Castration-resistant Prostate Cancer, Colorectal Cancer, Differentiated Thyroid Cancer, Endometrial Cancer, Gastric Cancer, Gastroesophageal Junction Adenocarcinoma, Head and Neck Cancer, Hepatocellular Carcinoma, Lower Esophageal Cancer, Non-Small Cell Lung Cancer, Ovarian Cancer, Renal Cell Carcinoma, Triple Negative Breast Cancer, Urothelial Carcinoma
Conditions
Keywords
Kidney, Bladder, Renal pelvis, Ureter, Urethra, Cancer, Prostate, Castration-resistant, Lung, Breast, Ovarian, Endometrial, Liver, Stomach
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
Interventions
DRUGcabozantinib
Supplied as 60-mg and 20-mg tablets; administered orally daily at dose levels of 20 mg, 40 mg, or 60 mg.
DRUGatezolizumab
Supplied as 1200-mg vials; administered as an IV infusion once every 3 weeks (q3w).
Sponsors
Exelixis
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose Escalation followed by Dose Expansion
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation: MTD/Recommended Dose | Up to Day 21 | 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 | Up to a maximum of 59 months | To evaluate preliminary efficacy by estimating the Objective Response Rate (ORR) as assessed by the Investigator per RECIST 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of nonserious AEs and SAEs (Safety) | From first dose to 30 days following last dose (up to a maximum of 59 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) and adverse events of special interest (AESIs). |
Countries
Australia, Belgium, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Outcome results
None listed