This randomized phase II trial studies the side effects of durvalumab and tremelimumab and to see how well they work with or without high or low-dose radiation therapy in treating patients with colorectal or non-small cell lung cancer that has spread to other parts of the body (metastatic). Immunotherapy with durvalumab and tremelimumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving durvalumab and tremelimumab with radiation therapy may work better in treating patients with colorectal or non-small cell lung cancer.
PRIMARY OBJECTIVES: I. To assess safety and tolerability of combined checkpoint blockade with MEDI4736 (durvalumab) and tremelimumab alone or with high or low-dose radiation in non-small cell lung cancer (NSCLC). (NSCLC Cohort) II. To compare the overall response (excluding the irradiated lesion\[s\]) between combined checkpoint blockade with MEDI4736 and tremelimumab alone or combined checkpoint blockade with low or high dose radiation. (NSCLC Cohort) III. To assess safety and tolerability of combined checkpoint blockade with MEDI4736 and tremelimumab with high or low-dose radiation. (Colorectal Cohort) IV. To determine the overall response rate (excluding the irradiated lesion\[s\]) with combined checkpoint blockade with MEDI4736 and tremelimumab with either low or high dose radiation. (Colorectal Cohort) SECONDARY OBJECTIVES: I. To estimate median progression-free survival and overall survival. (NSCLC Cohort) II. To determine local control within the irradiated field(s) and abscopal response rates. (NSCLC Cohort) III. To evaluate associations between PD-L1 expression as well as levels of infiltrating CD3+, CD8+ T-cells and overall response. (NSCLC Cohort) IV. To explore changes in PD-L1 expression, circulating T-cell populations, T-cell infiltration, ribonucleic acid (RNA) expression, spatial relationship of immune markers, and mutational burden as a result of low or high dose radiation. (NSCLC Cohort) V. To estimate median progression-free survival and overall survival. (Colorectal Cohort) VI. To determine local control within the irradiated field and abscopal response rates. (Colorectal Cohort) VII. To evaluate associations between PD-L1 expression as well as levels of infiltrating CD3+ CD8+ T-cells and overall response. (Colorectal Cohort) VIII. To evaluate changes between PD-L1 expression as well as levels of infiltrating CD3+, CD8+ T-cells induced by targeted low or high dose radiation. (Colorectal Cohort) IX. To explore changes in circulating T-cell populations, T-cell infiltration, RNA expression, spatial relationship of immune markers, and mutational burden as a result of low or high dose radiation. (Colorectal Cohort) OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT 1: Patients with NSCLC are randomized to 1 of 3 arms. ARM A: Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive high dose radiation therapy once per day (QD) over 10 days for up to 3 fractions. ARM B: Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive low dose radiation therapy every 6 hours twice per day (BID) on weeks 2, 6, 10 and 14. ARM C: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. COHORT 2: Patients with CRC are randomized to 1 of 2 arms. ARM A: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. Beginning at week 2, patients receive high dose radiation therapy once per day (QD) over 10 days for up to 3 fractions. ARM B: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. Beginning at week 2, patients receive low dose radiation therapy every 6 hours twice per day (BID) on weeks 2, 6, 10 and 14. After completion of study treatment, patients are followed for up to 12 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
110
Given IV
Undergo radiation therapy
Given IV
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, United States
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
Overall Response Rate
Determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. NSCLC: The proportion of patients with response (complete response or partial response according to RECIST) will be compared for each pair-wise comparison of radiotherapy (RT)-containing therapy and control using chi- squared tests. The difference between the proportions responding will be presented with a 90% confidence interval. CRC: The proportion of patients with response will be presented with a 90% exact confidence interval.
Time frame: Up to 2 years
Progression-free Survival (PFS)
Distributions are summarized using the Kaplan-Meier method. Median times for each therapy arm are accompanied by 90% confidence intervals based on log(-log(endpoint)) methodology. NSCLC: The pairwise comparisons between the durvalumab/tremelimumab alone and durvalumab/tremelimumab with RT arms will be conducted using Cox regression. CRC: No statistical comparisons conducted between Arms A and B.
Time frame: From date of randomization until objective disease progression or death, whichever occurs first [up to 2 years]
Overall Survival (OS)
Distributions are summarized using the method of Kaplan-Meier. Median times for each therapy arm are accompanied by 90% confidence intervals based on log(-log(endpoint)) methodology. NSCLC: The pairwise comparisons between the durvalumab/tremelimumab alone and durvalumab/tremelimumab with RT arms are conducted using Cox regression. CRC: No statistical comparisons between arms were conducted.
Time frame: From time of randomization to death from any cause [up to 2 years]
Objective Response Per Immune-related Response (irRC) Criteria
NSCLC only: Proportions with irCR, irPR, irSD, irPD, and NA are presented with 90% exact binomial confidence intervals. The Immune-Related Response Criteria (irRC) is a set of published rules that defines when cancer tumors improve, stay the same, or worsen during treatment with an immuno-oncology drug. The response criteria are: irCR: Complete disappearance of all lesions, no new lesions, and confirmation by a repeat consecutive assessment no less than 4 weeks from date first documented; irPR: decrease in tumor burden \>50% relative to baseline confirmed by repeat consecutive assessment at least 4 weeks later; irPD: increase in tumor burden \>25% relative to nadir (minimum recorded tumor burden) confirmed by repeat consecutive assessment at least 4 weeks later; irSD: not meeting criteria for irCR or irPR in the absence of irPD.
Time frame: Up to 2 years
Incidence of Grade 3-5 Adverse Events
Assessed by Common Terminology Criteria for Adverse Events version 4.0. The proportions of subjects with grade-3 or higher adverse events (all attributions) are presented with 90% exact binomial confidence intervals.
Time frame: Up to 2 years
Local Control Rate and Abscopal Response Rate
NSCLC: Local control - Having two or more scans with RECIST response of stable disease (SD), one response of SD followed by non-confirmed PR, or a confirmed response of PR. Abscopal response occurs when a local therapy, such as radiation therapy, not only shrinks the targeted tumor(s) but also leads to the shrinkage of untreated tumors elsewhere in the body. Abscopal response is measured using RECIST criteria (proportion of patients with complete (CR) or partial (PR) response to therapy).
Time frame: Up to 2 years
Prognostic Effect of PD-L1 Expression
NSCLC participants only: Pre-treatment levels of PD-L1 percent will be compared according to RECIST response using Wilcoxon rank-sum testing. PD-L1 percent: The percentage of tumor cells that positively express the PD-L1 protein (programmed cell death ligand 1). Tumors that express high amounts of PD-L1 (\>50%) may respond well to checkpoint inhibitors (a type of immunotherapy drug).
Time frame: Up to 2 years
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Smilow Cancer Hospital Care Center - Guilford
Guilford, Connecticut, United States
Smilow Cancer Hospital Care Center at Saint Francis
Hartford, Connecticut, United States
Smilow Cancer Center/Yale-New Haven Hospital
New Haven, Connecticut, United States
Yale University
New Haven, Connecticut, United States
Yale-New Haven Hospital North Haven Medical Center
North Haven, Connecticut, United States
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