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

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ClinicalTrials.gov Identifier: NCT03170960
Recruitment Status : Recruiting
First Posted : May 31, 2017
Last Update Posted : June 4, 2018
Sponsor:
Information provided by (Responsible Party):
Exelixis

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 advanced urothelial carcinoma (UC) (including bladder, renal pelvis, ureter, urethra), renal cell carcinoma (RCC), castration-resistant prostate cancer (CRPC), and non-small-cell lung cancer (NSCLC). 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.

Condition or disease Intervention/treatment Phase
Urothelial Carcinoma Renal Cell Carcinoma Non-Small Cell Lung Cancer Castration-resistant Prostate Cancer Drug: cabozantinib Drug: atezolizumab Phase 1 Phase 2

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 and safety of the recommended combination dose in eight tumor-specific cohorts including subjects with advanced UC, RCC, CRPC, and NSCLC

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 360 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Dose Escalation followed by Dose Expansion
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Dose-Escalation Study of Cabozantinib (XL184) Administered in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors
Actual Study Start Date : September 5, 2017
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : October 2020


Arm Intervention/treatment
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.
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

Experimental: Expansion Cohort 1
Subjects with advanced RCC with clear cell histology who have not received prior systemic anticancer therapy.
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 CRC-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

Experimental: Expansion Cohort 2
Subjects with UC with transitional cell histology (including bladder, renal pelvis, ureter, urethra) who have progressed on or after platinum-containing chemotherapy.
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 CRC-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

Experimental: Expansion Cohort 3
Subjects with UC with transitional cell histology (including bladder, renal pelvis, ureter, urethra) who are ineligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy for inoperable, locally advanced, or metastatic disease.
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 CRC-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

Experimental: Expansion Cohort 4
Subjects with UC with transitional cell histology (including bladder, renal pelvis, ureter, urethra) eligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy for inoperable, locally advanced, or metastatic disease.
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 CRC-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

Experimental: Expansion Cohort 5
Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior immune check-point inhibitor (anti-PD1 or anti-PD-L1) as the most recent therapy for the treatment of inoperable, locally advanced, or metastatic disease.
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 CRC-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

Experimental: Expansion Cohort 6
Subjects with metastatic CRPC (adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features) who have radiographically progressed in soft tissue on or after enzalutamide and/or abiraterone acetate for metastatic disease.
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 CRC-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

Experimental: Expansion Cohort 7
Subjects with Stage IV non-squamous NSCLC who have radiographically progressed on or after treatment with one prior immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) as the most recent therapy for metastatic disease.
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 CRC-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

Experimental: Expansion Cohort 8
Subjects with Stage IV non-squamous NSCLC who have not received prior immune checkpoint inhibitor therapy (anti-PD-1 or anti-PD-L1).
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 CRC-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

      • Expansion Cohort 1: Subjects with RCC with clear cell histology who have not received prior systemic anticancer therapy
      • Expansion Cohort 2: Subjects with UC with transitional cell histology (including renal pelvis, ureter, bladder, urethra) who have progressed on or after platinum-containing chemotherapy
      • Expansion Cohort 3: Subjects with UC with transitional cell histology (including bladder, renal pelvis, ureter, urethra) who are ineligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy for inoperable, locally advanced, or metastatic disease
      • Expansion Cohort 4: Subjects with UC with transitional cell histology (including bladder, renal pelvis, ureter, urethra) eligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy for inoperable, locally advanced, or metastatic disease
      • Expansion Cohort 5: Subjects with UC with transitional cell histology (including renal pelvis, ureter, urinary bladder, urethra) who have radiographically progressed on or after one prior immune check-point inhibitor (anti-PD1 or anti-PD-L1) as the most recent therapy for the treatment of inoperable, locally advanced, or metastatic disease.
      • Expansion Cohort 6: Subjects with metastatic CRPC (adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features) who have radiographically progressed in soft tissue on or after enzalutamide and/or abiraterone acetate for metastatic disease.
      • Expansion Cohort 7: Subjects with Stage IV non-squamous NSCLC who have radiographically progressed on or after treatment with one prior immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) as the most recent therapy for metastatic disease.
      • Expansion Cohort 8: Subjects with Stage IV non-squamous NSCLC who have not received prior immune checkpoint inhibitor therapy (anti-PD-1 or anti-PD-L1).
  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 and 7 in which prior anti-PD-1 or anti-PD-L1 therapy is required for eligibility. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03170960


Contacts
Contact: Exelixis Clinical Trials 1-888-EXELIXIS (888-393-5494) druginfo@exelixis.com
Contact: Backup or International 650-837-7400

Locations
United States, California
Exelixis Clinical Site #1 Recruiting
Duarte, California, United States, 91010
United States, Massachusetts
Exelixis Clinical Site #10 Recruiting
Boston, Massachusetts, United States, 02215
United States, Michigan
Exelixis Clinical Site #3 Recruiting
Detroit, Michigan, United States, 48201
United States, Oklahoma
Exelixis Clinical Site #6 Not yet recruiting
Oklahoma City, Oklahoma, United States, 73120
United States, Utah
Exelixis Clinical Site #2 Recruiting
Salt Lake City, Utah, United States, 84112
France
Exelixis Clinical Site #8 Recruiting
Villejuif, Cedex, France, 94805
Exelixis Clinical Site #7 Recruiting
Paris, France, 75010
Italy
Exelixis Clinical Site #4 Recruiting
Milano, Italy, 20133
Spain
Exelixis Clinical Site #9 Recruiting
Barcelona, Spain, 08035
Exelixis Clinical Site #5 Recruiting
Madrid, Spain, 28041
Sponsors and Collaborators
Exelixis

Responsible Party: Exelixis
ClinicalTrials.gov Identifier: NCT03170960     History of Changes
Other Study ID Numbers: XL184-021
First Posted: May 31, 2017    Key Record Dates
Last Update Posted: June 4, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by Exelixis:
Kidney
Bladder
Renal pelvis
Ureter
Urethra
Cancer
Prostate
Castration-resistant
Lung

Additional relevant MeSH terms:
Atezolizumab
Carcinoma
Carcinoma, Non-Small-Cell Lung
Carcinoma, Renal Cell
Prostatic Neoplasms
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Genital Neoplasms, Male
Genital Diseases, Male
Prostatic Diseases
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs