Brief Title: XL092 as Single-Agent and Combination Therapy in Subjects With Solid Tumors

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Dose-Escalation Stage: MTD/recommended dose for XL092

Primary Outcome 1 - Timeframe: Up to 24 months

Primary Outcome 2 - Measure: Cohort-Expansion Stage: Objective Response Rate (ORR)

Primary Outcome 2 - Timeframe: Up to 24 months

Primary Outcome 3 - Measure: Cohort-Expansion Stage (except Cohort H): Progression-Free Survival (PFS)

Primary Outcome 3 - Timeframe: Up to 24 months

Primary Outcome 4 - Measure: Cohort-Expansion Stage (Cohort H only): Overall Survival (OS)

Primary Outcome 4 - Timeframe: Up to 24 months

CONDITION

• Neoplasm Malignant
• Renal Cell Carcinoma
• Hormone Receptor Positive Breast Carcinoma
• Metastatic Castration-resistant Prostate Cancer
• Urothelial Carcinoma
• Colorectal Cancer

ELIGIBILITY

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

- Dose-escalation (single-agent and combination therapy): 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 A (ccRCC): Subjects with previously treated advanced RCC with clear cell histology (including those with a sarcomatoid component) who have radiographically progressed following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.

- Expansion Cohorts B and E (nccRCC): Subjects with previously treated advanced RCC with non-clear cell histology who have radiographically progressed following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.

- Expansion Cohorts C and F (HR+ BC): Subjects with breast cancer that is hormone receptor positive (ER+ and/or PR+) and negative for human epidermal growth factor receptor 2 (HER-2) and who have radiographically progressed during or following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.

- Expansion Cohorts D and G (mCRPC): Subjects with metastatic CRPC (adenocarcinoma of the prostate). Neuroendocrine differentiation and other features permitted if adenocarcinoma is the primary histology.
Expansion Cohort H (CRC): Subjects with histologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the colon or rectum, KRAS/NRAS wild-type (confirmed via local testing report) and determined NOT to have microsatellite instability high (MSI-high) or mismatch repair deficient (dMMR) by local testing, who received the following standard of care chemotherapy regimens as prior therapy for metastatic CRC:
Fluoropyrimidine, irinotecan and oxaliplatin, with or without an anti-VEGF monoclonal antibody (bevacizumab)

- Anti-EGFR monoclonal antibody (cetuximab or panitumumab)

- BRAF inhibitor (in combination with cetuximab +/- binimetinib) for subjects with BRAF V600E mutations

- Expansion Cohort I (UC, Maintenance Therapy): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who received first-line chemotherapy of gemcitabine + cisplatin and/or gemcitabine + carboplatin.

- Expansion Cohort J (UC, ICI-refractory): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who progressed on or after PD-1/PD-L1 targeting ICI therapy.

- Expansion Cohort K (UC, platinum-refractory): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who progressed on or after first-line platinum-based combination therapy.

- Expansion Cohorts: Subjects must have measurable disease per RECIST 1.1, with exception of Cohort I (UC, Maintenance Therapy).
Tumor tissue material:
Subjects in the non-biomarker cohort provide archival, if available, or fresh tumor tissue if it can be safely obtained.

- Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from adverse events (AEs), including immune-related adverse events (irAEs), related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

- 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:
Prior treatment with XL092 (all cohorts), prior treatment with PD-L1/PD-1 targeting immune checkpoint inhibitor (Cohorts E, F, G, H, I, and K only), prior treatment with avelumab (Cohort J only), or prior treatment with regorafenib and/or TAS-102 (Cohort H only).

- Receipt of any type of small molecule kinase inhibitor within 2 weeks before first dose of study treatment.

- Receipt of any type of anticancer antibody, systemic chemotherapy, or hormonal anticancer therapy within 4 weeks before first dose of study treatment.

- Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.

- 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.

- Uncontrolled, significant intercurrent or recent illness.

- Concomitant use of certain medications.

- Corrected QT interval calculated by the Fridericia formula (QTcF) > 450 ms for males and > 470 ms for females. Single ECGs are no longer permitted.

- Pregnant or lactating females.

- Diagnosis of another malignancy within 2 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.
Additional Exclusion Criteria for XL092 + Atezolizumab Combination Therapy Cohorts ONLY:
Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment.

- Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.
Additional Exclusion Criteria for XL092 + Avelumab Combination Therapy Cohorts ONLY:
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent.

- Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.

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: N/A

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

Email: druginfo@exelixis.com

LOCATION