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

• ClinicalTrials.gov Identifier: NCT03170960
• Recruitment Status: Active, not recruiting
• First Posted: May 31, 2017
• Last Update Posted: April 12, 2022
• Sponsor: Exelixis
• Information provided by (Responsible Party): Exelixis

Tracking Information

• First Submitted Date: May 23, 2017
• First Posted Date: May 31, 2017
• Last Update Posted Date: April 12, 2022
• Actual Study Start Date: September 5, 2017
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 22, 2018)

• Dose Escalation: MTD/Recommended Dose [ Time Frame: Up to 6 months ]
  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.
• Dose Expansion: ORR [ Time Frame: Up to 31 months ]
  To evaluate preliminary efficacy by estimating the Objective Response Rate (ORR) as assessed by the Investigator per RECIST 1.1.

Original Primary Outcome Measures (submitted: May 30, 2017)

• Dose Escalation: MTD/Recommended Dose [ Time Frame: Up to 6 months ]
  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.
• Dose Expansion: ORR [ Time Frame: Up to 26 months ]
  To evaluate preliminary efficacy by estimating the Objective Response Rate (ORR) as assessed by the Investigator per RECIST 1.1.

Current Secondary Outcome Measures (submitted: February 22, 2018)

Incidence and severity of nonserious AEs and SAEs (Safety) [ Time Frame: Up to 41 months ]

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).

Original Secondary Outcome Measures (submitted: May 30, 2017)

Incidence and severity of nonserious AEs and SAEs (Safety) [ Time Frame: Up to 36 months ]

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).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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 Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Dose Escalation followed by Dose Expansion

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• 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

Intervention

• Drug: cabozantinib
  Supplied as 60-mg and 20-mg tablets; administered orally daily at dose levels of 20 mg, 40 mg, or 60 mg.
  Other Names:

  • Cabometyx
  • XL184
• Drug: atezolizumab
  Supplied as 1200-mg vials; administered as an IV infusion once every 3 weeks (q3w).
  Other Name: Tecentriq
• Drug: cabozantinib
  Supplied as 60-mg and 20-mg tablets; administered orally daily at the Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
  Other Names:

  • Cabometyx
  • XL184
• Drug: cabozantinib
  Supplied as 60-mg and 20-mg tablets; administered orally daily at 60 mg qd
  Other Names:

  • Cabometyx
  • XL184

Study Arms

• Experimental: Dose Escalation
  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.
  Interventions:

  • Drug: cabozantinib
  • Drug: atezolizumab
• Experimental: Expansion Cohort 1
  RCC subjects with clear cell histology who have not received prior systemic anticancer therapy.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 2
  UC subjects (including bladder, renal pelvis, ureter, urethra) who have progressed on or after platinum-containing chemotherapy.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 3
  UC subjects (including bladder, renal pelvis, ureter, urethra) who are ineligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 4
  UC subjects (including bladder, renal pelvis, ureter, urethra) eligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 5
  UC 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.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 6
  CRPC subjects who have radiographically progressed in soft tissue on or after enzalutamide and/or abiraterone acetate for metastatic disease.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 7
  Stage 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.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 8
  Stage IV non-squamous NSCLC subjects with positive PD-L1 expression and without prior systemic anticancer therapy.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 9
  Stage 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.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 10
  RCC subjects with non-clear cell histology who have had up to one prior VEGFR-targeting TKI therapy.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 11
  TNBC 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.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 12
  OC 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.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 13
  EC subjects (serous or endometrioid histology) who have radiographically progressed during or following treatment with at least one prior systemic anticancer therapy.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 14
  HCC subjects (Child-Pugh score A) who have not received prior systemic anticancer therapy.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 15
  GC/GEJC/LEC subjects who have radiographically progressed during or following platinum-containing or fluoropyrimidine-containing chemotherapy.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 16
  CRC subjects who have radiographically progressed during or following systemic chemotherapy that contained fluoropyrimidine in combination with oxaliplatin or irinotecan.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 17
  H&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.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 18
  DTC subjects (follicular, papillary, and poorly differentiated histologies) who are radioactive iodine (RAI) refractory or deemed ineligible for treatment with RAI.
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 19 (SAC)
  UC 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). Subjects may be allowed to receive combination therapy at the Cohort Review Committee recommended dose following radiographic disease progression.
  Intervention: Drug: cabozantinib
• Experimental: Expansion Cohort 20 (SAC)
  Stage IV non-squamous NSCLC subjects who have radiographically progressed on or after treatment with one prior ICI (anti-PD-1 or anti-PD-L1). Subjects may be allowed to receive combination therapy at the Cohort Review Committee recommended dose following radiographic disease progression.
  Intervention: Drug: cabozantinib
• Experimental: Expansion Cohort 21 (SAC)
  Metastatic 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. Subjects may be allowed to receive combination therapy at the Cohort Review Committee recommended dose following radiographic disease progression.
  Intervention: Drug: cabozantinib
• Experimental: Expansion Cohort 22 (SAA)
  Metastatic 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. Subjects may be allowed to receive combination therapy at the Cohort Review Committee recommended dose following radiographic disease progression.
  Intervention: Drug: atezolizumab
• Experimental: Expansion Cohort 23
  Metastatic 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
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib
• Experimental: Expansion Cohort 24
  Metastatic 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
  Interventions:

  • Drug: atezolizumab
  • Drug: cabozantinib

Publications *

• Agarwal N, McGregor B, Maughan BL, Dorff TB, Kelly W, Fang B, McKay RR, Singh P, Pagliaro L, Dreicer R, Srinivas S, Loriot Y, Vaishampayan U, Goel S, Curran D, Panneerselvam A, Schwickart M, Choueiri TK, Pal S. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Lancet Oncol. 2022 Jul;23(7):899-909. doi: 10.1016/S1470-2045(22)00278-9. Epub 2022 Jun 9.
• Pal SK, McGregor B, Suarez C, Tsao CK, Kelly W, Vaishampayan U, Pagliaro L, Maughan BL, Loriot Y, Castellano D, Srinivas S, McKay RR, Dreicer R, Hutson T, Dubey S, Werneke S, Panneerselvam A, Curran D, Scheffold C, Choueiri TK, Agarwal N. Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study. J Clin Oncol. 2021 Nov 20;39(33):3725-3736. doi: 10.1200/JCO.21.00939. Epub 2021 Sep 7.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 16, 2019): 1732
• Original Estimated Enrollment (submitted: May 30, 2017): 156
• Estimated Study Completion Date: December 2022
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03170960
• Other Study ID Numbers: XL184-021
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Exelixis
• Original Responsible Party: Same as current
• Current Study Sponsor: Exelixis
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Exelixis
• Verification Date: April 2022