This study will evaluate the efficacy, safety, and pharmacokinetics of atezo + cobi + vem compared with placebo plus cobimetinib plus vemurafenib (placebo+ cobi + vem) in patients with previously untreated, BRAFV600 mutation*positive, metastatic or…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PFS, defined as the time from randomization to the first occurrence of disease
progression, as determined by the investigator according to RECIST v1.1, or
death from any cause, whichever occurs first.
Secondary outcome
• PFS, defined as the time from randomization to the first occurrence of
disease progression, as determined by an IRC according to RECIST v1.1, or
death from any cause, whichever occurs first
• Objective response, defined as a CR or PR on two consecutive occasions >= 4
weeks apart, as determined by the investigator according to RECIST v1.1.
• DOR, defined as the time from the first occurrence of a documented objective
response to disease progression, as determined by the investigator according to
RECIST v1.1, or death from any cause, whichever occurs first.
• OS, defined as the time from randomization to death from any cause.
• 2-year landmark survival, defined as survival at 2 years.
More secondary study parameters and corresponding endpoints are described in
protocol paragraph 2 on page 35-37.
Background summary
Although the outcome for promptly diagnosed superficial tumors is good, in the
metastatic setting, melanoma is associated with high rates of mortality and
disease-related morbidity. The clinical outcome of patients with melanoma is
highly dependent on the stage at presentation. Despite recent therapeutic
advances, metastatic melanoma continues to be one of the most deadly cancers,
with a relative 5-year survival rate of 15%*17%.
In 2012, there were around 232,000 new cases and 55,000 deaths from melanoma
worldwide, with more than 100,000 new cases and 22,000 deaths in Europe.
Moreover, the number of melanoma cases worldwide is increasing faster than any
other cancer, especially in fair-skinned, Caucasian populations; estimates
suggest a doubling of melanoma incidence every 10*20 years. Approximately 50%
of all cutaneous melanomas harbor an activating mutation in BRAF, a major
driver of signaling in the RAS/RAF/MEK/ERK MAP kinase (MAPK) pathway. In the
past several years, new agents, including targeted therapies and
immunotherapies, have been approved in the European Union and the United States
for the treatment of BRAFV600 mutation*positive advanced melanoma. Melanoma
cells are also highly immunogenic and thus an appropriate target for
immunotherapy. Despite recent advances in treatments for patients with advanced
melanoma, a significant unmet medical for more efficacious treatment options
remains.
Study objective
This study will evaluate the efficacy, safety, and pharmacokinetics of atezo +
cobi + vem compared with placebo plus cobimetinib plus vemurafenib (placebo+
cobi + vem) in patients with previously untreated, BRAFV600 mutation*positive,
metastatic or unresectable locally advanced melanoma.
Study design
Approximately 500 patients will be randomized in the study. Patients will be
randomized in a 1:1 ratio to Arm A (placebo + cobi + vem) or Arm B (atezo +
cobi + vem). Patients in both arms will be treated with cobimetinib and
vemurafenib during a run-in period of 28 days. Patients in Arm A (control arm)
will receive atezolizumab placebo, cobimetinib, and vemurafenib (960 mg twice
daily [BID]). Patients in Arm B (experimental arm) will receive active
atezolizumab, cobimetinib, and vemurafenib (720 mg BID). As the vemurafenib
doses are different between in the two treatments arms, vemurafenib will be
blinded in both study arms. To ensure adequate blinding, patients in both arms
will receive the same number of vemurafenib tablets, with patients in Arm A
receiving all active vemurafenib tablets and patients in Arm B receiving a
combination of active vemurafenib tablets and vemurafenib placebo tablets.
Following randomization, patients will enter a 28-day run-in period to receive
treatment with cobi + vem, followed by treatment with either atezo placebo +
cobi + vem (Arm A) or atezo + cobi +vem+ vem placebo (Arm B) in the triple
combination period.
Intervention
Atezolizumab 840 mg or placebo will be administered by IV infusion on Days 1
and 15 of Cycle 1 and Days 1 and 15 (every 2 weeks) of subsequent cycles.
All patients will receive cobimetinib at a dose of 60 mg (three 20-mg tablets)
orally (PO) once daily on Days 1*21 of each 28-day cycle during the run-in and
triple combination periods. Cobimetinib should be taken approximately the same
time each day, with the morning vemurafenib dose, and no later than 4 hours
after the scheduled time. Cobimetinib may be taken with or without a meal.
Cobimetinib should be swallowed whole with a glass of water and should not be
chewed, cut, or crushed. If a dose of cobimetinib is missed (i.e., not taken
within 12 hours after the scheduled dosing time), the patient should resume
dosing with the next scheduled dose. Missed or vomited doses will not be made
up.
Each dose of vemurafenib will consist of four tablets, with patients in Arm A
(atezo placebo + cobi + vem) receiving four active tablets and patients in Arm
B (atezo + cobi + vem+ vem placebo) receiving three active tablets plus one
placebo tablet. All patients will receive vemurafenib at a dose of 960 mg (four
240-mg tablets) PO BID on Days 1*21 of the run-in period. Patients in Arm A
will continue to receive vemurafenib at a dose of 960 mg PO BID on Days 22*28
of the run-in period and Days 1*28 of each 28-day cycle during the triple
combination period. Patients in Arm B will receive vemurafenib at a dose of 720
mg (three 240-mg tablets) plus vemurafenib placebo (one tablet) PO BID on Days
22*28 of the run-in period and Days 1*28 each 28-day cycle during the triple
combination period.
Study burden and risks
The safety plan for patients in this study is based on clinical experience with
atezolizumab, cobimetinib, and vemurafenib in completed and ongoing studies.
The anticipated important safety risks are outlined in Sections 5.1.1
[atezolizumab], 5.1.2 [cobimetinib], 5.1.3 [vemurafenib], and 5.1.4
[combination use] of the protocol. Guidelines for dose modifications and
treatment interruption, as well as management of patients who experience
specific adverse events, are provided in Section 5.1.5.
Measures will be taken to ensure the safety of patients participating in this
study, including the use of stringent inclusion and exclusion criteria and
close monitoring of patients during the study. Administration of atezolizumab
will be performed in a monitored setting in which there is immediate access to
trained personnel and adequate equipment and medicine to manage potentially
serious reactions. Adverse events will be reported as described in Sections
5.2*5.6. In addition to the oversight provided by the Medical Monitor and drug
safety personnel for this trial, an iDMC will monitor and evaluate patient
safety throughout the study.
Beneluxlaan 2a
Woerden 3446 GR
NL
Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
- Age >= 18 years
- Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma, as defined by the American Joint Committee on Cancer, 7th revised edition
- Naïve to prior systemic anti-cancer therapy for melanoma (e.g., chemotherapy, hormonal therapy, targeted therapy, immunotherapy, or other biologic therapies), with the following exeptions: neoadjuvant and or adjuvant treatment with chemotherapy, if discontinued at least 28 days prior to initiation of study treatment
- Documentation of BRAFV600 mutation*positive status in melanoma tumor tissue (archival or newly obtained) through use of a clinical mutation test approved by the local health authority
- Eastern Cooperative Oncology Group Performance Status of 0 or 1 (see Appendix 3)
- Measurable disease according to RECIST v1.1
- Willingness to undergo tumor biopsies of accessible lesions during treatment and at progression for exploratory biomarker analyses
- Life expectancy >= 18 weeks
- Adequate hematologic and end-organ function, defined by standard laboratory test results, obtained within 14 days prior to initiation of study treatment, with the exception of amylase, lipase, and LDH where up to 28 days is acceptable (using central laboratory result).
- For patients not receiving therapeutic anticoagulation: INR or aPTT <= 1.5×ULN within 28 days prior to initiation of study treatment
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen and stable INR during the 28 days immediately preceding initiation of study treatment
- For women of childbearing potential: agreement to remain abstinent or use a contraceptive method with a failure rate of <1% per year during the treatment period and for 6 months after the last dose of study treatment
- For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm
Exclusion criteria
Cancer-Related Exclusion Criteria
- Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study
- Traumatic injury within 2 weeks prior to initiation of study treatment
- Palliative radiotherapy within 14 days prior to initiation of study treatment
- Active malignancy (other than BRAFV600 mutation*positive melanoma) or malignancy within 3 years prior to screening are excluded, with the exception of resected melanoma, resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or any other curatively treated malignancies from which the patient has been disease-free for at least 3 years;Ocular 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, retinal vein occlusion (RVO), or neovascular macular degeneration;Cardiac Exclusion Criteria
- History of clinically significant cardiac dysfunction including the following: poorly controlled hypertension, defined as sustained, uncontrolled, nonepisodic baseline hypertension consistently above 159/99 mmHg despite optimal medical management.;Central Nervous System Exclusion Criteria
- Untreated or actively progressing CNS lesions (carcinomatous meningitis)
- History of metastases to brain stem, midbrain, pons, or medulla, or within 10 mm of the optic apparatus (optic nerves and chiasm)
- History of leptomeningeal metastatic disease
- History of intracranial hemorrhage;Additional Exclusion Criteria
- Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease) other than cancer
- Anticipated use of any concomitant medication during or within 7 days prior to initiation of study treatment that is known to cause QT prolongation (which may lead to torsades de pointes)
- Any psychological, familial, sociological, or geographical condition that may hamper compliance with the protocol and follow-up after treatment discontinuation
- History of malabsorption or other clinically significant metabolic dysfunction that may interfere with absorption of oral study treatment
- Pregnant or breastfeeding, or intending to become pregnant during the study
- Prior allogeneic stem cell or solid organ transplantation
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
- History of autoimmune disease;For all exclusion criteria, see section 4.1.2 on pages 50-54 of the protocol
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002482-54-NL |
| ClinicalTrials.gov | NCT02908672 |
| CCMO | NL59004.056.16 |