A Phase 1b Clinical Trial of Cabozantinib and Abiraterone With Checkpoint Inhibitor Immunotherapy in Metastatic Hormone Sensitive Prostate Cancer (CABIOS Trial)

• Histologically or cytologically confirmed hormone-sensitive prostate adenocarcinoma.

• Must have evidence of metastatic disease on CT or MRI of the chest, abdomen, and pelvis, or technetium bone scan. May have any type or location of metastases (bone, lymph node, visceral). May have relapsed metastatic disease after initial primary therapy or de novo metastatic disease. Metastatic disease does not have to be confirmed by biopsy.

• May have been on androgen deprivation therapy (ADT) for metastatic hormone-sensitive prostate cancer for ≤ 12 weeks prior to study enrollment (GnRHR agonist such as leuprolide, goserelin, triptorelin, buserelin, histrelin; GnRHR antagonists such as degarelix, or relugolix). Prior ADT for localized prostate cancer is allowed.

• Prior palliative radiation therapy for bone metastasis (must be complete ≥14 days prior to enrollment) or any other radiation therapy (must be complete ≥28 days prior to enrollment) is allowed. Prior definitive radiation therapy for localized prostate cancer is allowed.

• If the patient has undergone bilateral orchiectomy, it must have occurred no more than 12 weeks before study enrollment.

• Recovery to baseline or ≤ grade 1 from toxicities related to any prior treatments, unless AEs are clinically nonsignificant and/or stable on supportive therapy.

• At least 18 years of age.

• ECOG performance status ≤ 1

• Normal bone marrow and organ function as defined below:

‣ Absolute neutrophil count ≥ 1,500 K/cumm without granulocyte colony-stimulating factor support

⁃ White blood cell count ≥ 2,500 K/cumm

⁃ Platelets ≥ 100,000 K/cumm without transfusion

⁃ Hemoglobin ≥ 9.0 g/DL

⁃ Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease ≤ 3.0 x IULN)

⁃ AST(SGOT), ALT(SGPT), and alkaline phosphatase (ALP) ≤ 3.0 x IULN; ALP ≤ 5.0 x IULN with documented bone metastases

⁃ Serum creatinine ≤ 2.0 x IULN or calculated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault

⁃ Serum albumin ≥ 2.8 g/dL

⁃ Urine protein/creatinine ration (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)), or 24h urine protein ≤1g

⁃ PT/INR or PTT \< 1.3 x IULN

• Castrate testosterone levels with serum testosterone ≤ 50 ng/mL at time of study drug start, with ongoing ADT throughout the study unless prior bilateral orchiectomy.

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

• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of the legally authorized representative, if applicable).

• Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment.