Clinical trial NCT01988896: Study of Atezolizumab in Combination With Cobimetinib in Participants With Locally Advanced or Metastatic Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-11-20
Enrollment: 153
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Phase I: Percentage of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Day 15 to Day 42 of Cycle 1 (cycle length=42 days) of dose-escalation phase
measure: Phase I: Maximum Tolerated Dose of Cobimetinib
timeFrame: Day 15 to Day 42 of Cycle 1 (cycle length=42 days) of dose-escalation phase
measure: Phase I: Recommended Phase II Dose of Cobimetinib when Combined with Atezolizumab
timeFrame: Day 15 to Day 42 of Cycle 1 (cycle length=42 days) of dose-escalation phase
Secondary outcomes:
measure: Percentage of Participants With Anti-Therapeutic Antibody (ATA) Response to Azetolizumab
timeFrame: 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)
measure: Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs)
timeFrame: Baseline up to approximately 3.5 years
measure: Serum Maximum Concentration (Cmax) of Atezolizumab
timeFrame: 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)
measure: Serum Minimum Concentration (Cmin) of Atezolizumab
timeFrame: 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)
measure: Plasma Cmax of Cobimetinib
timeFrame: 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)
measure: Plasma Cmin of Cobimetinib
timeFrame: Pre-dose (Hour 0) on Day 29 of Cycle 1 (cycle length=42 days) and Day 15 of Cycle 2 (cycle length=28 days)
measure: Area Under the Concentration-Time Curve (AUC) of Cobimetinib
timeFrame: 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)
measure: Percentage of Participants With Best Overall Response, as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: Baseline up to 3.5 years (detailed time frame is provided in the description)
measure: Percentage of Participants With Objective Response (OR; Confirmed Complete Response or Partial Response) as Assessed by Investigator Using RECIST v1.1
timeFrame: 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])
measure: Duration of OR, as Determined by Investigator Using RECIST v1.1
timeFrame: 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])
measure: Progression-Free Survival (PFS), as Determined by Investigator Using RECIST v1.1
timeFrame: 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])
measure: Overall Survival (OS)
timeFrame: Baseline up to death due to any cause (up to approximately 3.5 years)
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Center - Denver
state: Colorado
city: New Haven
country: United States
facility: Yale University School Of Medicine
state: Connecticut
city: Boston
country: United States
facility: Massachusets General Hospital Clinical Trial Network and Institute
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med Ctr; Neurology/MS Center
state: Massachusetts
city: New York
country: United States
facility: Sloan Kettering Cancer Center; Pediatric Hematology/Oncology
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Portland
country: United States
facility: Compass Oncology
state: Oregon
city: Nashville
country: United States
facility: SCRI-Tennessee Oncology
state: Tennessee
city: Arlington
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: Seattle
country: United States
facility: University of Washington Seattle Cancer Care Alliance
state: Washington
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre-East Melbourne
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Toronto
country: Canada
facility: Princess Margaret Hospital; Department of Med Oncology
state: Ontario
city: Montreal
country: Canada
facility: CHUM Hôpital Notre-Dame
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Dresden
country: Germany
facility: Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center - Oncology
city: Singapore
country: Singapore
facility: National University Hospital; Cancer Center
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Hellmann MD, Kim TW, Lee CB, Goh BC, Miller WH Jr, Oh DY, Jamal R, Chee CE, Chow LQM, Gainor JF, Desai J, Solomon BJ, Das Thakur M, Pitcher B, Foster P, Hernandez G, Wongchenko MJ, Cha E, Bang YJ, Siu LL, Bendell J. Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors. Ann Oncol. 2019 Jul 1;30(7):1134-1142. doi: 10.1093/annonc/mdz113.