ESK981 and Nivolumab for the Treatment of Metastatic Castration Resistant Prostate Cancer

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, unlessadverse event (AE)(s) are clinically non-significant and/or stable on supportivetherapy

• 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 > 30mL/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 hepaticmetastases)

• Alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN with known hepaticmetastases)

• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels =< 1.5x ULN (If patient is receiving anticoagulation that is expected to alter theselevels, 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 serumtestosterone 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 sumof diameters of all measurable lesions or the development of one or more newlesions. The short axis of a target lymph node must be more than 15 mm to beassessed for change in size

• Non-measurable (bone) disease: The appearance of two or more new areas ofuptake on bone scan consistent with metastatic disease compared to previousimaging during castration therapy. The increased uptake of pre-existing lesionson bone scan will not be taken to constitute progression, and ambiguous resultsmust 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 chemotherapyagent (docetaxel and/or cabazitaxel) in the metastatic castration resistant settingas per PCWG3 criteria

• Progression on chemotherapy (e.g. docetaxel, cabazitaxel) in the metastaticcastration resistant setting. Progression of disease within 6 months of completingdocetaxel in the metastatic castrate-sensitive setting is acceptable

• Have signed an informed consent document indicating that the subject understands thepurpose of and procedures required for the study and are willing to participate inthe study

• Be willing and able to adhere to the prohibitions and restrictions specified in thisprotocol

• Willingness to use contraception by a method that is deemed effective by theinvestigator throughout the treatment period and for at least 30 days following thelast 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 thecycle 3 visit

• Willingness and ability to undergo mandatory whole blood sample collections atbaseline, 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 thewell-being of the subject or the study or prevent the subject from meeting orperforming study requirements

• The patient is currently on warfarin or heparin therapy

• The patient has any pre-existing coagulopathy, recent hemoptysis, gross hematuria orgastrointestinal bleeding

• The patient has a history of a clinically significant cardiovascular orcerebrovascular event within 3 months prior to study entry

• The patient has uncontrolled hypertension defined as a blood pressure measurementgreater 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 tostudy registration. (> 6 weeks prior to registration is permitted as long as theyhave fully recovered from any such procedure)

• History of another primary malignancy except for: malignancy treated with curativeintent and no known active disease for >= 5 years, adequately treated non-melanomaskin cancer without evidence of disease, adequately treated carcinoma in situwithout evidence of disease

• Angina, myocardial infarction symptomatic congestive heart failure, cerebrovascularaccident, transient ischemic attack, arterial embolism, pulmonary embolism,percutaneous angioplasty or Coronary arterial bypass surgery within the past 3months

• The patient has received any investigational drug within 28 days prior toregistration or 5 half-lives of the investigational drug, whichever is sooner