Study of Zanzalintinib in Combination With Immuno-Oncology Agents in Participants With Solid Tumors

Key Inclusion Criteria:

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

• Dose-Escalation Cohorts: Participants 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): Participants with unresectable advanced or metastaticRCC with a clear cell component who have not received prior systemic therapy.

• Note: Prior non-vascular endothelial growth factor (VEGF) targeted adjuvant orneoadjuvant is allowed if disease recurrence occurred 6 months after the lastdose.

• Expansion Cohort 2 (ccRCC): Participants with unresectable advanced or metastaticRCC with a clear cell component.

• Must have radiographically progressed after a combination therapy consisting ofa Programmed Cell Death Protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1)targeting monoclonal antibody (mAb) with a Vascular endothelial growth factor (receptor) tyrosine kinase inhibitor (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): Participants 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 participants 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 (post enfortumab vedotin [EV] and ICI): Participants withhistologically confirmed unresectable, locally advanced or metastatic predominanturothelial carcinoma.

• Progressive disease following prior EV or ineligible for EV, and progressionfollowing prior PD-1/PD-L1 inhibitor or ineligible for PD-1/PD-L1 inhibitor.

• Prior receipt of platinum-based therapy allowed but not required.

• Prior therapy with other agents allowed but not required.

• Expansion Cohort 6 (nccRCC): Participants with unresectable advanced or metastaticnccRCC of the following subtypes: Papillary, unclassified RCC, andtranslocation-associated, Fumarate Hydratase (FH) deficient and SuccinateDehydrogenase (SDH) deficient. Among the eligible histologic subtypes, sarcomatoidfeatures 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): Participants with locally advanced, or metastatic and/orunresectable HCC that is not amenable to curative treatment or locoregional therapy.

• Expansion Cohort 8 (NSCLC): Participants with Stage IV non-squamous NSCLC withpositive PD-L1 expression (tumor proportion score [TPS] 1-49%) and without priorsystemic anticancer therapy for metastatic disease.

• Expansion Cohort 9 (NSCLC): Participants 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): Participants with histologically confirmed unresectable,locally advanced, or metastatic adenocarcinoma of the colon or rectum.

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

• Expansion Cohort 12 (ccRCC): Participants with unresectable advance or metastaticRCC with a clear cell component, including participants who also have a sacromatoidfeature.

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

• Expansion Cohort 13 and Cohort 14 (ccRCC 1L): Participants with unresectableadvanced or metastatic RCC with a clear component, including participants who alsohave 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 participants and their partners must agree to use highlyeffective methods of contraception.

• Females of childbearing potential must not be pregnant at screening.

Key Exclusion Criteria:

• For all Dose-Escalation cohorts: Prior treatment with zanzalintinib. For allExpansion Cohorts: Prior treatment with zanzalintinib, nivolumab, ipilimumab orrelatlimab with the following exceptions: Prior PD-1/PD-L1, Lymphocyte-activationgene 3 (LAG-3) and cCytotoxic T lymphocyte associated protein 4 (CTLA-4) targetingtherapy for locally 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 and Cohort 14 (ccRCC 1L).

• 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.

• Participants 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): Participants who have had recurrence within the 6months of completing adjuvant anti-PD-(L)1 treatment.

• For Cohort 6 (nccRCC, 1L): Participants with chromophobe, renal medullary carcinoma,or pure 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.

• Participants who have received any local anticancer therapy including surgery,percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwaveablation (MWA), transarterial chemoembolization (TACE), or transarterialradioembolization (TARE) within 28 days prior to first dose.

• Participants 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, microsatellite stable [MSS], 2L+), and 11 (HNSCC):

• Troponin T (TnT) or I (TnI) > 2 × institutional upper limit of normal (ULN).

Note: Additional Inclusion and Exclusion criteria may apply.