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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02322814




Registration number
NCT02322814
Ethics application status
Date submitted
19/12/2014
Date registered
23/12/2014
Date last updated
1/09/2020

Titles & IDs
Public title
A Study of Cobimetinib Plus Paclitaxel, Cobimetinib Plus Atezolizumab Plus Paclitaxel, or Cobimetinib Plus Atezolizumab Plus Nab-Paclitaxel as Initial Treatment for Participants With Triple-Negative Breast Cancer That Has Spread
Scientific title
A Multistage, Phase II Study Evaluating the Safety and Efficacy of Cobimetinib Plus Paclitaxel, Cobimetinib Plus Atezolizumab Plus Paclitaxel, or Cobimetinib Plus Atezolizumab Plus Nab-Paclitaxel as First-Line Treatment for Patients With Metastatic Triple-Negative Breast Cancer
Secondary ID [1] 0 0
2014-002230-32
Secondary ID [2] 0 0
WO29479
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Cobimetinib
Treatment: Drugs - Paclitaxel
Treatment: Drugs - Placebo
Treatment: Drugs - Atezolizumab
Treatment: Drugs - Nab-Paclitaxel

Experimental: Cohort I: Cobimetinib, Paclitaxel - Participants will receive a combination of cobimetinib plus paclitaxel in 28-day cycles until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Placebo Comparator: Cohort I: Placebo, Paclitaxel - Participants will receive a combination of cobimetinib placebo plus paclitaxel in 28-day cycles until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Experimental: Cohort II:Cobimetinib,Paclitaxel,Atezolizumab - Participants will receive cobimetinib plus paclitaxel plus atezolizumab in 28-day cycles until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.

Experimental: Cohort III: Cobimetinib, Nab-Paclitaxel, Atezolizumab - Participants will receive cobimetinib plus nab-paclitaxel plus atezolizumab until disease progression, unacceptable toxicity, investigator decision, death, withdrawal of consent, or completion of study.


Treatment: Drugs: Cobimetinib
Cobimetinib will be administered orally at a dose of 60 milligrams (mg) per day, once a day, on Day 3 through Day 23 of each 28-day treatment cycle.

Treatment: Drugs: Paclitaxel
Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m^2) by intravenous (IV) infusion on Day 1, Day 8, and Day 15 of each 28-day cycle according to prescribing information.

Treatment: Drugs: Placebo
Placebo matching to cobimetinib will be administered orally, once a day, on Day 3 through Day 23 of each 28 day treatment cycle.

Treatment: Drugs: Atezolizumab
Atezolizumab will be administered to Cohorts II and III at a dose of 840 mg IV every 2 weeks on Days 1 and 15 of each 28-day treatment cycle.

Treatment: Drugs: Nab-Paclitaxel
Nab-Paclitaxel will be administered to Cohort III according to the local prescribing information at a starting dose of 100 mg/m^2 by IV infusion on Days 1, 8, and 15 of each 28 day cycle.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Cohort I: Progression-Free Survival, as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) - PFS was defined as the time from randomization to the first occurrence of disease progression or relapse, as determined by the investigator, using RECIST v1.1.
Timepoint [1] 0 0
Randomization up to disease progression or relapse, whichever occurs first (up to approximately 3.5 years)
Primary outcome [2] 0 0
Cohort II, III: Percentage of Participants With Confirmed Overall Response (OR) (Partial Response [PR] or Complete Response [CR]), as Determined by the Investigator Using RECIST v1.1
Timepoint [2] 0 0
Randomization up to disease progression or relapse, whichever occurs first (up to approximately 3.5 years)
Secondary outcome [1] 0 0
Cohort I, II, III: Overall Survival (OS)
Timepoint [1] 0 0
Randomization up to death from any cause (up to approximately 5.5 years)
Secondary outcome [2] 0 0
Cohort I: Percentage of Participants With Confirmed OR (PR or CR), as Determined by the Investigator Using RECIST v1.1
Timepoint [2] 0 0
Randomization up to disease progression or relapse, whichever occurs first (up to approximately 5.5 years)
Secondary outcome [3] 0 0
Cohort I, II, III: Duration of Response (DOR), as Determined by the Investigator Using RECIST v1.1
Timepoint [3] 0 0
Time from the first occurrence of documented objective response to time of relapse or death, whichever occurs first (up to approximately 5.5 years)
Secondary outcome [4] 0 0
Cohort I, II, III: Percentage of Participants With Unconfirmed Overall Response (OR_uc) (Unconfirmed PR or CR), as Determined by the Investigator Using RECIST v1.1
Timepoint [4] 0 0
Randomization up to disease progression or relapse, whichever occurs fist (up to approximately 5.5 years)
Secondary outcome [5] 0 0
Cohort II, III: Progression-Free Survival, as Determined by Investigator Using RECIST v1.1
Timepoint [5] 0 0
Randomization up to disease progression or relapse, whichever occurs first (up to approximately 5.5 years)
Secondary outcome [6] 0 0
Cohort I, II, III: Percentage of Participants With Adverse Events (AEs)
Timepoint [6] 0 0
Randomization up to end of study (up to approximately 5.5 years)
Secondary outcome [7] 0 0
Cohort I, II, III: Maximum Plasma Concentration (Cmax) of Cobimetinib
Timepoint [7] 0 0
Safety Run-In: Predose (Hour [Hr] 0) on Cycle (Cy) 1 Day (D) 8; predose (Hr 0), 0.5, 1, 2, 4, 6 Hr postdose (2, 4 Hr postdose for Cohorts II, III) on Cy1 D15; Expansion: predose (Hr 0), 1-4 Hr postdose on Cy1 D15; predose (Hr 0) on Cy2 D15 (Cy=28 days)
Secondary outcome [8] 0 0
Cohort I, II, III: Minimum Plasma Concentration (Cmin) of Cobimetinib
Timepoint [8] 0 0
Safety Run-In: Predose (Hr 0) on Cy 1 D8; predose (Hr 0), 0.5, 1, 2, 4, 6 Hr postdose (2, 4 Hr postdose for Cohorts II, III) on Cy1 D15; Expansion: predose (Hr 0), 1-4 Hr postdose on Cy1 D15; predose (Hr 0) on Cy2 D15 (Cy=28 days)
Secondary outcome [9] 0 0
Cohort I, II, III: Area Under the Concentration-Time Curve From Time Zero to Dosing Interval (AUC0-tau; Total Exposure) of Cobimetinib
Timepoint [9] 0 0
Safety Run-In: Predose (Hr 0) on Cy 1 D8; predose (Hr 0), 0.5, 1, 2, 4, 6 Hr postdose (2, 4 Hr postdose for Cohorts II, III) on Cy1 D15; Expansion: predose (Hr 0), 1-4 Hr postdose on Cy1 D15; predose (Hr 0) on Cy2 D15 (Cy=28 days)
Secondary outcome [10] 0 0
Cohort I, II: Cmax of Paclitaxel
Timepoint [10] 0 0
Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 0.5, 1, 2, 4, and 6 Hr postdose (2, 4 Hr postdose for Cohort II) (infusion duration: 1 Hr) on Cy1 D15 (Cy=28 days)
Secondary outcome [11] 0 0
Cohort I, II: Cmin of Paclitaxel
Timepoint [11] 0 0
Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 0.5, 1, 2, 4, and 6 Hr postdose (2, 4 Hr postdose for Cohort II) (infusion duration: 1 Hr) on Cy1 D15 (Cy=28 days)
Secondary outcome [12] 0 0
Cohort I, II: AUC0-tau of Paclitaxel
Timepoint [12] 0 0
Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 0.5, 1, 2, 4, and 6 Hr postdose (2, 4 Hr postdose for Cohort II) (infusion duration: 1 Hr) on Cy1 D15 (Cy=28 days)
Secondary outcome [13] 0 0
Cohort III: Cmax of Nab-Paclitaxel
Timepoint [13] 0 0
Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 2, 4 Hr postdose (infusion duration: 30 minutes) on Cy1 D15 (Cy=28 days)
Secondary outcome [14] 0 0
Cohort III: Cmin of Nab-Paclitaxel
Timepoint [14] 0 0
Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 2, 4 Hr postdose (infusion duration: 30 minutes) on Cy1 D15 (Cy=28 days)
Secondary outcome [15] 0 0
Cohort III: AUC0-tau of Nab-Paclitaxel
Timepoint [15] 0 0
Safety Run-In: Predose (Hr 0) on Cy1 D8; predose (Hr 0), 2, 4 Hr postdose (infusion duration: 30 minutes) on Cy1 D15 (Cy=28 days)
Secondary outcome [16] 0 0
Cohort II, III: Cmax (in Serum) of Atezolizumab
Timepoint [16] 0 0
Safety Run-In, Expansion:Predose (Hr0), 0.5Hr postdose (infusion duration:1Hr) on D1 of Cy1, 3; predose (Hr0) on D1 of Cy2, 4, 8, every 8 Cy up to end of treatment (EOT) (approximately 5.5 years); 120 days after EOT (approximately 5.5 years) (Cy=28 days)
Secondary outcome [17] 0 0
Cohort II, III: Cmin (in Serum) of Atezolizumab
Timepoint [17] 0 0
Safety Run-In, Expansion: Predose (Hr 0), 0.5 Hr postdose (infusion duration: 1 Hr) on D1 of Cy1, 3; predose (Hr 0) on D1 of Cy2, 4, 8, every 8 Cy up to EOT (approximately 5.5 years); 120 days after EOT (approximately 5.5 years) (Cy=28 days)
Secondary outcome [18] 0 0
Cohort II, III: AUC0-tau (in Serum) of Atezolizumab
Timepoint [18] 0 0
Safety Run-In, Expansion: Predose (Hr 0), 0.5 Hr postdose (infusion duration: 1 Hr) on D1 of Cy1, 3; predose (Hr 0) on D1 of Cy2, 4, 8, every 8 Cy up to EOT (approximately 5.5 years); 120 days after EOT (approximately 5.5 years) (Cy=28 days)

Eligibility
Key inclusion criteria
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Histologically confirmed estrogen receptor (ER)-negative, progesterone receptor
(PR)-negative, and human epidermal growth factor 2 (HER2)-negative adenocarcinoma of
the breast with measurable metastatic or locally advanced disease

- Locally advanced disease must not be amenable to resection with curative intent

- Measurable disease, according to RECIST, v1.1

- Adequate hematologic and end organ function

- Agreement to use highly effective contraceptive methods as stated in protocol
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Disease-Specific Exclusion Criteria

- Known HER2-, ER-positive, or PR-positive breast cancer by local laboratory assessment

- Any prior chemotherapy, hormonal, or targeted therapy, for inoperable locally advanced
or metastatic triple-negative breast cancer (mTNBC)

- Any systemic anticancer therapy within 3 weeks prior to Cycle 1, Day 1

- Any radiation treatment to metastatic site within 28 days of Cycle 1, Day 1

- Major surgical procedure, open biopsy, or significant traumatic injury within 30 days
prior to Cycle 1, Day 1 or anticipation of need for major surgical procedure during
the course of the study

- Prior exposure to experimental treatment targeting rapidly accelerated fibrosarcoma
(Raf), MAP kinase/ERK kinase (MEK), or the mitogen-activated protein kinase (MAPK)
pathway

- Brain metastases (symptomatic or nonsymptomatic) that have not been treated
previously, are progressive, or require any type of therapy (e.g., radiation, surgery,
or steroids) to control symptoms from brain metastases within 30 days prior to first
study treatment dose

Cobimetinib-Specific Exclusion Criteria

- 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

- Cobimetinib is metabolized by the hepatic cytochrome P3A4 (CYP3A4) enzyme. Drugs
CYP3A4/5 inhibitors and inducers should be avoided

Atezolizumab-Specific Exclusion Criteria (Cohorts II and III Only)

- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins

- Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
ovary cells or any component of the atezolizumab formulation

- History of autoimmune disease

- Prior allogenic stem cell or solid organ transplantation

- History of idiopathic pulmonary fibrosis (including pneumonitis), drug induced
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
organizing pneumonia), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan

- Positive test for Human Immunodeficiency Virus (HIV)

- Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]
or positive hepatitis B virus [HBV] deoxyribonucleic acid [DNA] test at screening) or
hepatitis C

- Active tuberculosis

- Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or
anticipation that such a live, attenuated vaccine will be required during the study

- Prior treatment with cluster of differentiation (CD) 137 (CD137) agonists or immune
checkpoint blockade therapies, including anti-cytotoxic T-lymphocyte-associated
protein 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), or anti-programmed death
ligand-1 (anti-PD-L1) therapeutic antibodies

- Treatment with systemic immunostimulatory agents (including but not limited to
interferons or Interlukin-2 [IL-2]) within 4 weeks or five half-lives of the drug
(whichever is shorter) prior to randomization

- Treatment with systemic corticosteroids or other systemic immunosuppressive
medications within 2 weeks prior to randomization, or anticipated requirement for
systemic immunosuppressive medications during the trial

Cardiac Exclusion Criteria

- History of clinically significant cardiac dysfunction

- Corrected QT interval at screening greater than (>) 480 milliseconds (ms) (average of
triplicate screening measurements)

- Left ventricular ejection fraction (LVEF) below the institutional lower limit of
normal or below 50 percent (%), whichever is lower

General Exclusion Criteria

- No other history of or ongoing malignancy that would potentially interfere with the
interpretation of the pharmacodynamic or efficacy assay

- Pregnancy (positive serum pregnancy test) or lactation

- Uncontrolled serious medical or psychiatric illness

- Active infection requiring IV antibiotics on Cycle 1, Day 1

- Participants who have a history of hypersensitivity reactions to paclitaxel or other
drugs formulated in Cremophor® EL (polyoxyethylated castor oil) or to nab-paclitaxel
and any of the excipients

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC,WA
Recruitment hospital [1] 0 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [2] 0 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [3] 0 0
Peter MacCallum Cancer Centre; Medical Oncology - Melbourne
Recruitment hospital [4] 0 0
St John of God Murdoch Hospital; Oncology West - Murdoch
Recruitment postcode(s) [1] 0 0
2298 - Waratah
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
3000 - Melbourne
Recruitment postcode(s) [4] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Illinois
Country [5] 0 0
United States of America
State/province [5] 0 0
Missouri
Country [6] 0 0
United States of America
State/province [6] 0 0
New York
Country [7] 0 0
United States of America
State/province [7] 0 0
Oregon
Country [8] 0 0
United States of America
State/province [8] 0 0
Pennsylvania
Country [9] 0 0
United States of America
State/province [9] 0 0
South Carolina
Country [10] 0 0
United States of America
State/province [10] 0 0
South Dakota
Country [11] 0 0
United States of America
State/province [11] 0 0
Washington
Country [12] 0 0
Belgium
State/province [12] 0 0
Bruxelles
Country [13] 0 0
Belgium
State/province [13] 0 0
Gent
Country [14] 0 0
Belgium
State/province [14] 0 0
Hasselt
Country [15] 0 0
Belgium
State/province [15] 0 0
Kortrijk
Country [16] 0 0
Belgium
State/province [16] 0 0
Veurne
Country [17] 0 0
Czechia
State/province [17] 0 0
Hradec Kralove
Country [18] 0 0
Czechia
State/province [18] 0 0
Pardubice
Country [19] 0 0
France
State/province [19] 0 0
Lille
Country [20] 0 0
France
State/province [20] 0 0
Montpellier
Country [21] 0 0
France
State/province [21] 0 0
Paris
Country [22] 0 0
France
State/province [22] 0 0
Rennes
Country [23] 0 0
Israel
State/province [23] 0 0
Ramat Gan
Country [24] 0 0
Italy
State/province [24] 0 0
Campania
Country [25] 0 0
Italy
State/province [25] 0 0
Emilia-Romagna
Country [26] 0 0
Italy
State/province [26] 0 0
Friuli-Venezia Giulia
Country [27] 0 0
Italy
State/province [27] 0 0
Lazio
Country [28] 0 0
Italy
State/province [28] 0 0
Lombardia
Country [29] 0 0
Italy
State/province [29] 0 0
Toscana
Country [30] 0 0
Korea, Republic of
State/province [30] 0 0
Gyeonggi-do
Country [31] 0 0
Korea, Republic of
State/province [31] 0 0
Seoul
Country [32] 0 0
Latvia
State/province [32] 0 0
Riga
Country [33] 0 0
Romania
State/province [33] 0 0
Cluj Napoca
Country [34] 0 0
Romania
State/province [34] 0 0
Craiova
Country [35] 0 0
Spain
State/province [35] 0 0
Barcelona
Country [36] 0 0
Spain
State/province [36] 0 0
Vizcaya
Country [37] 0 0
Spain
State/province [37] 0 0
Badajoz
Country [38] 0 0
Spain
State/province [38] 0 0
Madrid
Country [39] 0 0
Spain
State/province [39] 0 0
Malaga
Country [40] 0 0
Taiwan
State/province [40] 0 0
Kaohsiung Country
Country [41] 0 0
Taiwan
State/province [41] 0 0
Taipei City
Country [42] 0 0
United Kingdom
State/province [42] 0 0
Bournemouth
Country [43] 0 0
United Kingdom
State/province [43] 0 0
Middlesex
Country [44] 0 0
United Kingdom
State/province [44] 0 0
Nottingham

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This three-cohort, multi-stage, randomized, Phase II, multicenter trial will evaluate the
safety and tolerability and estimate the efficacy of cobimetinib plus paclitaxel versus
placebo plus paclitaxel in Cohort I, of cobimetinib plus atezolizumab plus paclitaxel in
Cohort II, and of cobimetinib plus atezolizumab plus nab-paclitaxel in Cohort III in
participants with metastatic or locally advanced, triple-negative adenocarcinoma of the
breast who have not received prior systemic therapy for metastatic breast cancer (MBC).
Participants may continue on study treatment until the development of progressive disease
(PD) or the loss of clinical benefit, unacceptable toxicity, and/or consent withdrawal. The
Cohort I target sample size is 12 participants for the safety run-in stage and approximately
90 participants in the expansion stage. Each of Cohorts II and III will consist of a safety
run-in stage of approximately 15 participants followed by an expansion stage of approximately
15 participants.
Trial website
https://clinicaltrials.gov/show/NCT02322814
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications