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

Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03170960
• Other study ID #: XL184-021
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: September 5, 2017
• Est. completion date: August 2024

Study information

• Verified date: April 2023
• Source: Exelixis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1732
• Est. completion date: August 2024
• Est. primary completion date: July 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Castration-resistant Prostate Cancer
• Colorectal Cancer
• Differentiated Thyroid Cancer
• Endometrial Cancer
• Endometrial Neoplasms
• 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
• Triple Negative Breast Neoplasms
• Urothelial Carcinoma

Intervention

Drug:
• cabozantinib
Supplied as 60-mg and 20-mg tablets; administered orally daily at dose levels of 20 mg, 40 mg, or 60 mg.
• atezolizumab
Supplied as 1200-mg vials; administered as an IV infusion once every 3 weeks (q3w).
• 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
• cabozantinib
Supplied as 60-mg and 20-mg tablets; administered orally daily at 60 mg qd

Locations

Country	Name	City	State
Australia	Exelixis Clinical Site #98	Albury	New South Wales
Australia	Exelixis Clinical Site #101	Camperdown	New South Wales
Australia	Exelixis Clinical Site #115	Gosford	New South Wales
Australia	Exelixis Clinical Site #112	North Ryde	New South Wales
Australia	Exelixis Clinical Site #123	Randwick	New South Wales
Australia	Exelixis Clinical Site #99	St Albans	Victoria
Belgium	Exelixis Clinical Site #52	Gent
Belgium	Exelixis Clinical Site #54	Leuven
France	Exelixis Clinical Site #92	Bordeaux
France	Exelixis Clinical Site #93	Brest
France	Exelixis Clinical Site #87	CAEN Cedex 05
France	Exelixis Clinical Site #88	La Roche-sur-Yon	Cedex 9
France	Exelixis Clinical Site #69	Le Mans
France	Exelixis Clinical Site #97	Lille
France	Exelixis Clinical Site #89	Lyon Cedex 08
France	Exelixis Clinical Site #109	Marseille
France	Exelixis Clinical Site #104	Nice Cedex 02
France	Exelixis Clinical Site #80	Nîmes Cedex 09
France	Exelixis Clinical Site #68	Paris
France	Exelixis Clinical Site #7	Paris
France	Exelixis Clinical Site #72	Paris
France	Exelixis Clinical Site #78	Paris
France	Exelixis Clinical Site #82	Saint-Grégoire
France	Exelixis Clinical Site #119	Strasbourg
France	Exelixis Clinical Site #107	Suresnes
France	Exelixis Clinical Site #105	Vandoeuvre les nancy
France	Exelixis Clinical Site #8	Villejuif	Cedex
Germany	Exelixis Clinical Site #56	Düsseldorf	Nordrhein-Westfalen
Germany	Exelixis Clinical Site #36	Tübingen
Italy	Exelixis Clinical Site #84	Meldola	FC
Italy	Exelixis Clinical Site #103	Milano
Italy	Exelixis Clinical Site #108	Milano
Italy	Exelixis Clinical Site #25	Milano
Italy	Exelixis Clinical Site #4	Milano
Italy	Exelixis Clinical Site #85	Napoli
Italy	Exelixis Clinical Site #121	Pavia
Italy	Exelixis Clinical Site #110	Roma
Italy	Exelixis Clinical Site #47	Rozzano	Milano
Netherlands	Exelixis Clinical Site #12	Nijmegen	Gelderland
Spain	Exelixis Clinical Site #113	Badalona	Barcelona
Spain	Exelixis Clinical Site #28	Barcelona
Spain	Exelixis Clinical Site #58	Barcelona
Spain	Exelixis Clinical Site #73	Barcelona
Spain	Exelixis Clinical Site #75	Barcelona
Spain	Exelixis Clinical Site #83	Barcelona
Spain	Exelixis Clinical Site #86	Barcelona
Spain	Exelixis Clinical Site #9	Barcelona
Spain	Exelixis Clinical Site #91	Elche	Alicante
Spain	Exelixis Clinical Site #118	Girona
Spain	Exelixis Clinical Site #96	Jeréz De La Frontera	Cádiz
Spain	Exelixis Clinical Site #117	La Laguna	Santa Cruz De Tenerife
Spain	Exelixis Clinical Site #106	Madrid
Spain	Exelixis Clinical Site #111	Madrid
Spain	Exelixis Clinical Site #22	Madrid
Spain	Exelixis Clinical Site #5	Madrid
Spain	Exelixis Clinical Site #77	Madrid
Spain	Exelixis Clinical Site #81	Madrid
Spain	Exelixis Clinical Site #100	Málaga
Spain	Exelixis Clinical Site #94	Oviedo	Asturias
Spain	Exelixis Clinical Site #70	Palma De Mallorca	Baleares
Spain	Exelixis Clinical Site #90	Pamplona	Navarra
Spain	Exelixis Clinical Site #116	Sabadell	Barcelona
Spain	Exelixis Clinical Site #74	Santiago De Compostela	A Coruña
United Kingdom	Exelixis Clinical Site #124	Cardiff	Wales
United Kingdom	Exelixis Clinical Site #19	London
United Kingdom	Exelixis Clinical Site #122	Middlesex	England
United Kingdom	Exelixis Clinical Site #120	Preston	England
United States	Exelixis Clinical Site #60	Atlanta	Georgia
United States	Exelixis Clinical Site #79	Atlanta	Georgia
United States	Exelixis Clinical Site #41	Bethlehem	Pennsylvania
United States	Exelixis Clinical Site #30	Blacksburg	Virginia
United States	Exelixis Clinical Site #65	Bolivar	Missouri
United States	Exelixis Clinical Site #10	Boston	Massachusetts
United States	Exelixis Clinical Site #37	Bronx	New York
United States	Exelixis Clinical Site #38	Camden	New Jersey
United States	Exelixis Clinical Site #95	Charleston	South Carolina
United States	Exelixis Clinical Site #14	Charlottesville	Virginia
United States	Exelixis Clinical Site #67	Cleveland	Ohio
United States	Exelixis Clinical Site #49	Columbus	Ohio
United States	Exelixis Clinical Site #13	Dallas	Texas
United States	Exelixis Clinical Site #26	Dallas	Texas
United States	Exelixis Clinical Site #34	Denver	Colorado
United States	Exelixis Clinical Site #50	Denver	Colorado
United States	Exelixis Clinical Site #3	Detroit	Michigan
United States	Exelixis Clinical Site #1	Duarte	California
United States	Exelixis Clinical Site #27	East Brunswick	New Jersey
United States	Exelixis Clinical Site #40	East Setauket	New York
United States	Exelixis Clinical Site #23	Fairway	Kansas
United States	Exelixis Clinical Site #114	Fort Worth	Texas
United States	Exelixis Clinical Site #53	Gilbert	Arizona
United States	Exelixis Clinical Site #32	Harvey	Illinois
United States	Exelixis Clinical Site #29	Houston	Texas
United States	Exelixis Clinical Site #39	Houston	Texas
United States	Exelixis Clinical Site #44	Houston	Texas
United States	Exelixis Clinical Site #16	Jacksonville	Florida
United States	Exelixis Clinical Site #43	Kansas City	Missouri
United States	Exelixis Clinical Site #64	Kettering	Ohio
United States	Exelixis Clinical Site #20	La Jolla	California
United States	Exelixis Clinical Site #61	Las Vegas	Nevada
United States	Exelixis Clinical Site #57	Lexington	Kentucky
United States	Exelixis Clinical Site #46	Los Angeles	California
United States	Exelixis Clinical Site #33	Lubbock	Texas
United States	Exelixis Clinical Site #31	New Brunswick	New Jersey
United States	Exelixis Clinical Site #42	New Haven	Connecticut
United States	Exelixis Clinical Site #24	New Orleans	Louisiana
United States	Exelixis Clinical Site #11	New York	New York
United States	Exelixis Clinical Site #51	Newport Beach	California
United States	Exelixis Clinical Site #6	Oklahoma City	Oklahoma
United States	Exelixis Clinical Site #71	Oklahoma City	Oklahoma
United States	Exelixis Clinical Site #35	Omaha	Nebraska
United States	Exelixis Clinical Site #59	Omaha	Nebraska
United States	Exelixis Clinical Site #15	Philadelphia	Pennsylvania
United States	Exelixis Clinical Site #55	Philadelphia	Pennsylvania
United States	Exelixis Clinical Site #18	Phoenix	Arizona
United States	Exelixis Clinical Site #66	Pittsburgh	Pennsylvania
United States	Exelixis Clinical Site #102	Portland	Oregon
United States	Exelixis Clinical Site #45	Portland	Oregon
United States	Exelixis Clinical Site #17	Rochester	Minnesota
United States	Exelixis Clinical Site #2	Salt Lake City	Utah
United States	Exelixis Clinical Site #63	San Antonio	Texas
United States	Exelixis Clinical Site #62	Santa Monica	California
United States	Exelixis Clinical Site #21	Stanford	California
United States	Exelixis Clinical Site #76	Tampa	Florida
United States	Exelixis Clinical Site #48	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Exelixis

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  France,  Germany,  Italy,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Up to 6 months
Primary	Dose Expansion: ORR	To evaluate preliminary efficacy by estimating the Objective Response Rate (ORR) as assessed by the Investigator per RECIST 1.1.	Up to 31 months
Secondary	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).	Up to 41 months