Protocol Summary

Protocol No.: OCR15832

Sponsor Protocol No.: FC-9

Study Title
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

Principal Investigator(s)
George, Thomas

Objective
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.

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 12, 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.

Phase: Phase II

Age Group: Adult

Scope: National

Treatment
Durvalumab:
Following three doses of hypofractionated palliative radiation (Days −2, −1, and Day 0 prior to Cycle 1), patients will receive durvalumab (1500 mg IV infusion) on Day 1 for 4 cycles (in combination with tremelimumab). Beginning with Cycle 5 through Cycle 12, patients will receive durvalumab alone (1500 mg/IV infusion) on Day 1 of each 28 day cycle.

Tremelimumab:
Following three doses of hypofractionated palliative radiation (Days −2, −1, and Day 0 prior to Cycle 1), patients will receive tremelimumab (75 mg IV infusion) on Day 1 for 4 cycles (in combination with durvalumab).

Detailed Eligibility
INCLUSION CRITERIA:
1. Ages 18 years old and older
2. The ECOG performance status must be 0 or 1.
3. There must be histologic confirmation of a diagnosis of colorectal adenocarcinoma.
4. The tumor must have been determined to be microsatellite stable (MSS).
5. There must be documentation by PET/CT scan, CT scan, or MRI, that the patient has evidence of measurable metastatic disease per RECIST 1.1.
6. Patients must have an accessible metastatic lesion for pretreatment core biopsy.
7. Unless either drug is medically contraindicated, patients must have received oxaliplatin and irinotecan as part of standard metastatic chemotherapy regimens.
8. 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 1.1.
9. At the time of study entry, blood counts performed within 2 weeks prior to study entry must meet the following criteria:
- ANC must be greater than or equal to 1500/mm3,
- Platelet count must be greater than or equal to 100,000/mm3; and
- Hemoglobin must be greater than or equal to 9 g/dL.
10. The following criteria for evidence of adequate hepatic function performed within 2 weeks prior to study entry must be met:
- Total bilirubin must be less than or equal to 1.5 x ULN (upper limit of normal) for the lab unless the patient has a bilirubin elevation greater than 1.5 x ULN to 3 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and
- AST and ALT must be less than or equal to 2.5 x ULN for the lab with the following exception: for patients with documented liver metastases, AST and ALT must be less than or equal to 5 x ULN.
11. Adequate renal function within 4 weeks prior to study entry, defined as serum creatinine less than or equal to 1.5 x ULN for the lab or measured or calculated creatinine clearance greater than 40 mL/min by Cockcroft-Gault formula.
12. All hematologic, gastrointestinal, and genitourinary chemotherapy toxicities must be less than Grade 2 at the time study therapy is to begin. (Note: Transfusions may be used to correct hemoglobin for patients experiencing anemia from therapy who otherwise would be eligible for the study.
13. Patients with reproductive potential (male/female) must agree to use accepted and highly effective methods of contraception while receiving study therapy and for at least 6 months after the completion of study therapy. The definition of effective method of contraception will be based on the investigator's discretion.
14. Female patients must either be of non-reproductive potential (i.e., post-menopausal by history: greater than or equal to 60 years old and no menses for greater than or equal to 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.

EXCLUSION CRITERIA:
1. Diagnosis of anal or small bowel carcinoma.
2. Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid.
3. Previous therapy with any PD-1 or PD-L1 inhibitor including durvalumab or anti-CTLA4 (including tremelimumab) for any malignancy.
4. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study therapy.
5. Active or chronic hepatitis B or hepatitis C.

** Contact study team for complete eligibility details

Applicable Disease Sites
Colon Cancer

Participating Institutions
UF Gainesville : Margaret Veal

Contact
Margaret Veal
Phone: +1 352-265-0680 ext. 87656

Email: mamcewan@ufl.edu