Cabozantinib and Atezolizumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer, The AtezoCab Trial

Inclusion Criteria:

• Male subject aged >= 18 years

• Histologically or cytologically confirmed prostatic adenocarcinoma without smallcell histology

• Metastatic disease progression after continuous androgen deprivation therapy forhormone sensitive state

• Patient must have non-measurable disease outside the pelvis (above aorticbifurcation) per RECIST 1.1 criteria. Non-measurable disease can be bone lesionsand/or extraskeletal disease

• Disease progression on or after at least one prior novel hormonal therapy (NHT) (defined as second-generation antiandrogen therapies that include but are notlimited to abiraterone acetate, enzalutamide, apalutamide, darolutamide)

• Eastern Cooperative Oncology Group (ECOG) performance Status =< 2

• Effective castration with serum testosterone levels =< 0.5 ng/mL (=<1.7 nmol/L)

• Tumor tissue available (archival or recent tumor biopsy). If no tumor tissue isavailable, patients can be enrolled after approval from Principal Investigator.

• Absolute neutrophil count (ANC) >= 1500/mm^3 without granulocyte colony-stimulatingfactor support

• White blood cell count >= 2500/uL

• Lymphocyte count >= 0.5 x 10^9/L (500/uL)

• Platelet count >= 100,000/mm^3 without transfusion in the 2 weeks prior to cycle 1day 1 (C1D1)

• Hemoglobin >= 9 g/dL

• Serum albumin >= 2.5 g/dl

• For patients not receiving therapeutic anticoagulation: prothrombin time (PT)/International normalized ratio (INR) or partial thromboplastin time (PTT) test < 1.5 x institutional upper limit of normal (ULN). For patients receivingtherapeutic anticoagulation: stable anticoagulant regimen as determined byInvestigator

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN). For subjectswith Gilbert's disease =< 3 x institutional ULN

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × institutional ULN

• Subjects with liver metastases will be allowed to enroll with AST and ALTlevels =< 5 x institutional ULN

• Alkaline phosphatase (ALP) =< 3 × institutional ULN. Patients with documented liveror bone metastases: ALP =< 5 x institutional ULN

• Serum creatinine =< 1.5 x institutional ULN or calculated creatinine clearance >= 40mL/min by Cockcroft-Gault formula

• Urine protein/creatinine ration (UPCR) =< 1mg/mg (=< 113.2 mg/mmol), or 24-hour (h)urine protein =< 1 g

• Sexually active fertile subjects and their partners must agree to use medicallyaccepted methods of contraception (e.g., barrier methods, including male condom,female condom, or diaphragm with spermicidal gel) during the course of the study andfor 5 months after the last dose of study treatment

• Male subjects must agree to use a condom during intercourse for the duration ofstudy therapy

• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) v5.0 from toxicities related to any prior cancer therapy, unless consideredclinically not significant by the treating investigator and/or stable on supportivetherapy

• Able to provide informed consent and willing to sign an approved consent form thatconforms to federal and institutional guidelines

• Capable of understanding and complying with the protocol requirements

Exclusion Criteria:

• Prior chemotherapy in the metastatic castration refractory prostate cancer settingis not allowed (taxane-based in metastatic castration-sensitive disease is allowed)

• Prior treatment with cabozantinib, CD137 agonists or immune checkpoint blockadetherapies, including anti-CTLA-a, anti-PD1 and anti-PD-L1 therapeutic antibodies

• Prior treatment with systemic immunostimulatory agents (including, but not limitedto, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment

• Receipt of any type of small molecule kinase inhibitor (including investigationalkinase inhibitor) within 2 weeks before first dose of study treatment

• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment

• Receiving other investigational agents

• Patients with measurable disease outside the pelvis (above aortic bifurcation) perRECIST 1.1 criteria

• History of Leptomeningeal disease

• Uncontrolled tumor-related pain

• Note: Patients requiring pain medication must be on a stable regimen at studyentry

• Symptomatic lesions (e.g., bone metastases or metastases causing nerveimpingement) amenable to palliative radiotherapy should be treated prior toenrollment. Patients should be recovered from the effects of radiation

• Asymptomatic metastatic lesions that would likely cause functional deficits orintractable pain with further growth (e.g., epidural metastasis that is notcurrently associated with spinal cord compression) should be considered forloco-regional therapy if appropriate prior to enrollment

• Radiation therapy for bone metastasis within 2 weeks or any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before first dose of study treatment. Subjects withclinically relevant ongoing complications from prior radiation therapy are noteligible

• Major surgery (e.g., laparoscopic nephrectomy, gastrointestinal (GI) surgery,removal or biopsy of brain metastasis) within 4 weeks before first dose of studytreatment or anticipation of need for a major surgical procedure during the study.Minor surgeries within 10 days before first dose of study treatment. Subjects musthave complete wound healing from major surgery or minor surgery before first dose ofstudy treatment. Subjects with clinically relevant ongoing complications from priorsurgery are not eligible

• Any other active malignancy at time of first dose of study treatment or diagnosis ofanother malignancy within 3 years prior to first dose of study treatment thatrequires active treatment, with the exception of malignancies with a negligible riskof metastasis or death (e.g., 5-year overall survival [OS] rate > 90%), such aslocally curable cancers that have been apparently cured, such as basal or squamouscell skin cancer, superficial bladder cancer, or carcinoma in situ of the breast

• Known brain metastases or cranial epidural disease

• Note: Brain metastases or cranial epidural disease adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4weeks before the first dose of study treatment after radiotherapy or at least 4weeks prior to the first dose of study treatment after major surgery (e.g.removal or biopsy of brain metastasis) will be allowed on trial. Subjects musthave complete wound healing from major surgery or minor surgery before firstdose of study treatment. Eligible subjects must be neurologically asymptomaticand without corticosteroid treatment at the time of the first dose of studytreatment

• Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombininhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or plateletinhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:

• Prophylactic use of low-dose aspirin for cardio-protection (per localapplicable guidelines), low-dose low molecular weight heparins (LMWH), orprophylactic dose of anticoagulation with direct factor Xa inhibitorsrivaroxaban, edoxaban, or apixaban.

• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitorsrivaroxaban, edoxaban, or apixaban in subjects without known brain metastaseswho are on a stable dose of the anticoagulant for at least 1 week before firstdose of study treatment without clinically significant hemorrhagiccomplications from the anticoagulation regimen or the tumor

• Administration of a live, attenuated vaccine (e.g., FluMist) within 30 days beforefirst dose of any study treatment and for 5 months after the last dose of any studytreatment

• Current evidence of uncontrolled, significant intercurrent or recent illnessincluding, but not limited to, the following conditions:

• Cardiovascular disorders:

• Congestive heart failure New York Heart Association Class II, III or IV,unstable angina pectoris, serious unstable cardiac arrhythmias

• Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), other ischemic events, or thromboembolic event (e.g., deep venousthrombosis, pulmonary embolism) within 6 months before the first dose ofstudy treatment

• Subjects with a diagnosis of incidental, sub segmental PE or DVTwithin 6 months are allowed if stable, asymptomatic, and treated witha stable dose of permitted anticoagulation for at least 1 week beforefirst dose of study treatment

• Uncontrolled hypertension defined as persistent systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg despite optimalantihypertensive treatment

• Gastrointestinal (GI) disorders including those associated with a high risk ofperforation or fistula formation:

• The subject has evidence of tumor invading the GI tract, active pepticulcer disease, inflammatory bowel disease (e.g., Crohn's disease),diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,acute pancreatitis, acute obstruction of the pancreatic duct or commonbile duct, or gastric outlet obstruction

• Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominalabscess within 6 months before first dose of study treatment. Note:Complete healing of an intra-abdominal abscess must be confirmed beforefirst dose of study treatment

• Any other condition that would, in the Investigator's judgment, contraindicatethe subject's participation in the clinical study due to safety concerns orcompliance with clinical study procedures (e.g., infection/inflammation,intestinal obstruction, unable to swallow medication, [subjects may not receivethe drug through a feeding tube], social/ psychological issues, etc.)

• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5ml) of red blood, or other history of significant bleeding (e.g., pulmonaryhemorrhage) within 12 weeks before first dose of study treatment

• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation

• Lesions invading or encasing any major blood vessels

• Any active or history of known or suspected autoimmune disease as determined to beclinically significant by treating investigator's clinical judgement will beexcluded , including, but not limited to, myasthenia gravis, myositis, autoimmunehepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory boweldisease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogrensyndrome, Guillain-Barre syndrome, or multiple sclerosis (see Appendix for a morecomprehensive list of autoimmune diseases and immune deficiencies), with thefollowing exceptions:

• Controlled Type 1 diabetes mellitus who are an insulin regimen

• Autoimmune-related hypothyroidism who are on thyroid replacement hormone

• Skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemictreatment

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of following conditions aremet:

• Rash must cover < 10% of body surface area

• Disease is well controlled at baseline and requires only low potencytopical corticosteroids

• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high potency or oralcorticosteroids within the previous 12 months

• Conditions not expected to recur in the absence of an external trigger

• Any condition requiring systemic treatment with either corticosteroids (> 10 mgdaily prednisone equivalent) or other immunosuppressive medications within 14 daysbefore first dose of study treatment, or anticipation of need for systemicimmunosuppressive medication during study treatment, with the following exceptions:

• Patients who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof corticosteroids for a contrast allergy) are eligible for the study afterPrincipal Investigator confirmation has been obtained

• Patients who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenal insufficiencyare eligible for the study

• Note: Inhaled, intranasal, intra-articular, or topical steroids are permitted.Adrenal replacement steroid doses > 10 mg daily prednisone equivalent arepermitted. Transient short-term use of systemic corticosteroids for allergicconditions (e.g., contrast allergy) is also allowed

• Severe infection within 4 weeks prior to initiation of study treatment, including,but not limited to, hospitalization for complications of infection, bacteremia, orsevere pneumonia

• Any active infection requiring systemic treatment. Patients receiving prophylacticantibiotics (e.g., to prevent a urinary tract infection or chronic obstructivepulmonary disease exacerbation) or oral valacyclovir (valaciclovir) are eligible forthe study

• Acute or chronic hepatitis B or C infection, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or knownpositive test for tuberculosis infection where there is clinical or radiographicevidence of active mycobacterial infection. Note: Subjects on effective HIVantiretroviral therapy with an undetectable viral load within 6 months of theanticipated start of treatment are eligible for this trial

• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-inducedpneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screeningchest computed tomography (CT) scan

• Serious non-healing wound/ulcer/bone fracture

• Malabsorption syndrome

• Uncompensated/symptomatic hypothyroidism

• Moderate to severe hepatic impairment (Child-Pugh B or C)

• Requirement for hemodialysis or peritoneal dialysis

• History of solid organ or allogenic stem cell transplant

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently)

• Note: Patients with indwelling catheters (e.g., PleurX) are allowed

• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)

• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG)