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.
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.
