Trial of XL092 in Combination With Immunotherapy in Patients Who Progress on Adjuvant Therapy in Clear Cell RCC

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal healthinformation prior to registration. NOTE: HIPAA authorization may be included in theinformed consent or obtained separately.

2. Age ≥ 18 years at the time of consent.

3. ECOG Performance Status of 0-1 within 28 days prior to registration.

4. Advanced or metastatic RCC with a clear cell component.

5. Subjects who have progressed on or after adjuvant anti-PD-1 will be eligible as longas they have received no other systemic therapy. For those who progress on adjuvanttherapy, a washout period of at least 2 weeks would be required.

6. Measurable disease per RECIST 1.1.

7. Prior cancer treatment must have included an anti-PD-1/L1. Prior treatment must havebeen completed at least 2 weeks prior to study treatment initiation and the subjectmust have recovered from all reversible acute toxic effects of the regimen (otherthan alopecia) to Grade ≤ 1 or baseline. Unresolved grade 2 or greater toxicity fromprior checkpoint inhibitor therapy will exclude a subject from enrolling.

8. Demonstrate adequate organ function as defined below. All screening labs are to beobtained within 2 weeks prior to registration.

• Absolute Neutrophil Count (ANC): ≥ 1500/mm3 without granulocytescolony-stimulating factor support within 2 weeks of screening laboratorycollection

• Platelet Count (PLT): ≥ 100,000/mm3; without transfusion within 2 weeks ofscreening laboratory sample collection.

• Hemoglobin (Hgb): ≥ 9 g/dL

• Serum Creatinine OR Calculated CrCl using Cockgroft Gault equation: Serumcreatinine < 1.5 upper limit of normal (ULN) OR calculated Cr Clearance >40mL/min

• Urine protein-to-creatinine ratio (UPCR): ≤1mg/mg (≤ 113.2mg/mmol) creatinine

• Bilirubin: ≤ 1.5 × ULN (for subjects with Gilbert's disease < 3 x ULN)

• Aspartate aminotransferase (AST): ≤ 3 × ULN

• Alanine aminotransferase (ALT): ≤ 3 × ULN

• Alkaline phosphatase (ALP): ≤ 3 × ULN. For subjects with documented bonemetastasis ALP ≤ 5x ULN

• International Normalized Ratio (INR): ≤ 1.5 x ULN

• Activated Partial Thromboplastin Time (aPTT): ≤ 1.2 × ULN

9. Females of childbearing potential must have a negative urine or serum pregnancy testwithin 2 weeks prior to registration. If a urine test is done and it is positive orcannot be confirmed as negative, a serum pregnancy test will be required.

10. Females of childbearing potential who are sexually active with a male able to fathera child must be willing to abstain from penile-vaginal intercourse or to use aneffective method(s) of contraception. Males able to father a child who are sexuallyactive with female of childbearing potential must be willing to abstain frompenile-vaginal intercourse or to use an effective method(s) of contraception.

11. Known HIV-infected patients on effective anti-retroviral therapy with undetectableviral load within 6 months of registration are eligible for this trial. Testing isnot required at screening unless mandated by local policy.

12. Patients with known chronic hepatitis B virus (HBV) infection, must have anundetectable HBV viral load on suppressive therapy, if indicated. Patients with ahistory of hepatitis C virus (HCV) infection must have been treated and cured. Forpatients with HCV infection who are currently on treatment, the HCV viral load mustbe undetectable to be eligible for this trial. Testing is not required at screeningunless mandated by local policy.

13. As determined by the enrolling physician or protocol designee, ability of thesubject to understand and comply with study procedures for the entire length of thestudy.

Exclusion Criteria:

1. Radiation therapy for bone metastasis within 2 weeks, 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.

2. 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 ofan isolated brain lesion < 1 cm in diameter may be eligible aftersponsor-investigator approval if the lesion is radiographically stable for 4 weeksbefore first dose and does not require treatment per Investigator judgement. Note:Eligible subjects must be neurologically asymptomatic and without corticosteroidtreatment at the time of first dose of study treatment.

3. Any complementary medications (eg, herbal supplements or traditional Chinesemedicines) to treat the disease under study within 2 weeks before first dose ofstudy treatment.

4. Active infection requiring systemic therapy. NOTE: Patients receiving prophylacticantibiotics (e.g., to prevent a urinary tract infection or chronic obstructivepulmonary disease exacerbation) are eligible for the study.

5. Positive TB test with active mycobacterial infection requiring systemic treatment.

6. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use whilethe mother is being treated on study).

7. History of severe allergic anaphylactic reactions to study drug(s) or any of theirexcipients.

8. Patients with a prior or concurrent malignancy whose natural history or treatmenthas the potential to interfere with the safety or efficacy assessment of theinvestigational regimen, per treating physician discretion, are not eligible forthis trial.

9. Administration of a live, attenuated vaccine within 30 days prior to first dose ofstudy treatment.

10. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-inducedpneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis.

11. Prior organ allograft including allogeneic stem cell transplant

12. Inability to swallow oral medications.

13. Uncontrolled major cardiovascular, pulmonary, hematologic, or psychiatric illnessesthat would make the subject a poor study candidate.

14. Subjects on therapeutic doses of LMWH or specified direct factor Xa inhibitorsrivaroxaban, edoxaban, or apixaban in subjects without known brain metastases whoare on a stable dose of the anticoagulant for at least 1 week before randomizationand without clinically significant hemorrhagic complications from theanticoagulation regimen or the tumor. Therapeutic doses of anticoagulants are notpermitted in subjects with known brain metastases at study entry.

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

• Unstable or deteriorating cardiovascular disease including but not limited to thefollowing:

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

• 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 12 months before first dose.

• Prior history of myocarditis.

16. Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinicallysignificant venous or non-CVA/TIA arterial thromboembolic events within 6 monthsbefore to first dose. NOTE: Subjects with a diagnosis of DVT within 6 months areallowed if asymptomatic and stable at screening and treated with anticoagulation perstandard of care before first dose of study treatment. Subjects who don't requireprior anticoagulation therapy may be eligible but must be discussed and approved bythe sponsor-investigator.

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

• Known gastric or esophageal varices

• 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 subjectis asymptomatic.

• Abdominal fistula, gastrointestinal perforation, bowel obstruction, orintra-abdominal abscess within 6 months before first dose. NOTE: Completehealing of an intra-abdominal abscess must be confirmed before first dose.

18. 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.

19. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.

20. Lesions invading major blood vessel including, but not limited to, inferior venacava, pulmonary artery, or aorta. NOTE: Subjects with intravascular tumor extension (eg, tumor thrombus in renal vein or inferior V. cava) may be eligible followingsponsor-investigator approval.

21. Other clinically significant disorders such as:

• Any active, known or suspected autoimmune disease. NOTE: Subjects with type Idiabetes mellitus, hypothyroidism only requiring hormone replacement, skindisorders (such as vitiligo, psoriasis, or alopecia) not requiring systemictreatment, or conditions not expected to recur in the absence of an externaltrigger are permitted to enroll.

• Any condition requiring systemic treatment with either corticosteroids (> 10 mgdaily prednisone equivalent) or other immunosuppressive medications within 2weeks of first dose of study treatment. NOTE: Inhaled, intranasal,intra-articular, or topical steroids are permitted. Adrenal replacement steroiddoses > 10 mg daily prednisone equivalent are permitted in the absence ofactive autoimmune disease. Transient short-term use of systemic corticosteroidsfor allergic conditions (eg, contrast allergy) is also allowed.

• Malabsorption syndrome.

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

• Pharmacologically uncompensated, symptomatic hypothyroidism.

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

• Requirement for hemodialysis or peritoneal dialysis.

• History of life-threatening toxicity related to prior immune therapy (eg,anti-CTLA-4, or anti-PD-1/PD-L1 treatment or any other antibody or drugspecifically targeting T-cell co-stimulation or immune checkpoint pathways)except those that are unlikely to recur and manageable by standard of caretreatment (eg, hypothyroidism).

22. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeksprior to first dose. Prior laparoscopic nephrectomy within 4 weeks prior to firstdose. Minor surgery (eg, simple excision, tooth extraction) within 10 days beforefirst dose of study treatment. Complete wound healing from major or minor surgerymust have occurred at least prior to first dose. NOTE: Fresh tumor biopsies shouldbe performed at least 7 days before the first dose of study treatment. Subjects withclinically relevant ongoing complications from prior surgical procedures, includingbiopsies, are not eligible.

23. Corrected QT interval calculated by the Fridericia formula (QTcF) > 450 ms for malesor > 470 ms for females per electrocardiogram (ECG) within 14 days before first doseof study treatment. NOTE: If a single ECG shows a QTcF with an absolute value > 450ms for males or > 470 ms for females, two additional ECGs at intervals ofapproximately 3 minutes must be performed within 30 minutes after the initial ECG,and the average of these three consecutive results for QTcF will be used todetermine eligibility.

24. Subjects with inadequately treated adrenal insufficiency.