Dose-Escalation Study of Cabozantinib in Combination With Lutetium-177 (177Lu)-PSMA-617 in Patients With Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria:

• Male subject aged ≥ 18 years.

• Histologically or cytologically confirmed adenocarcinoma of the prostate withoutsmall cell histology.

• Prior orchiectomy and/or ongoing androgen-deprivation therapy and a castrate levelof serum testosterone (<50 ng/dL or <1.7 nmol/L).

• Prior treatment with at least one prior Novel Hormone Therapy (NHT), defined assecond-generation anti-androgen therapies that include, but are not limited to,abiraterone acetate, enzalutamide, apalutamide, and darolutamide.

• Must have been previously treated with at least 2 cycles of a taxane containingregimen (such as docetaxel or cabazitaxel).

• ≥ 1 PSMA-positive lesion and/or metastatic disease that is predominantly PSMApositive and with no dominant PSMA-negative metastatic lesion.

• Must have progressive mCRPC per the treating investigator.

• ECOG Performance Status ≤ 1.

• Adequate organ function as defined as:

• Hematologic:

• Absolute neutrophil count (ANC) ≥ 1500/µL without granulocytecolony-stimulating factor support

• White blood cell count ≥ 3000/µL.

• Platelet count ≥ 100,000/µL

• Hemoglobin ≥ 9g/dL

• Serum albumin ≥ 2.5 g/dl

• PT/INR or partial thromboplastin time (PTT) test < 1.3x the laboratory ULN

• Hepatic:

• Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)

• For subjects with Gilbert's disease: ≤ 3x ULN

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3xupper limit of normal (ULN).

• Renal:

• Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-hurine protein ≤ 1 g

• Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula

• Sexually active fertile patients 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 6 months after the last dose of study treatment in accordance with section 5.4.2.

• Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any priortreatments, unless AE(s) are clinically nonsignificant and/or stable on supportivetherapy.

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

• Patients must have a life expectancy >3 months.

Exclusion Criteria:

• Receiving other investigational anti-cancer agents.

• Prior treatment with cabozantinib

• Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188,Radium-223 or hemi-body irradiation within 6 months prior to randomization.

• Previous PSMA-targeted radioligand therapy

• 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.

• Radiation therapy for bone metastasis within 2 weeks or any other radiation therapywithin 4 weeks before first dose of study treatment.

• Systemic treatment with radionuclides within 6 weeks before first dose of studytreatment.

• Subjects with clinically relevant ongoing complications from prior radiation therapyare not eligible.

• Symptomatic cord compression, or clinical or radiologic findings indicative ofimpending cord compression.

• Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksprior to first dose of study treatment after radiotherapy or at least 4 weeks priorto first dose of study treatment after major surgery (e.g., removal or biopsy ofbrain metastasis).

• Subjects must have complete wound healing from major surgery or minor surgery beforefirst dose of study treatment.

• Eligible subjects must be neurologically asymptomatic and without corticosteroidtreatment at the time of first dose of study treatment.

• Major surgery within 4 weeks prior to starting study drug, minor surgery within 10days, or subjects who have not fully recovered from major surgery.

• 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 OS rate > 90%), such as locally curable cancersthat have been apparently cured, such as basal or squamous cell skin cancer,superficial bladder cancer, or carcinoma in situ of the breast.

• 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) and low-dose low molecular weight heparins (LMWH)

• 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.

• Current evidence of uncontrolled, significant intercurrent illness including, butnot limited to, the following conditions:

• Cardiovascular disorders:

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

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

• Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6months are allowed if stable, asymptomatic, and treated with a stable doseof permitted anticoagulation (see exclusion criterion 14) for at least 1week before first dose of study treatment.

• Uncontrolled hypertension defined as sustained blood pressure (BP) ≥ 150mm Hg systolic or >90 mmHg diastolic despite optimal antihypertensivetreatment.

• 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 confirmedbefore first 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, social/ psychologicalissues, 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

• Other clinically significant disorders that would preclude safe study participation.

• Serious non-healing wound/ulcer/bone fracture.

• Uncompensated/symptomatic hypothyroidism.

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

• Known history of COVID-19 unless the subject has clinically recovered from thedisease at least 30 days prior to first dose of study treatment.

• Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy ofbrain metastasis) within 2 weeks before first dose of study treatment or minorsurgeries within 10 days before first dose of study treatment.

• Subjects must have complete wound healing from major surgery or minor surgery beforefirst dose of study treatment.

--Subjects with clinically relevant ongoing complications from prior surgery are noteligible.

• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG) within 14 days before first dose of study treatment.

--Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additionalECGs at intervals of approximately 3 min must be performed within 30 min after theinitial ECG, and the average of these three consecutive results for QTcF will beused to determine eligibility.

• Inability to swallow tablets

• Previously identified allergy or hypersensitivity to components of the studytreatment formulations.

• Known HIV infection with a detectable viral load within 6 months of the anticipatedstart of treatment.

--Note: Subjects on effective antiretroviral therapy with an undetectable viral loadwithin 6 months of the anticipated start of treatment are eligible for this trial.

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination, radiographic findings, and TB testing in line withlocal practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), orhepatitis C.

• Note: Subjects with a past or resolved HBV infection (defined as the presence ofhepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjectspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV RNA.

• Medical, psychiatric, cognitive, or other conditions that may compromise thesubject's ability to understand the subject information, give informed consent,comply with the study protocol or complete the study.

• Subjects taking prohibited medications as described in Section 6.8.2. A washoutperiod of prohibited medications for a period of at least five half-lives or asclinically indicated should occur before the start of treatment.