This phase I/II trial studies the side effects of avelumab when given in different combinations with utomilumab, anti-OX40 antibody PF-04518600, and radiation therapy in treating patients with malignancies that have spread to other places in the body (advanced). Immunotherapy with monoclonal antibodies, such as avelumab, utomilumab, and anti-OX40 antibody PF-04518600, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high-energy rays to kill tumor cells and shrink tumors. It is not yet known how well avelumab works in combination with these other anti-cancer therapies in patients with advanced malignancies.
PRIMARY OBJECTIVES: I. For Arm D, to establish the safety, tolerability, and dose-limiting toxicities (DLTs) of different treatment combinations of avelumab when administered in combination with a checkpoint agonist with radiation in patients with metastatic solid tumors in order to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). II. To correlate pre- and post-treatment CD8 expression with clinical benefit (complete response \[CR\], partial response \[PR\], or stable disease \[SD\] for \> 6 months). SECONDARY OBJECTIVES: I. To evaluate the efficacy of the different treatment combinations in patients with metastatic solid tumors by assessing objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune-related RECIST (irRECIST). II. To evaluate the efficacy of the different treatment combinations in patients with metastatic solid tumors by assessing progression-free survival (PFS), duration of response (DOR), and overall survival (OS). EXPLORATORY OBJECTIVES: I. To understand the mechanism of action of the avelumab plus an immune modulator combination, as well as potential mechanisms of resistance. II. To characterize the effect of avelumab combinations on immune biomarkers in peripheral blood and tumor tissue obtained from subjects pre- and post-treatment. III. To compare the response in irradiated versus non-irradiated lesions in Arm D. IV. To investigate immune biomarkers that are potentially predictive of response and resistance with the combination of avelumab and an immune modulator. OUTLINE: Patients are assigned to 1 of 6 arms. ARM A: Patients receive utomilumab intravenously (IV) over 60 minutes on day 1 of each cycle and avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive anti-OX40 agonist monoclonal antibody PF-04518600 IV over 60 minutes on days 1 and 15 of each cycle and avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive anti-OX40 agonist monoclonal antibody PF-04518600 IV over 60 minutes on days 1 and 15 of each cycle, utomilumab over 60 minutes on day 1, and avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM D: Patients undergo radiation therapy on days -5 to -1. Patients receive avelumab IV over 60 minutes on days 1 and 15 of beginning day 15 of cycle 1 and utomilumab IV over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM E: DISCONTINUED AS OF AMENDMENT 9 (02/11/2020) Patients undergo radiation therapy on days -14 to -1. Patients receive avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1 and anti-OX40 agonist monoclonal antibody PF-04518600 IV over 60 minutes on days 1 and 15, and. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM F: DISCONTINUED AS OF AMENDMENT 9 (02/11/2020) Patients undergo radiation therapy on days -14 to -1. Patients receive avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1, utomilumab IV over 60 minutes on day 1, and anti-OX40 agonist monoclonal antibody PF-04518600 IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients will be followed up at 30 days and then every 12 weeks.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
173
Given IV
Given IV
Undergo radiation therapy
Given IV
M D Anderson Cancer Center
Houston, Texas, United States
Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria)
DLTs were adverse events (AEs) related to study drug in the first 2 cycles and fulfilled one of the following * Discontinuation due to drug and/or XRT-related toxicity before DLT period ends * Delay \>28 days in receiving the next cycle due to drug and/or XRT-related toxicity * Hematologic * Gr4 neutropenia ≥7 days * Febrile neutropenia * Gr ≥3 thrombocytopenia associated with bleeding, or Gr 4 thrombocytopenia * Gr 4 anemia * Non-hematologic * Gr ≥3 nausea/vomiting or diarrhea ≥72 hours despite optimal supportive medications * Gr ≥3 fatigue ≥7 days * Gr≥2 pneumonitis ≥7 days despite corticosteroids * Gr≥3 rash ≥7 days despite treatment * Gr≥3 immune related toxicities ≥7 days despite corticosteroids * Any other Gr≥3 non-hematological toxicity (except for asymptomatic electrolytes abnormalities or hair loss which is not dose-limiting) * Gr≥3 AST, ALT, or total bilirubin elevation ≥7 days. Delay of treatment \> 14 days due to non-hematologic toxicity
Time frame: DLT was assessed during the first 2 cycles or 8 weeks (56 days) since C1D1 of treatment.
Objective Response Rate Per RECIST v1.1
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) using CT, MRI,or PET-CT scan: Complete Response (CR),Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Objective Response Rate Per irRECIST
Per Immune-related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST) using CT, MRI,or PET-CT scan: Immune-related Complete Response (irCR),Disappearance of all target lesions; Immune-related Partial Response (irPR), \>=30% decrease in the sum of the longest diameter of target and new lesions; OR = irCR + irPR.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Clinical Benefit Rate Per RECIST v1.1
Per RECIST v1.0 using CT, MRI,or PET-CT scan: CR,Disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), Increase ≥20% of the sum of longest diameter compared with nadir (minimum 5 mm) or progression of non-target lesions or new lesion; Stable Disease (SD), Neither PR nor PD; Clinical benefit (CB) = CR + PR + SD ≥6 months.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Clinical Benefit Rate Per irRECIST
Per irRECIST using CT, MRI,or PET-CT scan: irCR,Disappearance of all target lesions; irPR, \>=30% decrease in the sum of the longest diameter of target and new lesions; Immune-related Progressive Disease (irPD), Increase ≥20% of the sum of longest diameter of target and new lesion compared with nadir (minimum 5 mm) or progression of non-target lesions ; Immune-related Stable Disease (irSD), Neither irPR nor irPD; Clinical benefit (CB) = irCR + irPR + irSD ≥6 months.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Disease Control Rate Per RECIST v1.1
Per RECIST v1.0 using CT, MRI,or PET-CT scan: CR,Disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; PD, Increase ≥20% of the sum of longest diameter compared with nadir (minimum 5 mm) or progression of non-target lesions or new lesion; SD, Neither PR nor PD; Disease control (DC) = CR + PR + SD.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Disease Control Rate Per irRECIST
Per irRECIST using CT, MRI,or PET-CT scan: irCR,Disappearance of all target lesions; irPR, \>=30% decrease in the sum of the longest diameter of target and new lesions; irPD, Increase ≥20% of the sum of longest diameter of target and new lesion compared with nadir (minimum 5 mm) or progression of non-target lesions ; irSD, Neither irPR nor irPD; Disease control (DC) = irCR + irPR + irSD.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
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