A Study to Evaluate the Safety and Activity of Belvarafenib as a Single Agent and in Combination With Either Cobimetinib or Cobimetinib Plus Atezolizumab in Patients With NRAS-mutant Advanced Melanoma.

Sponsor

Genentech, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04835805

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

4.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will evaluate the safety, pharmacokinetics, and activity of belvarafenib as a single agent and in combination with either cobimetinib or cobimetinib plus atezolizumab in patients with NRAS-mutant advanced melanoma who have received anti-PD-1/PD-L1 therapy.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: Belvarafenib Drug: Cobimetinib Drug: Atezolizumab	Phase 1

Detailed Description

The study will evaluate three treatment regimens in three arms: a belvarafenib monotherapy arm (Belva arm) of up to 15 patients; a belvarafenib plus cobimetinib arm (Belva + Cobi arm) in an initial dose-finding phase followed by an expansion phase and a belvarafenib plus cobimetinib plus atezolizumab arm (Belva + Cobi + Atezo arm) in a run-in phase followed by an expansion phase.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

98 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib, Open-Label, Multicenter Study to Evaluate the Safety, Pharmacokinetics, and Activity of Belvarafenib as a Single Agent and in Combination With Either Cobimetinib or Cobimetinib Plus Atezolizumab in Patients With NRAS-Mutant Advanced Melanoma Who Have Received Anti-PD-1/PD-L1 Therapy

Actual Study Start Date :

May 13, 2021

Anticipated Primary Completion Date :

Nov 11, 2024

Anticipated Study Completion Date :

Nov 11, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Belvarafenib Monotherapy Twice daily (BID), continuous dosing.	Drug: Belvarafenib Twice daily (BID), continuous dosing
Experimental: Belvarafenib Plus cobimetinib Recommended dose (RD) and schedule of belvarafenib and cobimetinib selected based on the safety data, tolerability, pharmacokinetics, and anti-tumor activity tested in dose-finding phase followed by an expansion phase.	Drug: Cobimetinib Once daily (QD) 21 days, 7 days off
Experimental: Belvarafenib Plus Cobimetinib Plus Atezolizumab Recommended dose (RD) and schedule of belvarafenib and cobimetinib plus atezolizumab IV infusion every 4 weeks (Q4W) followed by an expansion phase	Drug: Atezolizumab Once every 4 weeks (Q4W) Other Names: Tecentriq

Arm

Intervention/Treatment

Experimental: Belvarafenib Monotherapy

Twice daily (BID), continuous dosing.

Drug: Belvarafenib

Twice daily (BID), continuous dosing

Experimental: Belvarafenib Plus cobimetinib

Recommended dose (RD) and schedule of belvarafenib and cobimetinib selected based on the safety data, tolerability, pharmacokinetics, and anti-tumor activity tested in dose-finding phase followed by an expansion phase.

Drug: Cobimetinib

Once daily (QD) 21 days, 7 days off

Experimental: Belvarafenib Plus Cobimetinib Plus Atezolizumab

Recommended dose (RD) and schedule of belvarafenib and cobimetinib plus atezolizumab IV infusion every 4 weeks (Q4W) followed by an expansion phase

Drug: Atezolizumab

Once every 4 weeks (Q4W)

Other Names:

Tecentriq

Outcome Measures

Primary Outcome Measures

Percentage of Participants With Dose Limiting Toxicity (DLTs) [28 Days from Cycle 1, Day 1]
Percentage of Participants With Adverse Events [From Cycle 1, Day 1 Up to 4 Years]
Severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0

Secondary Outcome Measures

Objective response rate (ORR) according to RECIST v1.1 [Up to Approximately 4 Years]
Defined as the percentage of participants with a CR or PR on two consecutive occasions >/= 4 weeks apart, as determined by the investigator according to RECIST v1.1
Progression free survival (PFS) according to RECIST v1.1 [Up to Approximately 4 Years]
Defined as the time from the first study treatment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
Duration of response (DOR) according to RECIST v1.1 [Up to Approximately 4 Years]
Defined as the time from the first occurrence of a confirmed objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
Overall survival (OS) [Up to Approximately 4 Years]
Defined as the time from the first study treatment to death from any cause
Plasma concentration of belvarafenib at specified timepoints [Up to 30 Days After the Final Dose of Study Drug]
Plasma concentration of cobimetinib at specified timepoints [Up to 30 Days After the Final Dose of Study Drug]
Serum concentration of atezolizumab at specified timepoints [Up to 30 Days After the Final Dose of Study Drug]
Concentration of atezolizumab anti-drug antibody (ADA) [Up to 30 Days After the Final Dose of Study Drug]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

ECOG Performance Status of 0 or 1
Histologically confirmed, metastatic (recurrent or de novo Stage IV) or unresectable locally advanced (Stage III) cutaneous melanoma, that has progressed on or after treatment with anti-PD-1 or anti-PD-L1 therapy. Patients may have received up to two lines of systemic cancer therapy. Treatment with anti-PD-1/PD-L1 in the adjuvant setting is acceptable. Patients must have progressive disease at study entry
Documentation of NRAS mutation-positive within 5 years prior to screening
Tumor specimen availability
Adequate hematologic and end-organ function
Measurable disease per RECIST v1.1

Exclusion Criteria:

Treatment with systemic immunotherapy agents (e.g., anti-CTLA4, anti-PD(L)1, cytokine therapy, investigational therapy, etc.) within 28 days prior to C1D1
Symptomatic, untreated, or actively progressing CNS metastases
History or signs/symptoms of clinically significant cardiovascular disease
Known clinically significant liver disease
History of autoimmune disease or immune deficiency
Prior treatment with a MEK inhibitor (cobimetinib arm)
History of or evidence of retinal pathology on ophthalmologic examination (cobimetinib arm)
History of immune-related AE attributed to prior anti-PD(L)1 therapy that resulted in permanent discontinuation of anti-PD(L)1 therapy (atezolizumab arm)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Chao Family Comprehensive Cancer Center UCI	Orange	California	United States	92868
2	California Pacific Medical Center Research Institute	San Francisco	California	United States	94115
3	UCSF Helen Diller Family CCC	San Francisco	California	United States	94158
4	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
5	University of Iowa	Iowa City	Iowa	United States	52242
6	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
8	Memorial Sloan Kettering	New York	New York	United States	10065
9	Tennessee Oncology, PLLC - SCRI - PPDS	Nashville	Tennessee	United States	37203-1625
10	Calvary Mater Newcastle	Waratah	New South Wales	Australia	2298
11	Peter MacCallum Cancer Centre-East Melbourne	Melbourne	Victoria	Australia	3000
12	Linear Clinical Research Ltd	Nedlands	Western Australia	Australia	6009
13	Ottawa Hospital Regional Cancer Centre	Ottawa	Ontario	Canada	K1H 8M2
14	Princess Margaret Hospital; Department of Med Oncology	Toronto	Ontario	Canada	M5G 2M9
15	The Sir Mortimer B. Davis General Hospital	Montreal	Quebec	Canada	H3T 1E2
16	Charité - Universitätsmedizin Berlin	Berlin		Germany	10117
17	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
18	Klinikum Mannheim GmbH Universitätsklinikum	Mannheim		Germany	68167
19	Universitätsklinikum Tübingen	Tübingen		Germany	72076
20	Universitätsklinikum Würzburg	Würzburg		Germany	97080
21	Asan Medical Center - PPDS	Seoul		Korea, Republic of	05505
22	Samsung Medical Center - PPDS	Seoul		Korea, Republic of	06351
23	Haukeland Universitetssykehus	Bergen		Norway	5021
24	Oslo universitetssykehus HF	Oslo		Norway	0379

Sponsors and Collaborators

Genentech, Inc.

Investigators

Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Genentech, Inc.

ClinicalTrials.gov Identifier:

NCT04835805

Other Study ID Numbers:

GO42273
2020-003674-41

First Posted:

Apr 8, 2021

Last Update Posted:

Aug 25, 2022

Last Verified:

Aug 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Melanoma

Atezolizumab

Study Results

No Results Posted as of Aug 25, 2022