Immunotherapy study on dbGaP (76 participants)

phs003295 — Durvalumab Plus Tremelimumab Alone or in Combination with Low-Dose or    Hypofractionated Radiotherapy in Metastatic Non-Small-Cell Lung Cancer    Refractory to Previous PD(L)-1 Therapy: an Open-Label, Multicentre,    Randomised, Phase 2 Trial

Brief SummaryThis 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.Detailed DescriptionPRIMARY 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 <a href="https://www.ncbi.nlm.nih.gov/gene/29126">PD-L1</a> 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. NOTE: This Study is only for Cohort 1. Please see <a href="https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs003294">phs003294</a> for Cohort 2COHORT 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.Official TitleA Phase 2 Study of MEDI4736 (Durvalumab) and Tremelimumab Alone or in Combination With High or Low-Dose Radiation in Metastatic Colorectal and NSCLC Conditions <ul><li>Metastatic Colorectal Carcinoma</li><li>Metastatic Lung Non-Small Cell Carcinoma</li><li>Stage IV Colorectal Cancer AJCC v7</li><li>Stage IV Lung Non-Small Cell Cancer AJCC v7</li><li>Stage IVA Colorectal Cancer AJCC v7</li><li>Stage IVB Colorectal Cancer AJCC v7</li></ul> Intervention/Treatment <ul><li>Biological: Durvalumab</li><li>Radiation: Radiation Therapy</li><li>Biological: Tremelimumab</li></ul> Other Study ID Numbers <ul><li>NCI-2016-01325</li><li>NCI-2016-01325 ( Registry Identifier ) (REGISTRY: CTRP (Clinical Trial Reporting Program))</li><li>17-719</li><li>10021 ( Other Identifier ) (OTHER: Dana-Farber - Harvard Cancer Center LAO)</li><li>10021 ( Other Identifier ) (OTHER: CTEP)</li></ul> Molecular Technologies / Assays<ul><li>CyTOF</li><li>IHC</li><li>mIF</li><li>Olink</li><li>RNAseq</li><li>WES</li></ul>

Durvalumab Plus Tremelimumab Alone or in Combination with Low-Dose or    Hypofractionated Radiotherapy in Metastatic Non-Small-Cell Lung Cancer    Refractory to Previous PD(L)-1 Therapy: an Open-Label, Multicentre,    Randomised, Phase 2 Trial