Tremelimumab and Durvalumab in Treating Patients With Colorectal Cancer With Liver Metastases That Can Be Removed by Surgery

Phase 1

Completed

Conditions: Stage IV Colorectal Cancer AJCC v7
Resectable Mass
Stage IVA Colorectal Cancer AJCC v7
Stage IVB Colorectal Cancer AJCC v7
Metastatic Carcinoma in the Liver

Interventions: Biological: Durvalumab
Other: Laboratory Biomarker Analysis
Procedure: Therapeutic Conventional Surgery
Biological: Tremelimumab

Registration Number: NCT02754856

Lead Sponsor: M.D. Anderson Cancer Center

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

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
Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
Known or ordered molecular testing for MSI, BRAF, and KRAS status
Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients; women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply:
- Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
- Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
Ability to understand and the willingness to sign a written informed consent document
Weight > 30 kg (required for flat dose-based administration of study agents)

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
Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria: a) patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician; b) patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the study physician
Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment, concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
Major surgical procedure within 28 days prior to the first dose of IP; Note: local surgery of isolated lesions for palliative intent is acceptable
History of allogenic organ transplantation
Known active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies); patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible; patients positive for hepatitis C (hepatitis C virus [HCV]) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (tremelimumab, durvalumab)	Laboratory Biomarker Analysis	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.
Treatment (tremelimumab, durvalumab)	Therapeutic Conventional Surgery	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.
Treatment (tremelimumab, durvalumab)	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.
Treatment (tremelimumab, durvalumab)	Tremelimumab	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.

Primary Outcome Measures

Name	Time	Method
Post-operative Toxicity	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	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 Outcome Measures

Name	Time	Method
Treatment Related Toxicity	3 years	Treatment related toxicity graded by CTCAE v5
Pre-operative Response Rate	2 years	Pre-operative response rate evaluation using RECIST v1.1. RECIST 1.1 will be used to identify measurable disease on baseline CT scans. Tumor measurements will be made upon restaging CT scans prior to surgery. No tumor measurements will take place post-operatively as the goal of therapy is no evidence of disease. Pre-surgery response will be classified into Complete Response, Partial Response, Stable Disease and Progressive Disease.
Relapse-Free Survival (RFS)	3 years	The time from date of curative surgery to the time of recurrence or death
Overall Survival	3 years	The time from treatment to death, regardless of disease recurrence.
Translational Evaluation of Various Immune-relevant Factors	3 years	Tumor immune markers was evaluated using flow cytometry, Multiplex Immunofluorescence (mIF) and Immunohistochemistry (IHC) analyses, RNA sequencing, Microbial DNA isolation and 16S rRNA gene sequencing (using QIAamp DNA stool mini kit on pretreatment feacal samples)

Trial Locations

Locations (1): M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States

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