XL092 in Patients With Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria:

• Participant aged ≥ 18 years

• Disease criteria:

• Histologically or cytologically confirmed prostatic adenocarcinoma withoutsmall cell histology

• Radiographic evidence of metatstatic disease

• Progression on or after prior treatment with 177Lu-PSMA-617 as determined byclinical investigator

• ECOG Performance Status ≤ 2.

• Adequate organ function as defined as:

--Absolute neutrophil count ≥ 1500/mm3 .

• Platelet count ≥ 100,000/mm3 .

• Hemoglobin ≥ 9 g/dL .

• Total Bilirubin ≤ 1.5x institutional ULN. For subject's with Gilbert's disease, ≤ 3 x ULN.

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkalinephosphatase (ALP) ≤ 3 x ULN. For subjects with documented bone metastasis ALP ≤ 5 x ULN. For subjects with CRPC and bone metastasis ALP ≤ 10 x ULN ifpredominantly bone-specific ALP.

• International Normalized Ratio (INR) ≤ 1.5 and activated partial thromboplastintime (aPTT) ≤ 1.2 upper limit of normal (ULN)

• Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 40 mL/min byCockcroft-Gault formula: ---Males: ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72)

• Urine protein-to-creatinine ratio (UPCR) ≤ 1.5 mg/mg (≤ 169.8 mg/mmol)creatinine or 24-hour urine protein <1.5 g.

• Sexually active fertile subjects and their partners must agree to use highlyeffective method of contraception (defined in Section 5.4.1) during the course ofthe study and for 96 days after the last dose of treatment (whichever is later). Anadditional contraceptive method, such as a barrier method (eg, condom), is required.In addition, men must agree not to donate sperm for the purpose of reproductionduring these same periods.

• Must have recovered from adverse effects of any prior oncologic treatment (e.g.prior surgery, radiotherapy, or other antineoplastic therapy). CTCAE adverse eventsless than or equal to grade 1 are acceptable. CTCAE adverse events grade 2 orgreater may be acceptable as determined by the Clinical Investigator.

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

Exclusion Criteria:

• Prior treatment with XL092

• Receipt of any type of small molecule kinase inhibitor, cytotoxic, biologic or othersystemic anticancer therapy (including investigational) within 2 weeks or at least 5half-lives, whichever shorter before first dose of study treatment.

Note: Concomitant use of megestrol acetate, androgen-deprivation therapy and bone loss prevention treatment is permitted. Other types of hormonal therapies with similar use require prior approval from the Principal Investigator.

• Radiation therapy for bone metastasis or any other radiation therapy within 2 weeksbefore first dose of study treatment. Subjects with clinically relevant ongoingcomplications from prior radiation therapy are not eligible.

• Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksbefore first dose of study treatment.

Note: Subjects with an incidental finding of an isolated brain lesion < 1 cm in diameter may be eligible after Principal Investigator approval if the lesion is radiographically stable for 4 weeks before first dose and does not require treatment per Investigator judgement.

Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.

-Concomitant anticoagulation with oral anticoagulants except for those specified below:-

• (a) Prophylactic use of low-dose aspirin for cardioprotection (per local applicableguidelines), low-dose low molecular weight heparins (LMWH) or prophylactic dose ofspecified direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban

• (b) Therapeutic doses of LMWH or specified direct factor Xa inhibitors rivaroxaban,edoxaban, or apixaban in subjects without known brain metastases who are on a stabledose of the anticoagulant for at least 1 week before enrollment and withoutclinically significant hemorrhagic complications from the anticoagulation regimen orthe tumor.

-Any complementary medications (eg, herbal supplements or traditional Chinesemedicines) to treat the disease under study within 2 weeks or at least 5 half-lives,whichever shorter before first dose of study treatment.

-The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions:

• Cardiovascular disorders:

• Congestive heart failure New York Heart Association Class 3 or 4, unstableangina pectoris, serious cardiac arrhythmias [eg, ventricular flutter,ventricular fibrillation, Torsades de pointes (TdP)].

• Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hgsystolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.

• Stroke (including transient ischemic attack [TIA]), myocardial infarction, orother clinically significant ischemic event within 6 months before first doseof study treatment.

• Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinicallysignificant venous or non-CVA/TIA arterial thromboembolic events within 3months before to first dose of study treatment.

Note: Subjects with a diagnosis of DVT within 3 months are allowed if asymptomatic and stable at screening and treated with anticoagulation per standard of care before first dose of study treatment.

Note: Subjects who don't require prior anticoagulation therapy may be eligible but must be discussed and approved by the Principal Investigator.

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

---Tumors invading the GI-tract from external viscera

---Active peptic ulcer disease, inflammatory bowel disease, diverticulitis,cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis

---Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary ductwithin 6 months unless cause of obstruction is definitively managed and subject isasymptomatic

---Abdominal fistula, gastrointestinal perforation, bowel obstruction, orintra-abdominal abscess within 6 months before first dose. Note: Complete healing ofan intra-abdominal abscess must be confirmed before first dose of study treatment.

---Known gastric or esophageal varices

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

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

• Lesions invading major blood vessel including, but not limited to, inferiorvena cava, pulmonary artery, or aorta.

Note: Subjects with intravascular tumor extension (eg, tumor thrombus in renal vein or inferior V. cava) may be eligible following Principal Investigator approval.

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

• Active infection requiring systemic treatment. Note: Prophylactic antibiotictreatment is allowed.

• Known infection with acute or chronic hepatitis B or C, known humanimmunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.

• Known positive test for or suspected infection with clinically significantSARS-CoV-2 within one month before enrollment. Note: demonstration that thesubject has fully recovered from the infection as determined by clinicalinvestigator is required to be eligible for enrollment

• Serious non-healing wound/ulcer/bone fracture. Note: non-healing wounds orulcers are permitted if due to tumor-associated skin lesions.

• Malabsorption syndrome.

• Pharmacologically uncompensated, symptomatic hypothyroidism.

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

• Requirement for hemodialysis or peritoneal dialysis.

• History of solid organ or allogeneic stem cell transplant.

• Major surgery (as defined in Appendix B; eg, GI surgery, removal or biopsy of brainmetastasis) within 8 weeks prior to first dose of study treatment. Priorlaparoscopic nephrectomy within 4 weeks prior to first dose of study treatment.Minor surgery (eg, simple excision, tooth extraction) within 10 days before firstdose of study treatment. Complete wound healing from major or minor surgery musthave occurred at least prior to first dose of study treatment.

Note: Fresh tumor biopsies should be performed at least 7 days before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible.

-Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms for males within 14 days per electrocardiogram (ECG) before first dose of study treatment.

Note: Triplicate ECG evaluations will be performed and the average of these 3 consecutive results for QTcF will be used to determine eligibility.

• History of psychiatric illness likely to interfere with ability to comply withprotocol requirements or give informed consent.

• Inability to swallow tablets.

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

• Any other active malignancy or diagnosis of another malignancy within 2 years beforefirst dose of study treatment requiring systemic treatment, except for superficialskin cancers, or localized, low grade tumors deemed cured and not treated withsystemic therapy.

Note: Patients with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial as approved by the Principal Investigator.

• Other conditions, which in the opinion of the Investigator, would compromise thesafety of the patient or the patient's ability to complete the study.

• Participants taking prohibited medications as described in Section 6.8. A washoutperiod of prohibited medications for a period of at least five half-lives or asclinically indicated should occur before the start of treatment.