Phase I/II Study to Evaluate the Safety and Tolerability of Avelumab in Combination With Other Anti-Cancer Therapies in Patients With Advanced Malignancies
Phase I/II Study to Evaluate the Safety and Tolerability of Avelumab in Combination With Other Anti-Cancer Therapies in Patients With Advanced Malignancies
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.
Inclusion Criteria:
Exclusion Criteria:
Subjects with primary central nervous system (CNS) tumor or CNS tumor involvement. However, subjects with metastatic CNS tumors may participate in this study if the subject is:
Major surgery, radiation therapy or systemic anti-cancer therapy within 4 weeks of study drug administration (6 weeks for mitomycin C or nitrosoureas). Palliative radiotherapy to a limited field is allowed after consultation with the medical monitor at any time during study participation, including during screening, unless it's clearly indicative of disease progression.
Subjects with prior anti-PD-1, anti-PD-L1 treatment. For Arms A and D, subjects may not have had prior 4-1BB treatment. For Arm B, subjects may not have had prior OX40 treatment. For Arm C, subjects may not have had prior 4-1BB or OX40 treatment.
Diagnosis or recurrence of invasive cancer other than the present cancer within 3 years (except basal or squamous cell carcinoma of the skin that has been definitively treated).
Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medication.
Active infection requiring systemic therapy.
Treatment with an investigational anti-cancer study drug within 4 weeks prior to study drug administration date.
Concurrent therapy with approved or investigational anticancer therapeutics.
Known prior severe hypersensitivity to investigational product(s) or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v 4.03 grade >= 3).
Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent; c. steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication).
Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
Prior organ transplantation including allogenic stem-cell transplantation.
Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test positive).
Vaccination (live attenuated virus) within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety risk based on investigator's judgment are acceptable.
Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
Pregnancy or lactation.
Men whose partner is a woman of child-bearing potential, (i.e. biologically able to conceive), and who is not employing two forms of highly effective contraception. Highly effective contraception (e.g. male condom with spermicide, diaphragm with spermicide, intra-uterine device) must be used by both sexes during the study and must be continued for 90 days after the end of study treatment. Women of child-bearing potential is defined as sexually mature women who are not surgically sterile or who have not been naturally postmenopausal for at least 12 consecutive months (e.g., who has had menses any time in the preceding 12 consecutive months).
A diagnosis of active scleroderma, lupus, or other rheumatologic disease which in the opinion of the treating radiation oncologist precludes safe radiation therapy.
Has had prior radiation therapy within the past 3 months where the high dose area of the prior radiation would overlap with the high dose area of the intended radiation based on the judgement of the treatment oncologist.