Study of XL092 in Combination With Immuno-Oncology Agents in Subjects With Solid Tumors

Inclusion Criteria:

• Cytologically or histologically confirmed solid tumor that is unresectable, locallyadvanced or metastatic.

• Dose-Escalation Cohorts: Subjects with a solid tumor that is unresectable ormetastatic and for which life-prolonging therapies do not exist or availabletherapies are intolerable or no longer effective.

• Expansion Cohort 1 (ccRCC): Subjects with unresectable advanced or metastatic RCCwith a clear cell component who have not received prior systemic therapy.

• Note: Prior non-VEGF targeted adjuvant or neoadjuvant is allowed if diseaserecurrence occurred 6 months after the last dose.

• Expansion Cohort 2 (ccRCC): Subjects with unresectable advanced or metastatic RCCwith a clear cell component.

• Must have radiographically progressed after a combination therapy consisting ofa PD-1/PD-L1 targeting mAb with a VEGFR-TKI or a PD-1 targeting mAb with aCTLA-4 mAb as the preceding line of therapy.

• Must have received no more than one prior systemic anticancer therapy forunresectable advanced or metastatic renal cell carcinoma.

• Expansion Cohort 3 (mCRPC): Men with metastatic adenocarcinoma of the prostate.

• Must have progressed during or after one novel hormone therapy (NHT) given forcastration-sensitive locally advanced (T3 or T4) or metastaticcastration-sensitive prostate cancer (CSPC), M0 CRPC, or mCRPC.

• Expansion Cohort 4 (UC, ICI-naive): Subjects with histologically confirmedunresectable, locally advanced or metastatic transitional cell carcinoma of theurothelium (including the renal pelvis, ureter, urinary bladder, or urethra).

• Must have progressed during or after prior first-line platinum-basedcombination therapy, including subjects who received prior neoadjuvant oradjuvant platinum-containing therapy with disease recurrence < 12 months fromthe end of last therapy.

• Must have received no more than 1 prior line of systemic anticancer therapy forunresectable, locally advanced or metastatic disease.

• Expansion Cohort 5 (UC, ICI-experienced): Subjects with histologically confirmedunresectable, locally advanced or metastatic transitional cell carcinoma of theurothelium (including the renal pelvis, ureter, urinary bladder, or urethra).

• Must have progressed during or after prior PD-1/PD-L1 targeting ICI therapygiven as monotherapy, combination therapy, maintenance therapy or adjuvanttherapy.

• Must have received no more than 2 prior lines of systemic anticancer therapyfor unresectable advanced or metastatic disease.

• Expansion Cohort 6 (nccRCC): Subjects with unresectable advanced or metastaticnccRCC of the following subtypes: Papillary, unclassified RCC, andtranslocation-associated, FH deficient and SDH deficient. Among the eligiblehistologic subtypes, sarcomatoid features are allowed.

• No prior systemic anticancer therapy is allowed except adjuvant or neoadjuvanttherapy if disease recurrence occurred at least 6 months after the last dose.

• Expansion Cohort 7 (HCC): Subjects with locally advanced, or metastatic and/orunresectable HCC that is not amenable to curative treatment or locoregional therapy.

• Expansion Cohort 8 (NSCLC): Subjects with Stage IV non-squamous NSCLC with positivePD-L1 expression (tumor proportion score [TPS] 1-49%) and without prior systemicanticancer therapy for metastatic disease.

• Expansion Cohort 9 (NSCLC): Subjects with Stage IV non-squamous NSCLC who haveradiologically progressed following treatment with one prior immune checkpointinhibitor (anti-PD-1 or anti-PD-L1) for metastatic disease.

• Expansion Cohort 10 (CRC): Subjects with histologically confirmed unresectable,locally advanced, or metastatic adenocarcinoma of the colon or rectum.

• Expansion Cohort 11 (HNSCC): Subject with inoperable, refractory, recurrent ormetastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx. PD-L1combined positive score (CPS) ≥1.

• Expansion Cohort 12 (ccRCC): Subjects with unresectable advance or metastatic RCCwith a clear cell component, including subjects who also have a sacromatoid feature.

• Must have received no more than two prior lines of systemic anticancer therapyfor unresectable advanced or metastatic renal cell carcinoma

• Expansion Cohort 13 (ccRCC): Subjects with unresectable advanced or metastatic RCCwith a clear component, including subjects who also have a sacromatoid feature.

• For all Expansion Cohorts except Cohort 3: Measurable disease per RECIST 1.1 asdetermined by the Investigator.

• For Expansion Cohorts 1 - 11 Only: Archival tumor tissue material, if available, orfresh tumor tissue if it can be safely obtained.

• Recovery to baseline or ≤ Grade 1 common terminology criteria for adverse events (CTCAE) v5 from AE(s) related to any prior treatments unless AE(s) are deemedclinically nonsignificant by the Investigator and/or stable on supportive therapy.

• Karnofsky Performance Status (KPS) ≥ 70%.

• Adequate organ and marrow function.

• Sexually active fertile subjects and their partners must agree to use highlyeffective methods of contraception.

• Female subjects of childbearing potential must not be pregnant at screening.

Exclusion Criteria:

• For all Dose-Escalation cohorts: Prior treatment with XL092. For all ExpansionCohorts: Prior treatment with XL092, nivolumab, ipilimumab or relatlimab with thefollowing exceptions: Prior PD-1/PD-L1, LAG-3 and CTLA-4 targeting therapy forlocally advanced or metastatic disease is allowed for Cohort 2 (ccRCC), Cohort 5 (UC), Cohort 9 (NSCLC), and Cohort 12 (ccRCC), and prior treatment in theneoadjuvant or adjuvant setting is allowed for Cohort 13 (ccRCC).

• For all Dose-Escalation Cohorts and Expansion Cohort 2 (ccRCC), 3 (mCRPC), Cohort 5 (UC), Cohort 9 (NSCLC), Cohort 10 (CRC), and Cohort 12: Receipt of any type of smallmolecule kinase inhibitor (including investigational kinase inhibitor) within 2weeks before first dose of study treatment.

• For Cohort 3 (mCRPC): Receipt of abiraterone within 1 week; cyproterone within 10days; or receipt of flutamide, nilutamide, bicalutamide, enzalutamide, or otherandrogen receptor inhibitors within 2 weeks before first dose of study treatment.

• For all Dose-Escalation Cohorts and Expansion Cohort 2 (ccRCC), Cohort 3 (mCRPC),Cohort 5 (UC), Cohort 9 (NSCLC) and Cohort 10 (CRC), and Cohort 12: Receipt of anytype of anticancer antibody or systemic chemotherapy within 4 weeks before firstdose of study treatment.

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

• Prior external radiation therapy for bone metastasis within 2 weeks, for other tumorsites within 4 weeks, and prior radium-223 therapy within 6 weeks before first doseof study treatment, unless otherwise specified.

• 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.

• Concomitant anticoagulation with oral anticoagulants, except for specified directfactor Xa inhibitors.

• Administration of a live, attenuated vaccine within 30 days prior to first dose.

• Uncontrolled, significant intercurrent or recent illness.

• Corrected QT interval calculated by the Fridericia formula (QTcF) > 460 ms forfemales and > 450 ms for males per electrocardiogram (ECG) within 14 days beforefirst dose of study treatment.

• Subjects with inadequately treated adrenal insufficiency.

• Pregnant or lactating females.

• Any other active malignancy within two years before first dose of study treatment,except for superficial skin cancers, or localized, low-grade tumors deemed cured andnot treated with systemic therapy. Incidentally diagnosed prostate cancer is allowedif assessed as stage ≤ T2N0M0 and Gleason score ≤ 6.

• For Cohort 2 (ccRCC, 2L): Receipt of a prior triplet therapy including a VEGFR-TKI,a PD1 targeting mAb, and a CTLA-4 mAb.

• For Cohort 3 (mCRPC): Receipt of a taxane-based chemotherapy for mCRPC.

• For Cohort 4 (UC, ICI-naïve): Subjects who have had recurrence within the 6 monthsof completing adjuvant anti-PD-(L)1 treatment.

• For Cohort 6 (nccRCC, 1L): Subjects with chromophobe, renal medullary carcinoma, orpure collecting duct nccRCC.

• For Cohort 7 (HCC):

• Documented hepatic encephalopathy (HE) within 6 months before the first dose.

• Clinically meaningful ascites (ie, ascites requiring paracentesis or escalationin diuretics) within 6 months before randomization.

• Subjects who have received any local anticancer therapy including surgery, PEI,RFA, MWA, transarterial chemoembolization (TACE), or transarterialradioembolization (TARE) within 28 days prior to first dose.

• Subjects with known fibrolamellar carcinoma, sarcomatoid HCC, or mixedhepatocellular cholangiocarcinoma

• For Cohort 10 (CRC, 2L+): Receipt of prior therapy with regorafenib and/ortrifluridine + tipiracil (TAS-102).

• For Cohort 11 (HNSCC): Primary tumor site of the nasopharyngeal area.

• For Cohorts 1 (ccRCC, 1L), 2 (ccRCC, 2L), 4, 5 (UC), 7 (HCC), 8 (NSCLC 1L PD-L1low), 9 (NSCLC, 2L+), 10 (CRC, MSS, 2L+), and 11 (HNSCC):

• Troponin T (TnT) or I (TnI) > 2 × institutional ULN.

Note: Additional Inclusion and Exclusion criteria may apply.