Renal Cell Carcinoma (RCC) Clinical Trials

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

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

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

‣ Note: Prior non-vascular endothelial growth factor (VEGF) targeted adjuvant or neoadjuvant is allowed if disease recurrence occurred 6 months after the last dose.

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

‣ Must have radiographically progressed after a combination therapy consisting of a 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 a CTLA-4 mAb as the preceding line of therapy.

⁃ Must have received no more than one prior systemic anticancer therapy for unresectable 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 for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer (CSPC), M0 CRPC, or mCRPC.

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

‣ Must have progressed during or after prior first-line platinum-based combination therapy, including participants who received prior neoadjuvant or adjuvant platinum-containing therapy with disease recurrence \< 12 months from the end of last therapy.

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

• Expansion Cohort 5 (post enfortumab vedotin \[EV\] and ICI): Participants with histologically confirmed unresectable, locally advanced or metastatic predominant urothelial carcinoma.

‣ Progressive disease following prior EV or ineligible for EV, and progression following 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 metastatic nccRCC of the following subtypes: Papillary, unclassified RCC, and translocation-associated, Fumarate Hydratase (FH) deficient and Succinate Dehydrogenase (SDH) deficient. Among the eligible histologic subtypes, sarcomatoid features are allowed.

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

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

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

• Expansion Cohort 9 (NSCLC): Participants with Stage IV non-squamous NSCLC who have radiologically progressed following treatment with one prior immune checkpoint inhibitor (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 or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx. PD-L1 combined positive score (CPS) ≥1.

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

‣ Must have received no more than two prior lines of systemic anticancer therapy for unresectable advanced or metastatic renal cell carcinoma

• Expansion Cohort 13 and Cohort 14 (ccRCC 1L): Participants with unresectable advanced or metastatic RCC with a clear component, including participants who also have a sacromatoid feature.

• Cohort 15 (mCRPC, post-ARPI, visceral metastases): Men with metastatic adenocarcinoma of the prostate.

• Cohort 16 (Drug-drug interaction \[DDI\]):

‣ Participants with a solid tumor that is unresectable or metastatic and for which life prolonging therapies do not exist or available therapies are intolerable or no longer effective.

⁃ Able to swallow capsules or tablets.

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

• For Expansion Cohorts 1 - 11 Only: Archival tumor tissue material, if available, or fresh 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 deemed clinically 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 highly effective methods of contraception.

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