients receive tremelimumab IV over 1 hour and durvalumab IV over 4 hours during week 11. Between weeks 15 and 17, patients undergo liver surgery. Patients then receive durvalumab IV over 1 hour during weeks 21, 25, 29, and 33.
Intervention: Tremelimumab
Outcomes
Primary Outcomes
Post-operative Toxicity
Time Frame: 3 years
Post-operative toxicity graded by the Clavien-Dindo classification. The Clavien Dindo Classification is used to rank the severity of a surgical complication. It is based on the type of therapy needed to correct the complication. The scale consists of several grades (Grade I, II, IIIa, IIIb, IVa, IVb and V). Grade I complications are usually mild but Grade II and higher complications are more significant.
Feasibility and Safety in the Conduct of the Trial
Time Frame: 3 years
Feasibility and safety assessed by the rate of on-trial surgical resection of liver metastases, post-operative toxicity graded by the Clavien-Dindo classification, and treatment related toxicity graded by CTCAE v5. The combination was defined as feasible if at least 80% of participants could undergo resection or if between 60% and 80% could undergo resection with a positive toxicity and efficacy profile.
Secondary Outcomes
- Treatment Related Toxicity(3 years)
- Pre-operative Response Rate(2 years)
- Relapse-Free Survival (RFS)(3 years)
- Overall Survival(3 years)
- Translational Evaluation of Various Immune-relevant Factors(3 years)