Clinical Trials /

Avelumab, Utomilumab, Anti-OX40 Antibody PF-04518600, and Radiation Therapy in Treating Patients With Advanced Malignancies

NCT03217747

Description:

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. 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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Avelumab, Utomilumab, Anti-OX40 Antibody PF-04518600, and Radiation Therapy in Treating Patients With Advanced Malignancies
  • Official Title: Phase I/II Study to Evaluate the Safety and Tolerability of Avelumab in Combination With Other Anti-Cancer Therapies in Patients With Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2017-0014
  • SECONDARY ID: NCI-2018-01118
  • SECONDARY ID: 2017-0014
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03217747

Conditions

  • Advanced Malignant Solid Neoplasm
  • Castration-Resistant Prostate Carcinoma
  • Malignant Neoplasm
  • Malignant Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Metastatic Prostate Carcinoma
  • Prostate Carcinoma Metastatic in the Bone
  • Refractory Malignant Solid Neoplasm
  • Stage IV Prostate Cancer AJCC v8
  • Stage IVA Prostate Cancer AJCC v8
  • Stage IVB Prostate Cancer AJCC v8

Interventions

DrugSynonymsArms
Anti-OX40 Antibody PF-04518600PF-04518600Arm B (PF-04518600, avelumab)
AvelumabBavencio, MSB-0010718C, MSB0010718CArm A (utomilumab, avelumab)
UtomilumabPF 05082566, PF 5082566, PF-05082566, PF-2566Arm A (utomilumab, avelumab)

Purpose

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. 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. For Arms D-F, to establish the safety, tolerability, and dose-limiting toxicities (DLTs)
      of different treatment combinations of avelumab when administered in combination with
      checkpoint agonist(s) with or without 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 Arms D-F.

      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 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 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 -14 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: 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 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: 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (utomilumab, avelumab)ExperimentalPatients receive utomilumab 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.
  • Avelumab
  • Utomilumab
Arm B (PF-04518600, avelumab)ExperimentalPatients receive anti-OX40 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.
  • Anti-OX40 Antibody PF-04518600
  • Avelumab
Arm C (PF-04518600, utomilumab, avelumab)ExperimentalPatients receive anti-OX40 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.
  • Anti-OX40 Antibody PF-04518600
  • Avelumab
  • Utomilumab
Arm D (avelumab, utomilumab, radiation therapy)ExperimentalPatients undergo radiation therapy on days -14 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.
  • Avelumab
  • Utomilumab
Arm E (avelumab, PF-04518600, radiation therapy)ExperimentalPatients 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 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.
  • Anti-OX40 Antibody PF-04518600
  • Avelumab
Arm F (avelumab, PF-04518600, radiation therapy)ExperimentalPatients 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 antibody PF-04518600 IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Anti-OX40 Antibody PF-04518600
  • Avelumab
  • Utomilumab

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must be refractory to, or intolerant of, established therapy known to provide
             clinical benefit for their conditions, or where subjects refuse existing therapies.

          -  Subjects must have measurable disease (RECIST v 1.1) or patients may have bone
             metastatic disease evaluable by Prostate Cancer Working Group 2 (PCWG2) for subjects
             with metastatic castration-resistant prostate cancer (CRPC) or according to tumor
             evaluation criteria best suitable and accepted for the tumor type evaluated.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          -  Platelets >= 100 x 10^9/L (For patients with hepatocellular carcinoma, platelets >= 70
             x 10^9/L).

          -  Hemoglobin >= 9 g/dL.

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.

          -  White blood cell (WBC) >= 3 x 10^9/L.

          -  Subjects must be transfusion independent (i.e., no blood product transfusions for a
             period of at least 14 days prior to cycle 1 day 1 [start of study treatment]).

          -  Alanine transaminase (ALT) =< 2.5 x upper normal limit (ULN) (=< 5 x ULN for subjects
             with documented metastatic disease to the liver).

          -  Aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with documented
             metastatic disease to the liver).

          -  Alkaline phosphatase < 4 x ULN.

          -  Total bilirubin =< 1.5 x ULN (In the expansion cohort, subjects with Gilbert's
             syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of
             =< 3 x ULN).

          -  Albumin >= 3 g/dL.

          -  Serum creatinine =< 2 x upper limit of normal (ULN) or estimated creatinine clearance
             >= 30 ml/min as calculated using the Cockcroft-Gault formula.

          -  Subject has recovered to grade =< 1 by the National Cancer Institute Common
             Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v 4.03) from the
             effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other
             targeted therapies, with the exception of alopecia. The exceptions for such effects
             are allowed lab values of =< grade 2 specified elsewhere in these inclusion criteria.

          -  Life expectancy of at least 12 weeks.

          -  Negative serum pregnancy test in women of childbearing potential within 7 days of
             first dose of treatment and patients of child-bearing potential must agree to use
             effective contraception during and after 90 days post dose. A woman of childbearing
             potential is defined as a premenopausal female capable of becoming pregnant. This
             includes women on oral, injectable or mechanical contraception; women who are single
             and women whose male sexual partners have been vasectomized or whose male sexual
             partners have received or are utilizing mechanical contraceptive devices.

          -  Subjects must have biopsiable disease. For Arms A, B, and C, subjects must have at
             least two lesions amenable to biopsy and response evaluation. For Arms D, E, and F,
             subjects should have at least three lesions amenable to biopsy, response evaluation,
             and radiation. Tumor lesions used for biopsy should not be lesions used as RECIST
             target lesions. However, if patients in Arms D, E, and F do not have three separate
             lesions, patients will be eligible if there are two lesions, in which one is > 2
             centimeters (short axis) and can be used for both biopsy and response evaluation.

          -  Subjects must give informed consent according to the rules and regulations of the
             individual participating sites.

        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: > 4 weeks from prior therapy completion (including radiation and/or
             surgery); clinically stable with respect to the CNS tumor at the time of study entry;
             not receiving steroid therapy in treating CNS tumor or CNS tumor involvement; not
             receiving anti-convulsive medications (that were started for brain metastases).

          -  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 Arms B and E, subjects may not have had prior
             OX40 treatment. For Arms C and F, 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 1 year
Safety Issue:
Description:Will be graded per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Descriptive statistics will be provided on the grade and type of toxicity by dose level.

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 1 year
Safety Issue:
Description:Will be assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 and immune-related RECIST (irRECIST). A 95% confidence interval of response rate will be estimated based on a binomial distribution.
Measure:Progression-free survival
Time Frame:From cycle 1 start date until the earliest date of disease progression, assessed up to 1 year
Safety Issue:
Description:Will be assessed per RECIST v1.1 and irRECIST.
Measure:Duration of response
Time Frame:From time from earliest date of disease response until the earliest date of disease progression, assessed up to 1 year
Safety Issue:
Description:Will be assessed per RECIST v1.1 and irRECIST.
Measure:Overall survival
Time Frame:From the cycle 1 start date until death due to any cause, assessed up to 1 year
Safety Issue:
Description:
Measure:Response data in irradiated and non-irradiated lesions
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Evaluation of various immune biomarkers from tumor and blood biospecimens
Time Frame:Up to 1 year
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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