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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03170960




Registration number
NCT03170960
Ethics application status
Date submitted
23/05/2017
Date registered
31/05/2017
Date last updated
8/04/2021

Titles & IDs
Public title
Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors
Scientific 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
Secondary ID [1] 0 0
XL184-021
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Urothelial Carcinoma 0 0
Renal Cell Carcinoma 0 0
Non-Small Cell Lung Cancer 0 0
Castration-resistant Prostate Cancer 0 0
Triple Negative Breast Cancer 0 0
Ovarian Cancer 0 0
Endometrial Cancer 0 0
Hepatocellular Carcinoma 0 0
Gastric Cancer 0 0
Gastroesophageal Junction Adenocarcinoma 0 0
Colorectal Cancer 0 0
Head and Neck Cancer 0 0
Differentiated Thyroid Cancer 0 0
Lower Esophageal Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney
Cancer 0 0 0 0
Liver
Cancer 0 0 0 0
Womb (Uterine or endometrial cancer)
Cancer 0 0 0 0
Thyroid
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - cabozantinib
Treatment: Drugs - atezolizumab
Treatment: Drugs - cabozantinib
Treatment: Drugs - cabozantinib

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.

Experimental: Expansion Cohort 1 - RCC subjects with clear cell histology who have not received prior systemic anticancer therapy.

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

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.

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

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.

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

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.

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

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.

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

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.

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.

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.

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

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

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

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.

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.

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.

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.

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.

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.

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

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


Treatment: Drugs: cabozantinib
Supplied as 60-mg and 20-mg tablets; administered orally daily at dose levels of 20 mg, 40 mg, or 60 mg.

Treatment: Drugs: atezolizumab
Supplied as 1200-mg vials; administered as an IV infusion once every 3 weeks (q3w).

Treatment: Drugs: 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

Treatment: Drugs: cabozantinib
Supplied as 60-mg and 20-mg tablets; administered orally daily at 60 mg qd

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Dose Escalation: MTD/Recommended Dose - 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.
Timepoint [1] 0 0
Up to 6 months
Primary outcome [2] 0 0
Dose Expansion: ORR - To evaluate preliminary efficacy by estimating the Objective Response Rate (ORR) as assessed by the Investigator per RECIST 1.1.
Timepoint [2] 0 0
Up to 31 months
Secondary outcome [1] 0 0
Incidence and severity of nonserious AEs and SAEs (Safety) - 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).
Timepoint [1] 0 0
Up to 41 months

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Exelixis Clinical Site #98 - Albury
Recruitment hospital [2] 0 0
Exelixis Clinical Site #101 - Camperdown
Recruitment hospital [3] 0 0
Exelixis Clinical Site #115 - Gosford
Recruitment hospital [4] 0 0
Exelixis Clinical Site #112 - North Ryde
Recruitment hospital [5] 0 0
Exelixis Clinical Site #123 - Randwick
Recruitment hospital [6] 0 0
Exelixis Clinical Site #99 - St Albans
Recruitment postcode(s) [1] 0 0
2640 - Albury
Recruitment postcode(s) [2] 0 0
2050 - Camperdown
Recruitment postcode(s) [3] 0 0
2250 - Gosford
Recruitment postcode(s) [4] 0 0
2109 - North Ryde
Recruitment postcode(s) [5] 0 0
2031 - Randwick
Recruitment postcode(s) [6] 0 0
3021 - St Albans
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
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Connecticut
Country [5] 0 0
United States of America
State/province [5] 0 0
District of Columbia
Country [6] 0 0
United States of America
State/province [6] 0 0
Florida
Country [7] 0 0
United States of America
State/province [7] 0 0
Georgia
Country [8] 0 0
United States of America
State/province [8] 0 0
Illinois
Country [9] 0 0
United States of America
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Kansas
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United States of America
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Kentucky
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Louisiana
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United States of America
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Massachusetts
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Michigan
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Minnesota
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Missouri
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Nebraska
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Nevada
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New Jersey
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New York
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Ohio
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Oklahoma
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Oregon
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Pennsylvania
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South Carolina
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Texas
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Utah
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United States of America
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Virginia
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Belgium
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Gent
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Belgium
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Leuven
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France
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Cedex 9
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France
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Cedex
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France
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Bordeaux
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France
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Brest
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France
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CAEN Cedex 05
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France
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Le Mans
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France
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Lille
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France
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Lyon Cedex 08
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France
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Marseille
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France
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Nice Cedex 02
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France
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Nîmes Cedex 09
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France
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Paris
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France
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Saint-Grégoire
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France
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Strasbourg
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France
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Suresnes
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France
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Vandoeuvre les nancy
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Germany
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Nordrhein-Westfalen
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Germany
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Tübingen
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Italy
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FC
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Italy
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Milano
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Italy
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Napoli
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Italy
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Pavia
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Italy
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Roma
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Netherlands
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Gelderland
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A Coruña
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Alicante
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Asturias
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Baleares
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Barcelona
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Cádiz
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Navarra
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Santa Cruz De Tenerife
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Girona
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Spain
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Madrid
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Spain
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Málaga
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United Kingdom
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England
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United Kingdom
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Wales
Country [67] 0 0
United Kingdom
State/province [67] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Exelixis
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT03170960
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Exelixis Clinical Trials
Address 0 0
Country 0 0
Phone 0 0
1-888-EXELIXIS (888-393-5494)
Fax 0 0
Email 0 0
druginfo@exelixis.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03170960