PRIMARY OBJECTIVES:
I. To determine the prostate specific antigen (PSA) >= 50% response rate (PSA50) from
baseline using the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria to
pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 (ESK981) plus nivolumab in men with
metastatic castration resistant prostate cancer (mCRPC) who have progressed on enzalutamide
(an oral androgen-receptor inhibitor) and/or abiraterone acetate (an androgen synthesis
inhibitor) and chemotherapy (docetaxel and/or cabazitaxel).
II. To assess the safety and tolerability of ESK981 plus nivolumab.
SECONDARY OBJECTIVES:
I. To determine the time to PSA response (TTPR) in patients with mCRPC. II. To determine the
duration of PSA response (PRD) in patients with mCRPC. III. To determine PSA progression
rates as defined by the PCWG3 criteria. IV. To determine PSA progression free survival (PPFS)
as defined by the PCWG3 criteria.
CORRELATIVE/EXPLORATORY/TERTIARY OBJECTIVE:
I. To assess exploratory biomarkers from blood and tumor biopsies.
OUTLINE:
Patients receive ESK981 orally (PO) once daily (QD) for 5 consecutive days per week, followed
by a 2-day break. Patients also receive nivolumab intravenously (IV) on day 1 of each cycle.
Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 5 years.
Inclusion Criteria:
- Eastern Cooperative Group (ECOG) performance status =< 1
- Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events
(CTCAE) version (v.)5 from toxicities related to any prior treatments, unless adverse
event (AE)(s) are clinically non-significant and/or stable on supportive therapy
- Absolute neutrophil count (ANC) >= 1.5 K/mm^3
- Hemoglobin (Hgb) >= 9 g/dL
- Platelets (Plt) >= 100,000/mm^3
- Serum creatinine =< 1.5 times the upper limit of normal OR creatinine clearance > 30
mL/min by Cockcroft-Gault formula
- Total bilirubin =< 1.5 x upper limit of normal (ULN)
- Aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN with known hepatic
metastases)
- Alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN with known hepatic metastases)
- Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels =< 1.5 x
ULN (If patient is receiving anticoagulation that is expected to alter these levels,
should be in targeted therapeutic range for that agent)
- Patient must have progressive disease while receiving androgen deprivation therapy
(ADT) defined by any one of the following as per the PCWG3 criteria for PSA,
measurable or non-measurable (bone) disease and must have a castrate serum
testosterone level (i.e. =< 50 ng/dL) at screening:
- PSA: At least two consecutive rises in serum PSA, obtained at a minimum of 1-week
intervals, with the final value >= 2.0 ng/mL
- Measurable disease (by Response Evaluation Criteria in Solid Tumors [RECIST]
1.1): >= 20% increase (with an absolute increase of at least 5 mm) in the sum of
diameters of all measurable lesions or the development of one or more new
lesions. The short axis of a target lymph node must be more than 15 mm to be
assessed for change in size
- Non-measurable (bone) disease: The appearance of two or more new areas of uptake
on bone scan consistent with metastatic disease compared to previous imaging
during castration therapy. The increased uptake of pre-existing lesions on bone
scan will not be taken to constitute progression, and ambiguous results must be
confirmed by other imaging modalities (e.g. X-ray, computed tomography [CT] or
magnetic resonance imaging [MRI])
- Metastatic prostate cancer (M1) as documented by appropriate medical imaging (i.e.
CT-Scan, positron emission tomography [PET] scan or bone scan)
- Progression on a hormonal agent (abiraterone/enzalutamide) and on a chemotherapy agent
(docetaxel and/or cabazitaxel) in the metastatic castration resistant setting as per
PCWG3 criteria
- Progression on chemotherapy (e.g. docetaxel, cabazitaxel) in the metastatic castration
resistant setting. Progression of disease within 6 months of completing docetaxel in
the metastatic castrate-sensitive setting is acceptable
- Have signed an informed consent document indicating that the subject understands the
purpose of and procedures required for the study and are willing to participate in the
study
- Be willing and able to adhere to the prohibitions and restrictions specified in this
protocol
- Willingness to use contraception by a method that is deemed effective by the
investigator throughout the treatment period and for at least 30 days following the
last dose of therapy
- Willingness and ability to comply with study procedures and follow-up examination
- Able to swallow and retain oral medication
- Willingness and ability to undergo mandatory tumor biopsy at baseline and at the cycle
3 visit
- Willingness and ability to undergo mandatory whole blood sample collections at
baseline, weeks 2-4 in the first cycle, and then monthly
Exclusion Criteria:
- Systemic therapy (other than a gonadotrophin releasing hormone [GnRH]
agonist/antagonist) for CRPC within the past two weeks from cycle 1/day 1 including:
- CYP-17 inhibitors (e.g. ketoconazole, abiraterone)
- Antiandrogens (e.g. bicalutamide, nilutamide)
- Second generation antiandrogens (e.g. enzalutamide, ARN-509, galeterone)
- Immunotherapy (e.g. sipuleucel-T, ipilimumab)
- Chemotherapy (e.g. docetaxel, cabazitaxel)
- Prior radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium-153, etc.)
within the past year
- Have any condition that, in the opinion of the investigator, would compromise the
well-being of the subject or the study or prevent the subject from meeting or
performing study requirements
- The patient is currently on warfarin or heparin therapy
- The patient has any pre-existing coagulopathy, recent hemoptysis, gross hematuria or
gastrointestinal bleeding
- The patient has a history of a clinically significant cardiovascular or
cerebrovascular event within 3 months prior to study entry
- The patient has uncontrolled hypertension defined as a blood pressure measurement
greater than 150 mm Hg systolic or 90 mm Hg diastolic with medication
- The patient has previously been enrolled in the study or received ESK981
- The patient has known hypersensitivity to gelatin or lactose monohydrate
- The patient has taken a medication known to be a potent inducer of CYP1A2, CYP2C8, or
CYP3A4 within 4 weeks prior to the first dose of study drug
- Prior treatment with anti-PD/PD-L1/CTLA4/IDO antibody
- Untreated brain metastases or spinal cord compression
- Major surgical procedure or significant traumatic injury within 6 weeks prior to study
registration. (> 6 weeks prior to registration is permitted as long as they have fully
recovered from any such procedure)
- History of another primary malignancy except for: malignancy treated with curative
intent and no known active disease for >= 5 years, adequately treated non-melanoma
skin cancer without evidence of disease, adequately treated carcinoma in situ without
evidence of disease
- Angina, myocardial infarction symptomatic congestive heart failure, cerebrovascular
accident, transient ischemic attack, arterial embolism, pulmonary embolism,
percutaneous angioplasty or Coronary arterial bypass surgery within the past 3 months
- The patient has received any investigational drug within 28 days prior to registration
or 5 half-lives of the investigational drug, whichever is sooner
