Durvalumab and Tremelimumab, Oleclumab, or Monalizumab in Treating Patients with Colorectal Cancer with Lung or Liver Metastases That Can Be Removed by Surgery
- Patients must have histologically or cytologically confirmed colorectal cancer with liver or lung metastases deemed resectable by a liver or thoracic surgeon, respectively (resectability may involve the use of ablative techniques to some but not all liver or lung metastases); patients with a primary colorectal tumor that is planned for surgical resection are eligible. In addition patients with nonspecific lung lesions (lesions that are uncertain to be metastases given their small size, defined here as < 1 cm) are eligible
- 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)
- Hemoglobin >= 9g/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 >= 35 kg (required for flat dose-based administration of study agents)
- 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 (excluding short course radiation for rectal primaries)
- 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: * Patients with vitiligo or alopecia; * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; * Any chronic skin condition that does not require systemic therapy; * Patients without active disease in the last 5 years may be included but only after consultation with the study physician; * Patients with celiac disease controlled by diet alone
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab; the following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
- Prior exposure to T cell checkpoint inhibitor therapies for colorectal cancer, including durvalumab and tremelimumab, monalizumab, oleclumab
- 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: * Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician; * 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 investigational product (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 and tremelimumab or durvalumab and oleclumab or durvalumab and monalizumab combination therapy
- For cohort B only (durvalumab and oleclumab), patients with a recent (within three months) myocardial infarction, stroke, transient ischemic attack or thromboembolism are not eligible
I. Assess the safety and feasibility of adding immune-therapy with durvalumab (MEDI4736) (anti-PD-L1) combined with either tremelimumab (anti-CTLA-4) or monalizumab (anti-NKG2A) or oleclumab (MEDI9447) administered once pre-operatively and post-operatively in patients who are candidates for resection for colorectal cancer with liver or lung metastases (CRCLM).
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 are assigned to 1 of 3 cohorts.
COHORT A: Patients receive tremelimumab intravenously (IV) over 1 hour and durvalumab IV over 1 hour during week 1. Between weeks 4 and 11, patients undergo lung or liver surgery. Beginning 4 weeks after surgery, patients then receive durvalumab IV over 1 hour every 4 weeks for up to 4 months in the absence of disease progression or unacceptable toxicity.
COHORT B: Patients receive oleclumab IV over 1 hour and durvalumab IV over 1 hour during week 1. Between weeks 4 and 11, patients undergo lung or liver surgery. Beginning 4 weeks after surgery, patients then receive oleclumab IV over 1 hour every 2 weeks and durvalumab IV over 1 hour every 4 weeks for up to 4 months in the absence of disease progression or unacceptable toxicity.
COHORT C: Patients receive durvalumab IV over 1 hour and monalizumab IV during week 1. Between weeks 4 and 11, patients undergo lung or liver surgery. Beginning 4 weeks after surgery, patients then receive durvalumab IV over 1 hour and monalizumab IV every 4 weeks for up to 4 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for up to 2 years from liver surgery or until death.
Trial Phase Phase I
Trial Type Treatment
M D Anderson Cancer Center
Michael James Overman
- Primary ID 2015-0828
- Secondary IDs NCI-2016-00772
- Clinicaltrials.gov ID NCT02754856