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

Exelixis

Status and phase: Active, not recruiting; Phase 2; Phase 1

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

Treatments: Drug: cabozantinib; Drug: atezolizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT03170960

XL184-021

Details and patient eligibility

About

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.

Full 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

Enrollment: 1,732 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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1,732 participants in 25 patient groups

Dose Escalation

Experimental group

Description:

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.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 1

Experimental group

Description:

RCC subjects with clear cell histology who have not received prior systemic anticancer therapy.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 2

Experimental group

Description:

UC subjects (including bladder, renal pelvis, ureter, urethra) who have progressed on or after platinum-containing chemotherapy.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 3

Experimental group

Description:

UC subjects (including bladder, renal pelvis, ureter, urethra) who are ineligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 4

Experimental group

Description:

UC subjects (including bladder, renal pelvis, ureter, urethra) eligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 5

Experimental group

Description:

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.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 6

Experimental group

Description:

CRPC subjects who have radiographically progressed in soft tissue on or after enzalutamide and/or abiraterone acetate for metastatic disease.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 7

Experimental group

Description:

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.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 8

Experimental group

Description:

Stage IV non-squamous NSCLC subjects with positive PD-L1 expression and without prior systemic anticancer therapy.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 9

Experimental group

Description:

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.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 10

Experimental group

Description:

RCC subjects with non-clear cell histology who have had up to one prior VEGFR-targeting TKI therapy.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 11

Experimental group

Description:

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.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 12

Experimental group

Description:

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.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 13

Experimental group

Description:

EC subjects (serous or endometrioid histology) who have radiographically progressed during or following treatment with at least one prior systemic anticancer therapy.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 14

Experimental group

Description:

HCC subjects (Child-Pugh score A) who have not received prior systemic anticancer therapy.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 15

Experimental group

Description:

GC/GEJC/LEC subjects who have radiographically progressed during or following platinum-containing or fluoropyrimidine-containing chemotherapy.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 16

Experimental group

Description:

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

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 17

Experimental group

Description:

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.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 18

Experimental group

Description:

DTC subjects (follicular, papillary, and poorly differentiated histologies) who are radioactive iodine (RAI) refractory or deemed ineligible for treatment with RAI.

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 19 (SAC)

Experimental group

Description:

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.

Treatment:

Drug: cabozantinib

Expansion Cohort 20 (SAC)

Experimental group

Description:

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.

Treatment:

Drug: cabozantinib

Expansion Cohort 21 (SAC)

Experimental group

Description:

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.

Treatment:

Drug: cabozantinib

Expansion Cohort 22 (SAA)

Experimental group

Description:

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.

Treatment:

Drug: atezolizumab

Expansion Cohort 23

Experimental group

Description:

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

Treatment:

Drug: atezolizumab

Drug: cabozantinib

Expansion Cohort 24

Experimental group

Description:

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

Treatment:

Drug: atezolizumab

Drug: cabozantinib