A Phase II Study of the Dual Immune Checkpoint Blockade With Durvalumab (MEDI4736) Plus Tremelimumab Following Palliative Hypofractionated Radiation in Patients With Microsatellite Stable (MSS) Metastatic Colorectal Cancer Progressing on Chemotherapy
Overview
- Phase
- Phase 2
- Intervention
- durvalumab
- Conditions
- Colorectal Cancer Metastatic
- Sponsor
- NSABP Foundation Inc
- Enrollment
- 33
- Locations
- 18
- Primary Endpoint
- Overall Objective Response Rate (ORR) of Dual Immune Checkpoint Blockade by RECIST 1.1
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This study is being done to look at the safety and response to the combination of two investigational drugs, tremelimumab and durvalumab, when given after radiation therapy for patients with microsatellite stable (MSS) metastatic colorectal cancer. Tremelimumab and durvalumab recognize specific proteins on the surface of cancer cells and trigger the immune system to destroy the cancer cells.
In order to learn more about certain characteristics of colorectal cancer tumors, this study includes special research tests using samples from diagnostic tumors, fresh tumor samples from an area where the cancer has spread, and blood samples.
Detailed Description
The FC-9 study is designed as a phase II, open label, single arm study of the dual immune checkpoint blockade with the combination of durvalumab and tremelimumab following hypofractionated palliative radiation in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) who have progressed on chemotherapy. The primary aim is to determine the anti-tumor efficacy of the dual immune checkpoint blockade with durvalumab plus tremelimumab. The secondary aims are to determine the clinical benefit rate, duration of response, tolerability and correlates of response. Tumor response at unirradiated target lesions will be measured at baseline and every 2 cycles using RECIST 1.1. Following three doses of hypofractionated palliative radiation (Days -2, -1, and Day 0 prior to Cycle 1), patients will receive the combination of tremelimumab (75 mg IV infusion) and durvalumab (1500 mg IV infusion) on Day 1 for 4 cycles. Beginning with Cycle 5 through Cycle 24, patients will receive durvalumab alone (1500 mg/IV infusion) on Day 1 of each 28 day cycle. The sample size will be between 12 and 21 evaluable patients. Twelve evaluable patients will be treated in the first stage of the study. If there are no responses among the 12 evaluable patients, the study will be terminated. If the study goes on to the second stage, a total of 21 evaluable patients will be studied. Submission of tumor tissue and blood samples for FC-9 correlative science studies will be a study requirement for all patients. Requirements will include archived tumor samples from the diagnostic biopsy; additional biopsies of fresh tissue from an accessible lesion prior to radiation therapy and after 2 cycles of study therapy; and blood sample collections.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The ECOG performance status must be 0 or
- •There must be histologic confirmation of a diagnosis of colorectal adenocarcinoma.
- •The tumor must have been determined to be microsatellite stable (MSS).
- •There must be documentation by positron emission tomography (PET)/computed tomography (CT) scan, CT scan, or magnetic resonance imaging (MRI), that the patient has evidence of measurable metastatic disease per RECIST 1.
- •Patients must have an accessible metastatic lesion for pretreatment core biopsy.
- •Unless either drug is medically contraindicated, patients must have received oxaliplatin and irinotecan as part of standard metastatic chemotherapy regimens.
- •The patient must have multiple sites of metastatic disease with at least one lesion amenable to treatment with stereotactic radiation therapy (SBRT) in the lung or liver and at least one lesion not being irradiated and meeting RECIST 1.
- •At the time of study entry, blood counts performed within 2 weeks prior to study entry must meet the following criteria:
- •ANC (absolute neutrophil count) must be greater than or equal to 1500/mm3,
- •Platelet count must be greater than or equal to 100,000/mm3; and
Exclusion Criteria
- •Diagnosis of anal or small bowel carcinoma.
- •Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid.
- •Previous therapy with any PD-1 or PD-L1 (programmed cell death-1 (PD-1) protein, programmed death ligand-1 (PDL-1) protein inhibitor including durvalumab or anti-CTLA4 (including tremelimumab) for any malignancy.
- •Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study therapy.
- •Active or chronic hepatitis B or hepatitis C.
- •Symptomatic or uncontrolled brain metastases requiring concurrent treatments, uncontrolled spinal cord compression, carcinomatous meningitis, or new evidence of brain or leptomeningeal disease; uncontrolled seizures.
- •Active infection or chronic infection requiring chronic suppressive antibiotics.
- •Active or documented inflammatory disease.
- •Known history of human immunodeficiency virus (HIV) or acquired immunodeficiency-related (AIDS) illnesses.
- •Current or prior use of immunosuppressive medication within 28 days before the first dose of study therapy with the exceptions of intranasal corticosteroids or systemic corticosteroids at physiological doses that do not exceed 10mg/day of prednisone or an equivalent corticosteroid.
Arms & Interventions
durvalumab and tremelimumab
Intervention: durvalumab
durvalumab and tremelimumab
Intervention: Tremelimumab
Outcomes
Primary Outcomes
Overall Objective Response Rate (ORR) of Dual Immune Checkpoint Blockade by RECIST 1.1
Time Frame: Through treatment, up to 1.3 years
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be \<10mm on the short axis. Partial Response (PR): 30% or more decrease in the sum of diameters of target lesions. The reference the baseline sums of diameters. Progressive Disease (PD): 20% or more increase in the sum of diameters of target lesions. The reference is the smallest sum while on study (including the baseline sum if that is the smallest on study). In addition to the relative 20% increase, the sum must also demonstrate an absolute increase 5mm or more. (Note: any appearance of one or more new lesions is also considered progression).Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. The reference is the smallest sum of diameters while on study.
Secondary Outcomes
- Percentage of Patients Who Have Achieved Clinical Benefit(At 16 weeks)
- Median Duration of Response to mCRC (Metastic Colorectal Cancer) Responds to Study Therapy(Through study completetion (1.3 years))
- Frequency of Adverse Events Assessed by CTCAE 4.0, From Beginning of Treatment to 90 Days After Last Dose(During treatment (max of 12 cycles; each cycle 28 days) to 90 days after last dose of study therapy)