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Phase I

A Phase 1b Dose-Escalation Study of Cabozantinib (XL184) Administered Alone or in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors

  • Study HIC#:2000024340
  • Last Updated:07/12/2021

This is a multicenter Phase 1b, open-label study to assess safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of cabozantinib taken in combination with atezolizumab in subjects with multiple tumor types, including advanced urothelial carcinoma (UC) (including bladder, renal pelvis, ureter, urethra), renal cell carcinoma (RCC), castration-resistant prostate cancer (CRPC), non-small-cell lung cancer (NSCLC), triple negative breast cancer (TNBC), ovarian cancer (OC), endometrial cancer (EC), hepatocellular cancer (HCC), gastric cancer and gastroesophageal junction cancer (GC/GEJC), colorectal cancer (CRC), head and neck (H&N) cancer, and differentiated thyroid cancer (DTC). The study consists of two stages: in the Dose Escalation Stage, an appropriate recommended cabozantinib dose for the combination with standard dosing regimen of atezolizumab will be established; in the Expansion Stage, tumor-specific cohorts will be enrolled in order to further evaluate the safety and efficacy of the combination treatment in these tumor indications. Two exploratory single-agent cabozantinib (SAC) cohorts will also be enrolled with UC or NSCLC subjects.

  • Start Date07/05/2019
  • End Date12/01/2020

Trial Purpose and Description

  • Dose Escalation Stage: to determine the schedule and maximum tolerated dose (MTD) and/or recommended Expansion Stage dose of cabozantinib when taken in combination with a standard dosing regimen of atezolizumab (1200 mg infusion, once every 3 weeks).
  • Expansion Stage: to determine the preliminary efficacy (objective response rate [ORR] per RECIST 1.1) and safety of the recommended combination dose of cabozantinib with atezolizumab in eighteen tumor-specific cohorts including subjects with advanced UC, RCC, CRPC, NSCLC, TNBC, OC, EC, HCC, GC/GEJC, CRC, H&N, and DTC.
  • Exploratory SAC Cohorts: Descriptive efficacy, safety, PK, and biomarker analyses of single-agent cabozantinib in UC and NSCLC subjects

Eligibility Criteria

Inclusion Criteria:

  1. Cytologically or histologically and radiologically confirmed solid tumor that is inoperable, locally advanced, metastatic, or recurrent:
    • Dose-Escalation Stage:
      • Subjects with UC (including renal pelvis, ureter, bladder, urethra) after prior platinum-based therapy, or
      • Subjects with RCC (clear cell, non-clear cell histology) with or without prior systemic anticancer therapy
    • Expansion Stage:
      • Inoperable locally advanced or metastatic solid tumor (UC, RCC, CRPC, NSCLC, TNBC, OC, EC, HCC, GC/GEJC, CRC, H&N cancer, and DTC as outlined above)
  2. Measurable disease per RECIST 1.1 as determined by the investigator.
  3. Tumor tissue material available (archival or recent tumor biopsy)
  4. Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
  5. Age eighteen years or older on the day of consent.
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
  7. Adequate organ and marrow function.
  8. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception.
  9. Female subjects of childbearing potential must not be pregnant at screening.

Exclusion Criteria:

  1. Prior treatment with cabozantinib or immune checkpoint inhibitors including anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy except in Expansion Cohorts 5, 7,19 and 20. Other restrictions regarding prior therapy may apply.
  2. Known brain metastases or cranial epidural disease unless adequately treated and stable for at least 4 weeks before first dose of study treatment.
  3. Concomitant anticoagulation with oral anticoagulants.
  4. Subject is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment.
  5. Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.
  6. The subject has uncontrolled, significant intercurrent or recent illness, including, but not limited to, an active or history of autoimmune disease or immune deficiency; idiopathic pulmonary fibrosis, organizing pneumonia, pneumonitis; active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV), AIDS-related illness, acute or chronic hepatitis B or C infection, positive test for tuberculosis, moderate to severe hepatic impairment (Child-Pugh B or C).
  7. Pregnant or lactating females.
  8. Previously identified allergy or hypersensitivity to components of the study treatment formulations.
  9. Diagnosis of another malignancy within 2 years before first dose of study treatment.


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