Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors

Brief Title

Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors

Official Title

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

Brief Summary

      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/gastroesophageal junction cancer/lower esophageal cancer (GC/GEJC/LEC), 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. Three
      exploratory single-agent cabozantinib (SAC) cohorts may also be enrolled with UC, NSCLC, or
      CRPC subjects. One exploratory single-agent atezolizumab (SAA) cohort may also be enrolled
      with CRPC subjects. Subjects enrolled in the SAC cohorts and SAA cohort may receive
      combination treatment with both cabozantinib and atezolizumab after they experience
      radiographic progressive disease per the Investigator per RECIST 1.1. Due to the nature of
      this study design, some tumor cohorts may complete enrollment earlier than others.
    

Detailed 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/LEC, CRC, H&N, and DTC.

        -  Exploratory SAC Cohorts: Descriptive efficacy, safety, PK, and biomarker analyses of
           single-agent cabozantinib in UC, NSCLC, and CRPC subjects. Descriptive efficacy and
           safety analyses of combination therapy after progression on single-agent therapy

        -  Exploratory SAA Cohort: Descriptive efficacy, safety, PK, and biomarker analyses of
           single-agent atezolizumab in CRPC subjects. Descriptive efficacy and safety analyses of
           combination therapy after progression on single-agent therapy
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional

Primary Outcome

Dose Escalation: MTD/Recommended Dose

Secondary Outcome

 Incidence and severity of nonserious AEs and SAEs (Safety)

Condition

Urothelial Carcinoma

Intervention

cabozantinib

Study Arms / Comparison Groups

 Dose Escalation

Description:  Subjects will accrue in cohorts of 3-6 subjects for evaluation of cabozantinib tablet dose of either 20 mg, 40 mg, and 60 mg orally qd in combination with standard dosing regimen of atezolizumab (1200 mg infusion q3w). A standard "3 plus 3" design will be utilized to determine a recommended combination dosing regimen for the Expansion Stage.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

1732

Start Date

September 5, 2017

Completion Date

December 2022

Primary Completion Date

December 2021

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/LEC, 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, 9, 11, 17, 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 (>10 mg daily prednisone equivalent) 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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, 1-888-EXELIXIS (888-393-5494), [email protected]

Location Countries

Australia

Location Countries

Australia

NCT ID

NCT03170960

Organization ID

XL184-021

Responsible Party

Sponsor

Study Sponsor

Exelixis

Study Sponsor

, , 

Verification Date

April 2021