Study of Atezolizumab in Combination With Cobimetinib in Participants With Locally Advanced or Metastatic Solid Tumors

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Completed

CT.gov ID

NCT01988896

Collaborator

(none)

153

Enrollment

Locations

Arms

70.2

Actual Duration (Months)

7.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase Ib, open-label, multicenter study designed to assess the safety, tolerability, and pharmacokinetics of coadministration of intravenous (IV) dosing of atezolizumab (an engineered anti-programmed death-ligand 1 [anti-PD-L1] antibody) and oral dosing of cobimetinib in participants with metastatic or locally advanced cancer for which no standard therapy exists.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors	Drug: Atezolizumab Drug: Cobimetinib	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

153 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib Study of the Safety and Pharmacology of Atezolizumab Administered With Cobimetinib in Patients With Locally Advanced or Metastatic Solid Tumors

Actual Study Start Date :

Dec 27, 2013

Actual Primary Completion Date :

Nov 4, 2019

Actual Study Completion Date :

Nov 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose-Escalation: Cobimetinib, Atezolizumab Participants will receive single dose of 800 milligrams (mg) of atezolizumab IV infusion on Day 1, 15 and 29 of Cycle 1 (cycle length=42 days [14-day run-in period + 28-day concomitant dosing period]), thereafter with atezolizumab IV dosing every 2 weeks (q2w) in all subsequent treatment cycles (28 days each). Combination with cobimetinib will begin on Cycle 1 Day 15 and will be given at increasing dose levels during Stage 1. During Stage 1, cobimetinib will be administered once daily (QD) orally for 21 consecutive days out of 28 days (21/7 dosing schedule) at a starting dose of 20 mg with escalation of 20 mg until the maximum tolerated dose (MTD; not more than 60 mg) for the two-drug combination.	Drug: Atezolizumab Atezolizumab will be administered at a fixed dose as specified via IV infusion. Other Names: MPDL3280 Drug: Cobimetinib Cobimetinib will be administered orally at an escalating dose during Stage 1 and at RP2D during Stage 2. Other Names: GDC-0973
Experimental: Dose-Expansion: Cobimetinib, Atezolizumab Participants will receive single dose of 800 mg of atezolizumab IV infusion q2w in all subsequent treatment cycles (28 days each). Participants will receive cobimetinib at the selected recommended RP2D on Days 1-14 of each 28-day cycle during Stage 2.	Drug: Atezolizumab Atezolizumab will be administered at a fixed dose as specified via IV infusion. Other Names: MPDL3280 Drug: Cobimetinib Cobimetinib will be administered orally at an escalating dose during Stage 1 and at RP2D during Stage 2. Other Names: GDC-0973

Arm

Intervention/Treatment

Experimental: Dose-Escalation: Cobimetinib, Atezolizumab

Participants will receive single dose of 800 milligrams (mg) of atezolizumab IV infusion on Day 1, 15 and 29 of Cycle 1 (cycle length=42 days [14-day run-in period + 28-day concomitant dosing period]), thereafter with atezolizumab IV dosing every 2 weeks (q2w) in all subsequent treatment cycles (28 days each). Combination with cobimetinib will begin on Cycle 1 Day 15 and will be given at increasing dose levels during Stage 1. During Stage 1, cobimetinib will be administered once daily (QD) orally for 21 consecutive days out of 28 days (21/7 dosing schedule) at a starting dose of 20 mg with escalation of 20 mg until the maximum tolerated dose (MTD; not more than 60 mg) for the two-drug combination.

Drug: Atezolizumab

Atezolizumab will be administered at a fixed dose as specified via IV infusion.

Other Names:

MPDL3280

Drug: Cobimetinib

Cobimetinib will be administered orally at an escalating dose during Stage 1 and at RP2D during Stage 2.

Other Names:

GDC-0973

Experimental: Dose-Expansion: Cobimetinib, Atezolizumab

Participants will receive single dose of 800 mg of atezolizumab IV infusion q2w in all subsequent treatment cycles (28 days each). Participants will receive cobimetinib at the selected recommended RP2D on Days 1-14 of each 28-day cycle during Stage 2.

Drug: Atezolizumab

Atezolizumab will be administered at a fixed dose as specified via IV infusion.

Other Names:

MPDL3280

Drug: Cobimetinib

Cobimetinib will be administered orally at an escalating dose during Stage 1 and at RP2D during Stage 2.

Other Names:

GDC-0973

Outcome Measures

Primary Outcome Measures

Phase I: Percentage of Participants With Dose-Limiting Toxicities (DLTs) [Day 15 to Day 42 of Cycle 1 (cycle length=42 days) of dose-escalation phase]
Phase I: Maximum Tolerated Dose of Cobimetinib [Day 15 to Day 42 of Cycle 1 (cycle length=42 days) of dose-escalation phase]
Phase I: Recommended Phase II Dose of Cobimetinib when Combined with Atezolizumab [Day 15 to Day 42 of Cycle 1 (cycle length=42 days) of dose-escalation phase]

Secondary Outcome Measures

Percentage of Participants With Anti-Therapeutic Antibody (ATA) Response to Azetolizumab [Pre-infusion (Hour 0) on Day 1 of Cycles 1, 2, 3, 4, 8 (cycle length=42 days for Cycle 1; 28 days for subsequent cycles) and at treatment completion visit (up to approximately 3.5 years)]
Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) [Baseline up to approximately 3.5 years]
Serum Maximum Concentration (Cmax) of Atezolizumab [Pre-infusion (Hour 0) on Day 1 of Cycles 2, 3, 4, 8 (cycle length=28 days) and at treatment completion visit (up to approximately 3.5 years); 30 minutes post-infusion (duration=60 minutes) on Cycle 1 Day 1 (cycle length=42 days)]
Serum Minimum Concentration (Cmin) of Atezolizumab [Pre-infusion (Hour 0) on Day 1 of Cycles 2, 3, 4, 8 (cycle length=28 days) and at treatment completion visit (up to approximately 3.5 years)]
Plasma Cmax of Cobimetinib [Pre-dose (Hour 0) and Hours 2, 4, 6 post-dose on Day 29 of Cycle 1 (cycle length=42 days) and Day 15 of Cycle 2 (cycle length=28 days)]
Plasma Cmin of Cobimetinib [Pre-dose (Hour 0) on Day 29 of Cycle 1 (cycle length=42 days) and Day 15 of Cycle 2 (cycle length=28 days)]
Area Under the Concentration-Time Curve (AUC) of Cobimetinib [Pre-dose (Hour 0) and Hours 2, 4, 6 post-dose on Day 29 of Cycle 1 (cycle length=42 days) and Day 15 of Cycle 2 (cycle length=28 days)]
Percentage of Participants With Best Overall Response, as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [Baseline up to 3.5 years (detailed time frame is provided in the description)]
Baseline up to 3.5 years (assessed at Baseline then every 8 weeks for the first 48 weeks following Day 1 of Cycle 1 [cycle length=42 days]; thereafter every 12 weeks until progressive disease [PD] or death due to any cause, whichever occurs first [up to approximately 3.5 years])
Percentage of Participants With Objective Response (OR; Confirmed Complete Response or Partial Response) as Assessed by Investigator Using RECIST v1.1 [Baseline up to 3.5 years (assessed at Baseline then every 8 weeks for the first 48 weeks following Day 1 Cycle 1 [cycle length=42 days]; thereafter every 12 weeks until PD or death due to any cause, whichever occurs first [up to approximately 3.5 years])]
Duration of OR, as Determined by Investigator Using RECIST v1.1 [Baseline up to 3.5 years (assessed at Baseline then every 8 weeks for the first 48 weeks following Day 1 Cycle 1 [cycle length=42 days]; thereafter every 12 weeks until PD or death due to any cause, whichever occurs first [up to approximately 3.5 years])]
Progression-Free Survival (PFS), as Determined by Investigator Using RECIST v1.1 [Baseline up to 3.5 years (assessed at Baseline then every 8 weeks for the first 48 weeks following Day 1 Cycle 1 [cycle length=42 days]; thereafter every 12 weeks until PD or death due to any cause, whichever occurs first [up to approximately 3.5 years])]
Overall Survival (OS) [Baseline up to death due to any cause (up to approximately 3.5 years)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Solid tumor that is metastatic, locally advanced or recurrent
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Life expectancy greater than or equal to (>/=) 12 weeks
Measurable disease, as defined by RECIST v 1.1
Adequate hematologic and end organ function
Use of highly effective contraception
Histological tumor tissue specimen
Participants enrolling in the indication-specific expansion cohorts in Stage 2 must consent to tumor biopsies and must have one of the following types of cancer:
Metatastic colorectal cancer
Non-small cell lung cancer
Melanoma

Exclusion Criteria:

Cancer-Specific Exclusion Criteria:

Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment
Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment
Known active or untreated central nervous system (CNS) metastases
Leptomeningeal disease
Uncontrolled tumor-related pain or uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent (once monthly or more frequently) drainage procedures
Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab

General Medical Exclusion Criteria:

Pregnant and lactating women
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cell or any component of the atezolizumab formulation
History of autoimmune disease
Participants with prior allogeneic stem cell or solid organ transplantation
Positive test for human immunodeficiency virus (HIV)
Participants with active hepatitis B, hepatitis C, or tuberculosis
Severe infections within 4 weeks prior to Cycle 1 Day 1
Signs or symptoms of infection within 2 weeks prior to Cycle 1 Day 1
Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1
Significant cardiovascular disease
Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1 Day 1 or anticipation of need for a major surgical procedure during the course of the study
Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1

Exclusion Criteria Unique to Cobimetinib:

History of prior significant toxicity from another mitogen-activated protein kinase (MEK) pathway inhibitor requiring discontinuation of treatment
Allergy or hypersensitivity to components of the cobimetinib formulations
History of congenital long QT syndrome or corrected QT interval (QTc) greater than (>) 450 milliseconds at screening
Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower, as determined by echocardiogram or Multi Gated Acquisition Scan (MUGA) scan
History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
History of malabsorption syndrome or other condition that would interfere with enteral absorption

Exclusion Criteria Related to Medications:

Prior treatment with clusters of differentiation (CD) 137 agonists or immune checkpoint blockade therapies, systemic immunostimulatory agents, or systemic immunosuppressive medications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Medical Center	Palo Alto	California	United States	94304
2	Rocky Mountain Cancer Center - Denver	Denver	Colorado	United States	80220
3	Yale University School Of Medicine	New Haven	Connecticut	United States	06510
4	Massachusets General Hospital Clinical Trial Network and Institute	Boston	Massachusetts	United States	02114
5	Beth Israel Deaconess Med Ctr; Neurology/MS Center	Boston	Massachusetts	United States	02215
6	Sloan Kettering Cancer Center; Pediatric Hematology/Oncology	New York	New York	United States	10065
7	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27514
8	Compass Oncology	Portland	Oregon	United States	97225
9	SCRI-Tennessee Oncology	Nashville	Tennessee	United States	37203
10	Texas Oncology, P.A.	Arlington	Texas	United States	76012
11	University of Washington Seattle Cancer Care Alliance	Seattle	Washington	United States	98195
12	Peter MacCallum Cancer Centre-East Melbourne	Melbourne	Victoria	Australia	3000
13	Royal Melbourne Hospital	Parkville	Victoria	Australia	3050
14	Princess Margaret Hospital; Department of Med Oncology	Toronto	Ontario	Canada	M5G 2M9
15	CHUM Hôpital Notre-Dame	Montreal	Quebec	Canada	H2L 4M1
16	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
17	Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden	Dresden		Germany	01307
18	Universitaetsklinikum Freiburg	Freiburg		Germany	79106
19	Seoul National University Hospital	Seoul		Korea, Republic of	03080
20	Asan Medical Center - Oncology	Seoul		Korea, Republic of	05505
21	National University Hospital; Cancer Center	Singapore		Singapore	119074

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Hoffmann-La Roche

ClinicalTrials.gov Identifier:

NCT01988896

Other Study ID Numbers:

GP28363
2013-003329-27

First Posted:

Nov 20, 2013

Last Update Posted:

Dec 17, 2019

Last Verified:

Dec 1, 2019

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

Yes

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

Additional relevant MeSH terms:

Neoplasms

Atezolizumab

Study Results

No Results Posted as of Dec 17, 2019