A Dose-Escalation and Expansion Study of the Safety and Pharmacokinetics of XL092 as Single-Agent and Combination Therapy in Subjects With Inoperable Locally Advanced or Metastatic Solid Tumors

Study Identifier:
XL092-001
CT.gov Identifier:
NCT03845166
EudraCT Identifier:
2020-003569-21
EU Trial (CTIS) Number:
2024-515617-18-00
Study Contact Information:
N/A
Recruitment Complete

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Study Summary

To evaluate pharmacokinetics, safety and tolerability of XL092

To evaluate the safety, tolerability, pharmacokinetics (PK), preliminary antitumor activity, and effect on biomarkers of XL092 administered alone, in combination with atezolizumab, and in combination with avelumab to subjects with advanced solid tumors

To define the recommended dose (RD) of XL092 as a single-agent (SA) and in combination with atezolizumab and assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy in pts with solid tumors

Objectives were to evaluate median (m)OS, investigator-assessed ORR, and mPFS per RECIST 1.1, and safety

To evaluate zanzalintinib as a single agent or in combination with atezolizumab in patients with inoperable locally advanced or metastatic solid tumors. The trial is divided into two parts: a dose-escalation stage and an expansion cohort stage. The expansion cohorts evaluating zanzalintinib (100 mg) as a single agent or in combination with atezolizumab also include patients with clear cell renal cell carcinoma (RCC), non-clear cell RCC, breast cancer that is hormone receptor-positive and HER-2 negative and castration-resistant prostate cancer.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Bladder
  • Breast Cancers
  • Bowel (Colorectal)
  • Non-Small Cell Lung Cancer
  • Prostate
  • Renal
  • Solid Tumor
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: XL092 Single-Agent Dose-Escalation Cohorts
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  • Drug: Experimental: XL092 Single-Agent Expansion Cohorts
  • Drug: Experimental: XL092 + Atezolizumab Dose-Escalation Cohorts
  • Drug: Drug: Atezolizumab
  • Drug: Experimental: XL092 + Atezolizumab Expansion Cohorts
  • Drug: Experimental: XL092 + Avelumab Dose-Escalation Cohorts
  • Drug: Drug: Avelumab
  • Drug: Patients ts will receive escalating doses of XL092 w/wo atezolizumab (ATEZO) 1200 mg Q3W or avelumab (AVE) 800 mg Q2W.
  • Drug: Pts with advanced urothelial carcinoma will be enrolled in 3 cohorts: (i) pts with ongoing CR/PR/SD after 4-6 cycles of first-line chemotherapy (gemcitabine + cisplatin and/or gemcitabine + carboplatin) will receive XL092 + AVE; (ii) pts with progression on/after prior ICI therapy (=2 prior systemic therapies) will be randomized 1:1 to XL092 + AVE or single-agent XL092; (iii) pts with progression on/after first-line platinum-based chemotherapy will receive XL092 + AVE
  • Drug: ESMO 2022
  • Drug: ASCO GI 2025:
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruitment Complete

    Requirements information
    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.

    Clinical Study Information for Healthcare Providers

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START San Antonio
    San Antonio, TX, United States, 78229
    Investigator
    Amita Patnaik
    Status
    Recruitment Complete
    Condition(s) Treated at Site
    Bladder
    Breast Cancers
    Bowel (Colorectal)
    Non-Small Cell Lung Cancer
    Prostate
    Renal
    Solid Tumor
    Location
    START Midwest
    Grand Rapids, MI, United States, 49546
    Investigator
    Manish Sharma
    Status
    Recruiting
    Condition(s) Treated at Site
    Bladder
    Breast Cancers
    Bowel (Colorectal)
    Non-Small Cell Lung Cancer
    Prostate
    Renal
    Solid Tumor