Clinical trial NCT03170960: Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: 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
Lower Esophageal Cancer
Keywords: Kidney
Bladder
Renal pelvis
Ureter
Urethra
Cancer
Prostate
Castration-resistant
Lung
Breast
Ovarian
Endometrial
Liver
Stomach
Lead sponsor: Exelixis
Sponsor class: INDUSTRY
First posted: 2017-05-31
Enrollment: 1732
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose Escalation followed by Dose Expansion
Primary purpose: TREATMENT

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

Eligibility 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/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.

Primary outcomes:
measure: Dose Escalation: MTD/Recommended Dose
timeFrame: Up to 6 months
measure: Dose Expansion: ORR
timeFrame: Up to 31 months
Secondary outcomes:
measure: Incidence and severity of nonserious AEs and SAEs (Safety)
timeFrame: Up to 41 months
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Exelixis Clinical Site #53
state: Arizona
city: Phoenix
country: United States
facility: Exelixis Clinical Site #18
state: Arizona
city: Duarte
country: United States
facility: Exelixis Clinical Site #1
state: California
city: La Jolla
country: United States
facility: Exelixis Clinical Site #20
state: California
city: Los Angeles
country: United States
facility: Exelixis Clinical Site #46
state: California
city: Newport Beach
country: United States
facility: Exelixis Clinical Site #51
state: California
city: Santa Monica
country: United States
facility: Exelixis Clinical Site #62
state: California
city: Stanford
country: United States
facility: Exelixis Clinical Site #21
state: California
city: Denver
country: United States
facility: Exelixis Clinical Site #34
state: Colorado
city: Denver
country: United States
facility: Exelixis Clinical Site #50
state: Colorado
city: New Haven
country: United States
facility: Exelixis Clinical Site #42
state: Connecticut
city: Washington
country: United States
facility: Exelixis Clinical Site #48
state: District of Columbia
city: Jacksonville
country: United States
facility: Exelixis Clinical Site #16
state: Florida
city: Tampa
country: United States
facility: Exelixis Clinical Site #76
state: Florida
city: Atlanta
country: United States
facility: Exelixis Clinical Site #60
state: Georgia
city: Atlanta
country: United States
facility: Exelixis Clinical Site #79
state: Georgia
city: Harvey
country: United States
facility: Exelixis Clinical Site #32
state: Illinois
city: Fairway
country: United States
facility: Exelixis Clinical Site #23
state: Kansas
city: Lexington
country: United States
facility: Exelixis Clinical Site #57
state: Kentucky
city: New Orleans
country: United States
facility: Exelixis Clinical Site #24
state: Louisiana
city: Boston
country: United States
facility: Exelixis Clinical Site #10
state: Massachusetts
city: Detroit
country: United States
facility: Exelixis Clinical Site #3
state: Michigan
city: Rochester
country: United States
facility: Exelixis Clinical Site #17
state: Minnesota
city: Bolivar
country: United States
facility: Exelixis Clinical Site #65
state: Missouri
city: Kansas City
country: United States
facility: Exelixis Clinical Site #43
state: Missouri
city: Omaha
country: United States
facility: Exelixis Clinical Site #35
state: Nebraska
city: Omaha
country: United States
facility: Exelixis Clinical Site #59
state: Nebraska
city: Las Vegas
country: United States
facility: Exelixis Clinical Site #61
state: Nevada
city: Camden
country: United States
facility: Exelixis Clinical Site #38
state: New Jersey
city: East Brunswick
country: United States
facility: Exelixis Clinical Site #27
state: New Jersey
city: New Brunswick
country: United States
facility: Exelixis Clinical Site #31
state: New Jersey
city: Bronx
country: United States
facility: Exelixis Clinical Site #37
state: New York
city: East Setauket
country: United States
facility: Exelixis Clinical Site #40
state: New York
city: New York
country: United States
facility: Exelixis Clinical Site #11
state: New York
city: Cleveland
country: United States
facility: Exelixis Clinical Site #67
state: Ohio
city: Columbus
country: United States
facility: Exelixis Clinical Site #49
state: Ohio
city: Kettering
country: United States
facility: Exelixis Clinical Site #64
state: Ohio
city: Oklahoma City
country: United States
facility: Exelixis Clinical Site #71
state: Oklahoma
city: Oklahoma City
country: United States
facility: Exelixis Clinical Site #6
state: Oklahoma
city: Portland
country: United States
facility: Exelixis Clinical Site #102
state: Oregon
city: Portland
country: United States
facility: Exelixis Clinical Site #45
state: Oregon
city: Bethlehem
country: United States
facility: Exelixis Clinical Site #41
state: Pennsylvania
city: Philadelphia
country: United States
facility: Exelixis Clinical Site #15
state: Pennsylvania
city: Philadelphia
country: United States
facility: Exelixis Clinical Site #55
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Exelixis Clinical Site #66
state: Pennsylvania
city: Charleston
country: United States
facility: Exelixis Clinical Site #95
state: South Carolina
city: Dallas
country: United States
facility: Exelixis Clinical Site #13
state: Texas
city: Dallas
country: United States
facility: Exelixis Clinical Site #26
state: Texas
city: Fort Worth
country: United States
facility: Exelixis Clinical Site #114
state: Texas
city: Houston
country: United States
facility: Exelixis Clinical Site #29
state: Texas
city: Houston
country: United States
facility: Exelixis Clinical Site #39
state: Texas
city: Houston
country: United States
facility: Exelixis Clinical Site #44
state: Texas
city: Lubbock
country: United States
facility: Exelixis Clinical Site #33
state: Texas
city: San Antonio
country: United States
facility: Exelixis Clinical Site #63
state: Texas
city: Salt Lake City
country: United States
facility: Exelixis Clinical Site #2
state: Utah
city: Blacksburg
country: United States
facility: Exelixis Clinical Site #30
state: Virginia
city: Charlottesville
country: United States
facility: Exelixis Clinical Site #14
state: Virginia
city: Albury
country: Australia
facility: Exelixis Clinical Site #98
state: New South Wales
city: Camperdown
country: Australia
facility: Exelixis Clinical Site #101
state: New South Wales
city: Gosford
country: Australia
facility: Exelixis Clinical Site #115
state: New South Wales
city: North Ryde
country: Australia
facility: Exelixis Clinical Site #112
state: New South Wales
city: Randwick
country: Australia
facility: Exelixis Clinical Site #123
state: New South Wales
city: St Albans
country: Australia
facility: Exelixis Clinical Site #99
state: Victoria
city: Gent
country: Belgium
facility: Exelixis Clinical Site #52
city: Leuven
country: Belgium
facility: Exelixis Clinical Site #54
city: La Roche-sur-Yon
country: France
facility: Exelixis Clinical Site #88
state: Cedex 9
city: Villejuif
country: France
facility: Exelixis Clinical Site #8
state: Cedex
city: Bordeaux
country: France
facility: Exelixis Clinical Site #92
city: Brest
country: France
facility: Exelixis Clinical Site #93
city: CAEN Cedex 05
country: France
facility: Exelixis Clinical Site #87
city: Le Mans
country: France
facility: Exelixis Clinical Site #69
city: Lille
country: France
facility: Exelixis Clinical Site #97
city: Lyon Cedex 08
country: France
facility: Exelixis Clinical Site #89
city: Marseille
country: France
facility: Exelixis Clinical Site #109
city: Nice Cedex 02
country: France
facility: Exelixis Clinical Site #104
city: Nîmes Cedex 09
country: France
facility: Exelixis Clinical Site #80
city: Paris
country: France
facility: Exelixis Clinical Site #78
city: Paris
country: France
facility: Exelixis Clinical Site #7
city: Paris
country: France
facility: Exelixis Clinical Site #68
city: Paris
country: France
facility: Exelixis Clinical Site #72
city: Saint-Grégoire
country: France
facility: Exelixis Clinical Site #82
city: Strasbourg
country: France
facility: Exelixis Clinical Site #119
city: Suresnes
country: France
facility: Exelixis Clinical Site #107
city: Vandoeuvre les nancy
country: France
facility: Exelixis Clinical Site #105
city: Düsseldorf
country: Germany
facility: Exelixis Clinical Site #56
state: Nordrhein-Westfalen
city: Tübingen
country: Germany
facility: Exelixis Clinical Site #36
city: Meldola
country: Italy
facility: Exelixis Clinical Site #84
state: FC
city: Rozzano
country: Italy
facility: Exelixis Clinical Site #47
state: Milano
city: Milano
country: Italy
facility: Exelixis Clinical Site #108
city: Milano
country: Italy
facility: Exelixis Clinical Site #103
city: Milano
country: Italy
facility: Exelixis Clinical Site #25
city: Milano
country: Italy
facility: Exelixis Clinical Site #4
city: Napoli
country: Italy
facility: Exelixis Clinical Site #85
city: Pavia
country: Italy
facility: Exelixis Clinical Site #121
city: Roma
country: Italy
facility: Exelixis Clinical Site #110
city: Nijmegen
country: Netherlands
facility: Exelixis Clinical Site #12
state: Gelderland
city: Santiago De Compostela
country: Spain
facility: Exelixis Clinical Site #74
state: A Coruña
city: Elche
country: Spain
facility: Exelixis Clinical Site #91
state: Alicante
city: Oviedo
country: Spain
facility: Exelixis Clinical Site #94
state: Asturias
city: Palma De Mallorca
country: Spain
facility: Exelixis Clinical Site #70
state: Baleares
city: Badalona
country: Spain
facility: Exelixis Clinical Site #113
state: Barcelona
city: Sabadell
country: Spain
facility: Exelixis Clinical Site #116
state: Barcelona
city: Jeréz De La Frontera
country: Spain
facility: Exelixis Clinical Site #96
state: Cádiz
city: Pamplona
country: Spain
facility: Exelixis Clinical Site #90
state: Navarra
city: La Laguna
country: Spain
facility: Exelixis Clinical Site #117
state: Santa Cruz De Tenerife
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #75
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #58
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #83
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #86
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #28
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #9
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #73
city: Girona
country: Spain
facility: Exelixis Clinical Site #118
city: Madrid
country: Spain
facility: Exelixis Clinical Site #77
city: Madrid
country: Spain
facility: Exelixis Clinical Site #106
city: Madrid
country: Spain
facility: Exelixis Clinical Site #111
city: Madrid
country: Spain
facility: Exelixis Clinical Site #22
city: Madrid
country: Spain
facility: Exelixis Clinical Site #5
city: Madrid
country: Spain
facility: Exelixis Clinical Site #81
city: Málaga
country: Spain
facility: Exelixis Clinical Site #100
city: Middlesex
country: United Kingdom
facility: Exelixis Clinical Site #122
state: England
city: Preston
country: United Kingdom
facility: Exelixis Clinical Site #120
state: England
city: Cardiff
country: United Kingdom
facility: Exelixis Clinical Site #124
state: Wales
city: London
country: United Kingdom
facility: Exelixis Clinical Site #19
Study officials:
References:
citation: Agarwal N, McGregor B, Maughan BL, Dorff TB, Kelly W, Fang B, McKay RR, Singh P, Pagliaro L, Dreicer R, Srinivas S, Loriot Y, Vaishampayan U, Goel S, Curran D, Panneerselvam A, Schwickart M, Choueiri TK, Pal S. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Lancet Oncol. 2022 Jul;23(7):899-909. doi: 10.1016/S1470-2045(22)00278-9. Epub 2022 Jun 9.
citation: Pal SK, McGregor B, Suarez C, Tsao CK, Kelly W, Vaishampayan U, Pagliaro L, Maughan BL, Loriot Y, Castellano D, Srinivas S, McKay RR, Dreicer R, Hutson T, Dubey S, Werneke S, Panneerselvam A, Curran D, Scheffold C, Choueiri TK, Agarwal N. Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study. J Clin Oncol. 2021 Nov 20;39(33):3725-3736. doi: 10.1200/JCO.21.00939. Epub 2021 Sep 7.