Brief Title: XL092 in Combination With Immuno-Oncology Agents in Subjects With Solid Tumors

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)

Primary Outcome 1 - Timeframe: up to 36 months

Primary Outcome 2 - Measure: including immune-mediated adverse events (imAEs)

Primary Outcome 2 - Timeframe: up to 24 months

Primary Outcome 3 - Measure: Expansion Stage: Objective Response Rate (ORR)

Primary Outcome 3 - Timeframe: up to 24 months

Primary Outcome 4 - Measure: Expansion Stage: Progression-Free Survival (PFS)

Primary Outcome 4 - Timeframe: 6 months

Primary Outcome 5 - Measure: Expansion Stage: Overall Survival (OS)

Primary Outcome 5 - Timeframe: N/A

CONDITION

• Renal Cell Carcinoma
• Metastatic Castration-resistant Prostate Cancer
• Urothelial Carcinoma
• Solid Tumor
• Hepatocellular Carcinoma
• Non-small Cell Lung Cancer
• Colorectal Cancer
• Head and Neck Squamous Cell Carcinoma

ELIGIBILITY

Inclusion Criteria:
* Cytologically or histologically confirmed solid tumor that is unresectable, locally advanced or metastatic.

- * Dose-Escalation Cohorts: Subjects 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): Subjects with unresectable advanced or metastatic RCC with a clear cell component who have not received prior systemic therapy.
* Note: Prior non-VEGF targeted adjuvant or neoadjuvant is allowed if disease recurrence occurred 6 months after the last dose.

- * Expansion Cohort 2 (ccRCC): Subjects with unresectable advanced or metastatic RCC with a clear cell component.
* Must have radiographically progressed after a combination therapy consisting of a PD-1/PD-L1 targeting mAb with a 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): Subjects 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 subjects 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 (UC, ICI-experienced): Subjects 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 PD-1/PD-L1 targeting ICI therapy given as monotherapy, combination therapy, maintenance therapy or adjuvant therapy.

- * Must have received no more than 2 prior lines of systemic anticancer therapy for unresectable advanced or metastatic disease.

- * Expansion Cohort 6 (nccRCC): Subjects with unresectable advanced or metastatic nccRCC of the following subtypes: Papillary, unclassified RCC, and translocation-associated, FH deficient and 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): Subjects with locally advanced, or metastatic and/or unresectable HCC that is not amenable to curative treatment or locoregional therapy.

- * Expansion Cohort 8 (NSCLC): Subjects 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): Subjects 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): Subjects with histologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the colon or rectum.

- * Expansion Cohort 11 (HNSCC): Subject 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): Subjects with unresectable advance or metastatic RCC with a clear cell component, including subjects 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 (ccRCC): Subjects with unresectable advanced or metastatic RCC with a clear component, including subjects who also have a sacromatoid feature.

- * 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 subjects and their partners must agree to use highly effective 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 Expansion Cohorts: Prior treatment with XL092, nivolumab, ipilimumab or relatlimab with the following exceptions: Prior PD-1/PD-L1, LAG-3 and CTLA-4 targeting therapy 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 the neoadjuvant 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 small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.

- * For Cohort 3 (mCRPC): Receipt of abiraterone within 1 week; cyproterone within 10 days; or receipt of flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen 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 any type of anticancer antibody or systemic chemotherapy within 4 weeks before first dose of study treatment.

- * Any complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment.

- * Prior external radiation therapy for bone metastasis within 2 weeks, for other tumor sites within 4 weeks, and prior radium-223 therapy within 6 weeks before first dose of study treatment, unless otherwise specified.

- * Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment.

- * Concomitant anticoagulation with oral anticoagulants, except for specified direct factor 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 for females and > 450 ms for males per electrocardiogram (ECG) within 14 days before first 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 and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if 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 months of completing adjuvant anti-PD-(L)1 treatment.

- * For Cohort 6 (nccRCC, 1L): Subjects 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 escalation in diuretics) within 6 months before randomization.

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

- * Subjects with known fibrolamellar carcinoma, sarcomatoid HCC, or mixed hepatocellular cholangiocarcinoma

- * For Cohort 10 (CRC, 2L+): Receipt of prior therapy with regorafenib and/or trifluridine + 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-L1 low), 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.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: N/A

Role: N/A

Affiliation: N/A

Overall Contact

Name: Exelixis Clinical Trials, Backup or International

Phone: 1-888-EXELIXIS (888-393-5494), 650-837-7400

Email: [email protected]

LOCATION