Clinical Trials /

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

NCT03170960

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Endometrial Carcinoma
  • Esophageal Carcinoma
  • Gastric Carcinoma
  • Head and Neck Carcinoma
  • Hepatocellular Carcinoma
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Prostate Adenocarcinoma
  • Prostate Carcinoma
  • Renal Cell Carcinoma
  • Urothelial Carcinoma
  • Well-Differentiated Thyroid Gland Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: XL184-021
  • NCT ID: NCT03170960

Conditions

  • Urothelial Carcinoma
  • Renal Cell Carcinoma
  • Non-Small Cell Lung Cancer
  • Castration-resistant Prostate Cancer
  • Triple Negative Breast Cancer
  • Ovarian Cancer
  • Endometrial Cancer
  • Hepatocellular Carcinoma
  • Gastric Cancer
  • Gastroesophageal Junction Adenocarcinoma
  • Colorectal Cancer
  • Head and Neck Cancer
  • Differentiated Thyroid Cancer
  • Lower Esophageal Cancer

Interventions

DrugSynonymsArms
cabozantinibCabometyx, XL184Dose Escalation
atezolizumabTecentriqDose Escalation
cabozantinibCabometyx, XL184Expansion Cohort 1
cabozantinibCabometyx, XL184Expansion Cohort 19 (SAC)

Purpose

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. 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

        -  Exploratory SAA Cohort: Descriptive efficacy, safety, PK, and biomarker analyses of
           single-agent atezolizumab in CRPC subjects
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalSubjects 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.
  • cabozantinib
  • atezolizumab
Expansion Cohort 1ExperimentalRCC subjects with clear cell histology who have not received prior systemic anticancer therapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 2ExperimentalUC subjects (including bladder, renal pelvis, ureter, urethra) who have progressed on or after platinum-containing chemotherapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 3ExperimentalUC subjects (including bladder, renal pelvis, ureter, urethra) who are ineligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 4ExperimentalUC subjects (including bladder, renal pelvis, ureter, urethra) eligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 5ExperimentalUC subjects (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior immune check-point inhibitor (ICI) (anti-PD1 or anti-PD-L1) therapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 6ExperimentalCRPC subjects who have radiographically progressed in soft tissue on or after enzalutamide and/or abiraterone acetate for metastatic disease.
  • atezolizumab
  • cabozantinib
Expansion Cohort 7ExperimentalStage IV non-squamous NSCLC subjects who have radiographically progressed on or after treatment with one prior immune checkpoint inhibitor (ICI) (anti-PD-1 or anti-PD-L1) therapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 8ExperimentalStage IV non-squamous NSCLC subjects with positive PD-L1 expression and without prior systemic anticancer therapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 9ExperimentalStage IV nonsquamous NSCLC subjects with sensitizing EGFR mutation who have radiographically progressed during or following prior treatment with an EGFR-targeting TKI. Prior treatment with ICIs (anti-PD1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 10ExperimentalRCC subjects with non-clear cell histology who have had up to one prior VEGFR-targeting TKI therapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 11ExperimentalTNBC subjects who have radiographically progressed during or following treatment with at least one prior systemic anticancer therapy. Prior treatment with ICIs (anti-PD1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 12ExperimentalOC subjects (including primary peritoneal cancer and fallopian tube cancer) who have platinum-resistant or refractory disease who have had up to two lines of prior systemic anticancer therapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 13ExperimentalEC subjects (serous or endometrioid histology) who have radiographically progressed during or following treatment with at least one prior systemic anticancer therapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 14ExperimentalHCC subjects (Child-Pugh score A) who have not received prior systemic anticancer therapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 15ExperimentalGC/GEJC/LEC subjects who have radiographically progressed during or following platinum-containing or fluoropyrimidine-containing chemotherapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 16ExperimentalCRC subjects who have radiographically progressed during or following systemic chemotherapy that contained fluoropyrimidine in combination with oxaliplatin or irinotecan.
  • atezolizumab
  • cabozantinib
Expansion Cohort 17ExperimentalH&N cancer subjects who have radiographically progressed during or following prior platinum-containing chemotherapy. Prior treatment with ICIs (anti-PD1 or anti-PD-L1) is allowed if given in combination with chemotherapy.
  • atezolizumab
  • cabozantinib
Expansion Cohort 18ExperimentalDTC subjects (follicular, papillary, and poorly differentiated histologies) who are radioactive iodine (RAI) refractory or deemed ineligible for treatment with RAI.
  • atezolizumab
  • cabozantinib
Expansion Cohort 19 (SAC)ExperimentalUC subjects (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior ICI (anti-PD-1 or anti-PD-L1).
  • cabozantinib
Expansion Cohort 20 (SAC)ExperimentalStage IV non-squamous NSCLC subjects who have radiographically progressed on or after treatment with one prior ICI (anti-PD-1 or anti-PD-L1).
  • cabozantinib
Expansion Cohort 21 (SAC)ExperimentalMetastatic CRPC (mCRPC) subjects who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features who have had prior treatment with one, and only one, novel hormonal therapy (NHT) (eg, abiraterone, enzalutamide, apalutamide, daralutamide) for CSPC, mCRPC, or non-metastatic CRPC
  • cabozantinib
Expansion Cohort 22 (SAA)ExperimentalMetastatic CRPC (mCRPC) subjects who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features who have had prior treatment with one, and only one, novel hormonal therapy (NHT) (eg, abiraterone, enzalutamide, apalutamide, daralutamide) for CSPC, mCRPC, or non-metastatic CRPC
  • atezolizumab
Expansion Cohort 23ExperimentalMetastatic CRPC (mCRPC) subjects who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features who have had prior treatment with one, and only one, novel hormonal therapy (NHT) (eg, abiraterone, enzalutamide, apalutamide, daralutamide) for CSPC, mCRPC, or non-metastatic CRPC
  • atezolizumab
  • cabozantinib
Expansion Cohort 24ExperimentalMetastatic CRPC (mCRPC) subjects who have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features who have had prior treatment with at least one NHT and have received docetaxel for mCRPC
  • atezolizumab
  • cabozantinib

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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Escalation: MTD/Recommended Dose
Time Frame:Up to 6 months
Safety Issue:
Description:To determine the maximum tolerated dose (MTD) and/or recommended dose and schedule for the subsequent Expansion Stage of daily oral administration of cabozantinib in subjects with solid tumors when taken in combination with atezolizumab.

Secondary Outcome Measures

Measure:Incidence and severity of nonserious AEs and SAEs (Safety)
Time Frame:Up to 41 months
Safety Issue:
Description:To assess safety for the combination therapy through the evaluation of incidence and severity of nonserious adverse events (AEs) and serious adverse events (SAEs), including immune-related adverse events (irAEs).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Exelixis

Trial Keywords

  • Kidney
  • Bladder
  • Renal pelvis
  • Ureter
  • Urethra
  • Cancer
  • Prostate
  • Castration-resistant
  • Lung
  • Breast
  • Ovarian
  • Endometrial
  • Liver
  • Stomach

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