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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 : December 6, 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 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.

Condition or disease Intervention/treatment Phase
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 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 (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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1000 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 Alone or in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors
Actual Study Start Date : September 5, 2017
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : December 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
RCC subjects 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 Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

Experimental: Expansion Cohort 2
UC subjects (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 Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

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.
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

Experimental: Expansion Cohort 4
UC subjects (including bladder, renal pelvis, ureter, urethra) eligible for cisplatin-based chemotherapy and have not received prior systemic 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 Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

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.
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

Experimental: Expansion Cohort 6
CRPC subjects 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 Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

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.
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

Experimental: Expansion Cohort 8
Stage IV non-squamous NSCLC subjects with high PD-L1 expression and without 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 Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

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.
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

Experimental: Expansion Cohort 10
RCC subjects with non-clear cell histology who have had up to one prior VEGFR-targeting TKI 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 Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

Experimental: Expansion Cohort 11
TNBC subjects who have radiographically progressed during or following treatment with at least one 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 Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

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.
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

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.
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

Experimental: Expansion Cohort 14
HCC subjects (Child-Pugh score A) 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 Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

Experimental: Expansion Cohort 15
GC/GEJC subjects who have radiographically progressed during or following platinum-containing or fluoropyrimidine-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 Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

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

Experimental: Expansion Cohort 17
H&N cancer subjects who have radiographically progressed during or following prior 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 Cohort Review Committee-determined recommended dose from the Dose Escalation Stage
Other Names:
  • Cabometyx
  • XL184

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.
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

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

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).
Drug: cabozantinib
Supplied as 60-mg and 20-mg tablets; administered orally daily at 60 mg qd
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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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:

      • 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.

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

  Show 23 Study Locations
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: December 6, 2018
Last Verified: December 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
Breast
Ovarian
Endometrial
Liver
Stomach

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Non-Small-Cell Lung
Colorectal Neoplasms
Adenocarcinoma
Carcinoma, Hepatocellular
Stomach Neoplasms
Head and Neck Neoplasms
Carcinoma, Renal Cell
Endometrial Neoplasms
Thyroid Neoplasms
Triple Negative Breast Neoplasms
Prostatic Neoplasms
Carcinoma, Transitional Cell
Esophageal Neoplasms
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
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases