A Study of XL092 as Single-Agent and Combination Therapy in Subjects With Solid Tumors

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 Cohorts: Subjects must have measurable disease per RECIST 1.1.
* 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, and H 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.