A Phase 2 Study of MEDI4736 (Durvalumab) and Tremelimumab Alone or in Combination With High or Low-Dose Radiation in Metastatic Colorectal and NSCLC
Overview
- Phase
- Phase 2
- Intervention
- Durvalumab
- Conditions
- Metastatic Colorectal Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 110
- Locations
- 83
- Primary Endpoint
- Overall Response Rate
- Status
- Active, not recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically or cytologically confirmed non-small cell lung cancer (cohort 1) or colorectal cancer (cohort 2)
- •Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) with conventional techniques or as \>= 10 mm (\>= 1.5 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
- •Patients in both cohorts must have progressive disease following prior therapy; specifically:
- •Cohort 1 (NSCLC): Patients must have evidence of radiologic or clinical disease progression during previous treatment with systemic PD-1 directed therapy and/or have been deemed not to derive clinical benefit from PD-1 directed treatment; this includes patients who demonstrated an initial response and subsequent progression; no prior treatment with chemotherapy or targeted agents are required; intervening therapy is allowed between previous PD-1 directed treatment and there is no required interval from prior PD-1 treatment required; PD-1 directed treatment includes treatment with antibodies targeting the PD-1 receptor such as pembrolizumab or nivolumab, as well as PD-L1 targeted antibodies such as MEDI4736 (durvalumab), atezolizumab and avelumab; these agents may have been administered as part of a clinical trial
- •Cohort 2 (colorectal cancer): Patients must have progressed on \>= one-line chemotherapy
- •At least 21 days must have elapsed from prior systemic therapy (chemotherapy or radiation)
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 60%) and life expectancy greater than 6 months; furthermore, enrollment of patients with greater than 10 measurable lesions is discouraged
- •Patients must have normal organ and marrow function independent of transfusion for at least 7 days prior to screening and independent of growth factor support for at least 14 days prior to screening
- •Hemoglobin (Hgb) \>= 9 g/dl
- •Absolute neutrophil count \>= 1,500/mcL
Exclusion Criteria
- •Patients who have had systemic (chemotherapy, biologic therapy or radiotherapy) within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- •Receipt of prior radiotherapy or condition for any reason that would contribute radiation dose that would exceed tolerance of normal tissues, at the discretion of the treating physician
- •Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1)
- •Patients who are receiving any other investigational agents
- •Patients with untreated brain metastases, spinal cord compression, or leptomeningeal carcinomatosis should be excluded from this clinical trial; patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases; these imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression); in addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of =\< 10 mg/day of prednisone or its equivalent (and anti-convulsants) for at least 14 days prior to the start of treatment
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to tremelimumab and MEDI4736 or previous toxicity attributed to MEDI4736 or other PD-1 or PD-L1 directed therapy that led to drug discontinuation
- •Prior exposure to immune-mediated therapy, including durvalumab and tremelimumab, except for anti-PD-1 or anti-PD-L1 therapy (including durvalumab) in NSCLC patients; this includes anti-CTLA-4 agents (prior treatment with these agents is NOT allowed in either cohort) and, excludes therapeutic anticancer vaccines, excluding therapeutic anticancer vaccines; exposure to other investigational agents may be permitted after discussion with the study principal investigator (PI)
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant women are excluded from this study because MEDI4736 (durvalumab), tremelimumab are immune checkpoint inhibitors with the potential for teratogenic or abortifacient effects, as is radiation therapy; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MEDI4736(durvalumab), tremelimumab and radiation, breastfeeding should be discontinued if the mother is treated with MEDI4736(durvalumab), tremelimumab and radiation
- •Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy, whichever is later
Arms & Interventions
Cohort 1, Arm B (tremelimumab, Durvalumab, LD-RT)
Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive low dose radiation therapy every 6 hours BID on weeks 2, 6, 10 and 14.
Intervention: Durvalumab
Cohort 1, Arm B (tremelimumab, Durvalumab, LD-RT)
Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive low dose radiation therapy every 6 hours BID on weeks 2, 6, 10 and 14.
Intervention: Tremelimumab
Cohort 2, Arm A (tremelimumab, durvalumab, HD-RT)
Patients receive tremelimumab 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 QD over 10 days for up to 3 fractions.
Intervention: Durvalumab
Cohort 2, Arm B (tremelimumab, durvalumab, LD-RT)
Patients receive tremelimumab 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 BID on weeks 2, 6, 10 and 14.
Intervention: Durvalumab
Cohort 2, Arm B (tremelimumab, durvalumab, LD-RT)
Patients receive tremelimumab 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 BID on weeks 2, 6, 10 and 14.
Intervention: Tremelimumab
Cohort 1, Arm A (tremelimumab, durvalumab, HD-RT)
Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive high dose radiation therapy QD over 10 days for up to 3 fractions.
Intervention: Radiation Therapy
Cohort 1, Arm B (tremelimumab, Durvalumab, LD-RT)
Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive low dose radiation therapy every 6 hours BID on weeks 2, 6, 10 and 14.
Intervention: Radiation Therapy
Cohort 2, Arm A (tremelimumab, durvalumab, HD-RT)
Patients receive tremelimumab 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 QD over 10 days for up to 3 fractions.
Intervention: Radiation Therapy
Cohort 2, Arm B (tremelimumab, durvalumab, LD-RT)
Patients receive tremelimumab 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 BID on weeks 2, 6, 10 and 14.
Intervention: Radiation Therapy
Cohort 1, Arm A (tremelimumab, durvalumab, HD-RT)
Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive high dose radiation therapy QD over 10 days for up to 3 fractions.
Intervention: Durvalumab
Cohort 1, Arm C (tremelimumab, durvalumab)
Patients receive tremelimumab 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.
Intervention: Durvalumab
Cohort 2, Arm A (tremelimumab, durvalumab, HD-RT)
Patients receive tremelimumab 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 QD over 10 days for up to 3 fractions.
Intervention: Tremelimumab
Cohort 1, Arm C (tremelimumab, durvalumab)
Patients receive tremelimumab 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.
Intervention: Tremelimumab
Cohort 1, Arm A (tremelimumab, durvalumab, HD-RT)
Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive high dose radiation therapy QD over 10 days for up to 3 fractions.
Intervention: Tremelimumab
Outcomes
Primary Outcomes
Overall Response Rate
Time Frame: Up to 2 years
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.
Secondary Outcomes
- Overall Survival (OS)(From time of randomization to death from any cause [up to 2 years])
- Progression-free Survival (PFS)(From date of randomization until objective disease progression or death, whichever occurs first [up to 2 years])
- Objective Response Per Immune-related Response (irRC) Criteria(Up to 2 years)
- Incidence of Grade 3-5 Adverse Events(Up to 2 years)
- Local Control Rate and Abscopal Response Rate(Up to 2 years)
- Prognostic Effect of PD-L1 Expression(Up to 2 years)