Study of Durvalumab and Tremelimumab After Radiation for Microsatellite Stable Metastatic Colorectal Cancer Progressing on Chemotherapy

Sponsor

NSABP Foundation Inc (Other)

Overall Status

Completed

CT.gov ID

NCT03007407

Collaborator

(none)

Enrollment

Locations

Arm

24.3

Actual Duration (Months)

1.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Metastatic	Drug: durvalumab Drug: Tremelimumab	Phase 2

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 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

33 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official 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

Actual Study Start Date :

Jul 31, 2017

Actual Primary Completion Date :

Apr 18, 2019

Actual Study Completion Date :

Aug 9, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: durvalumab and tremelimumab	Drug: 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. Other Names: MEDI4736 Drug: 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).

Arm

Intervention/Treatment

Experimental: durvalumab and tremelimumab

Drug: 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.

Other Names:

MEDI4736

Drug: 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).

Outcome Measures

Primary Outcome Measures

Overall objective response rate of dual immune checkpoint blockade [Through treatment, up to 1.3 years]
Overall objective response rate (ORR) by RECIST 1.1 criteria

Secondary Outcome Measures

Proportion of patients who have achieved clinical benefit [Through study completion, up to 2.5 years]
Proportion of patients who have achieved clinical benefit defined as CR and PR and stable disease that lasts at least 4 months
The time during which mCRC responds to study therapy [After cycles 2, 4, 6, 8, 10, and 12 and through study completion, up to 2.5 years]
Time to first progression from study entry per RECIST 1.1 criteria
Frequency of adverse events assessed by CTCAE 4.0, from beginning of treatment to 90 days after last dose [During treatment to 90 days after last dose of study therapy]
Frequency of adverse events categorized using the NCI Common Terminology Criteria for Adverse Events version 4.0

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

The ECOG performance status must be 0 or 1.
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 PET/CT scan, CT scan, or MRI, that the patient has evidence of measurable metastatic disease per RECIST 1.1.
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 1.1.
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.
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.
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.
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.
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.
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:

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 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.
History of allogeneic organ transplantation.
Any of the following cardiac conditions:
Documented NYHA Class III or IV congestive heart failure,
Myocardial infarction within 6 months prior to study entry,
Unstable angina within 6 months prior to study entry,
Symptomatic arrhythmia. If QTc greater than or equal to 470ms, confirmation of eligible QTc requires mean calculation from 2 additional electrocardiograms (ECGs) 2-5 minutes apart using Fridericia's Correction Formula (mean less than 470 ms).
Uncontrolled high blood pressure defined as systolic blood pressure (BP) greater than or equal to 150 mmHg or diastolic BP greater than or equal to 100 mmHg with or without anti-hypertensive medication. Patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria.
Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
Ongoing or active gastritis or peptic ulcer disease.
Active bleeding diatheses.
Known history of previous diagnosis of tuberculosis.
History of hypersensitivity to durvalumab or tremelimumab or any excipients of these drugs.
Known history or confirmation of active pneumonia, pneumonitis, symptomatic interstitial lung disease, or definitive evidence of interstitial lung disease described on CT scan, MRI, or chest x-ray in asymptomatic patients; dyspnea at rest requiring current continuous oxygen therapy.
Active or prior documented autoimmune disease within the past 2 years. (Note: Patients with vitiligo, Grave disease, or psoriasis not requiring systemic treatment within the past 2 years are eligible.)
Other malignancies unless the patient is considered to be disease-free and has completed therapy for the malignancy greater than or equal to 12 months prior to study entry. Patients with the following cancers are eligible if diagnosed and treated within the past 12 months: carcinoma in situ of the cervix, and basal cell and squamous cell carcinoma of the skin.
Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing should be performed within 14 days prior to study entry according to institutional standards for women of childbearing potential.)
Use of any investigational agent. Use and/or receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal anti-bodies) within 14 days prior to the first dose of study therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Smilow Cancer Hospital at Yale-New Haven	New Haven	Connecticut	United States	06510
3	Smilow Cancer Hospital Care Center at North Haven	North Haven	Connecticut	United States	06473
4	UF Health Davis Cancer Pavilion and Shands Med Plaza	Gainesville	Florida	United States	32608
5	UF Health Shands Cancer Hospital	Gainesville	Florida	United States	32608
6	UF Health Shands Hospital	Gainesville	Florida	United States	32610
7	University of Florida	Gainesville	Florida	United States	32610
8	University of Florida Health Cancer Center at Orlando Health	Orlando	Florida	United States	32806
9	Centralia Oncology Clinic	Centralia	Illinois	United States	62801
10	Cancer Care Specialists of Central Illinois	Decatur	Illinois	United States	62526
11	Cancer Care Specialists of Central Illinois/Crossroads Cancer Center	Effingham	Illinois	United States	62401
12	Cancer Care Specialists of Central Illinois-Swansea	Swansea	Illinois	United States	62226
13	Trinity Health Michigan	Ann Arbor	Michigan	United States	48106
14	University of Michigan	Ann Arbor	Michigan	United States	48109
15	St. Joseph Mercy-Brighton	Brighton	Michigan	United States	48114
16	St. Joseph Mercy-Canton	Canton	Michigan	United States	48188
17	St Joseph Mercy-Chelsea	Chelsea	Michigan	United States	48118
18	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107