Efficacy ObjectivesThe primary efficacy objective of study GO28141 is as follows:* To evaluate the efficacy of vemurafenib in combination with GDC-0973, compared with vemurafenib and placebo, in previously untreated BRAFV600 mutation-positive…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome measure for this study is as follows:
* PFS, defined as the time from randomization to the first occurrence of
disease progression, as determined by the investigator using RECIST v1.1, or
death from any cause, whichever comes first.
Secondary outcome
The secondary outcome measures are as follows:
* Overall survival, defined as the time from randomization to death from any
cause
* Objective response rate for patients with measurable disease at baseline,
defined as complete or partial response as assessed by investigator according
to RECIST v1.1
* Duration of response for patients with measurable disease at baseline,
defined as the time from first occurrence of a documented objective response
until the time of disease progression, as determined by investigator review of
tumor assessments using RECIST v1.1, or death from any cause during the study
(i.e., within 30 days after the last dose of study treatment)
* progression-free survival (PFS)
Background summary
Metastatic melanoma is one of the most deadly cancers, with a 5-year survival
rate of 15% and a median overall survival of around 8 months.
The only medicinal products widely approved for the treatment of unresectable
or metastatic melanoma are dacarbazine and ipilimumab, both of which require IV
administration.
Vemurafenib is a compound (in tablet form) that selectively inhibits oncogenic
BRAF kinase. Oncogenic mutations in BRAF kinase, predominantly V600E, have been
observed in approximately 8% of all solid tumors, including 50% of metastatic
melanomas. Discovery of oncogenic BRAF mutations highlights the central role of
this kinase in signaling pathways that control cellular proliferation. The
best-characterized substrate of BRAF is MEK kinase.
Oncogenic mutations in BRAF result in constitutive activation of BRAF kinase,
which causes dysregulated downstream signaling via MEK and ERK, leading to
excessive cell proliferation and survival.
The objective for the clinical investigation of the combination of vemurafenib
with GDC-0973 (MEK inhibitor, in tablet form) is to simultaneously inhibit both
oncogenic BRAF kinase (vemurafenib) and MEK (GDC-0973) in patients with
previously untreated, BRAFV600E mutation-positive, locally advanced and
unresectable or metastatic Melanoma.
The addition of a MEK inhibitor to vemurafenib abrogates vemurafenib
resistance. These findings, together with preclinical evidence that combined
inhibition of BRAF and MEK prevents the emergence of resistance support the
clinical evaluation of combination therapy strategies incorporating MEK
inhibition with BRAF inhibitors (BRAFi) in order to combat emerging resistance.
Study objective
Efficacy Objectives
The primary efficacy objective of study GO28141 is as follows:
* To evaluate the efficacy of vemurafenib in combination with GDC-0973,
compared with vemurafenib and placebo, in previously untreated BRAFV600
mutation-positive patients with unresectable locally advanced or metastatic
melanoma, as measured by prolongation of progression-free survival (PFS), as
assessed by the study site investigator.
The secondary efficacy objectives of study GO28141 are as follows:
* To evaluate the efficacy of vemurafenib in combination with GDC-0973,
compared with vemurafenib and placebo, in previously untreated BRAFV600
mutation-positive patients with unresectable locally advanced or metastatic
melanoma, as measured by overall survival (OS), objective response rate (ORR),
and duration of response (DOR).
Safety Objectives
The safety objective of study GO28141 is as follows:
* To characterize the toxicity profile in patients receiving vemurafenib and
GDC-0973 versus vemurafenib and placebo.
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective of study GO28141 is as follows:
* To characterize the pharmacokinetics of GDC-0973 and vemurafenib and to
compare the pharmacokinetics of vemurafenib when administered with GDC-0973 to
the pharmacokinetics of vemurafenib when administered with placebo.
* To perform exploratory exposure-response analysis, including concentration-QT
interval corrected (QTc) analysis.
Patient-Reported Outcome Objectives
The patient-reported outcome (PRO) objective of study GO28141 is as follows:
* To evaluate health-related quality of life in patients receiving vemurafenib
and GDC-0973 versus vemurafenib and placebo as measured by the European
Organization for Research and Cancer (EORTC) Quality of Life Questionnaire
(QLQ-C30) and the EuroQol 5 dimension (EQ-5D) questionnaire.
Exploratory Objectives
The Sponsor is committed to the collection of biomarker samples in all clinical
study protocols. The objective of biomarker profiling is to enable
development of treatments specifically targeted for optimal patient benefit
(personalized healthcare). Specimens may be used for any of the following:
* To explore the intrinsic and acquired mechanisms of resistance to MEK and
BRAF inhibition in tumor samples obtained at baseline, during treatment, and at
disease progression.
* To study the association of biomarkers with efficacy and/or adverse events
(AEs) associated with medicinal products
* To increase knowledge and understanding of disease biology
Study design
GO28141 is a multicenter, randomized, double-blind, placebo-controlled Phase
III clinical study to evaluate the safety and efficacy of vemurafenib in
combination with GDC-0973 with vemurafenib alone.
Intervention
* Arm A (control arm): vemurafenib 960 mg by mouth (PO) twice daily (BID) on
Days 1 * 28 and placebo PO once daily (QD) on Days 1 * 21 of each 28-day
treatment cycle
* Arm B (investigational arm): vemurafenib 960 mg PO BID on Days 1 * 28 and
GDC 0973 60 mg PO QD on Days 1 * 21 of each 28-day treatment cycle
Study burden and risks
Taking into account the efficacy and safety data of single-agent vemurafenib
and GDC-0973 observed to date, and the favorable adverse effect profile of the
combination observed in the Phase Ib study, the potential benefits of
combination therapy and the extent of safety monitoring proposed, the potential
benefit for patients with unresectable locally advanced or metastatic melanoma
who participate in study GO28141 outweigh the potential risks.
Grenzacherstrasse 124
Basel CH-4070
CH
Grenzacherstrasse 124
Basel CH-4070
CH
Listed location countries
Age
Inclusion criteria
1. Patients with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist.
2. Patients must be naïve to treatment for locally advanced unresectable or metastatic disease (i.e., NO prior systemic anti-cancer therapy for advanced disease; stage IIIc and IV). Prior adjuvant immunotherapy (including ipilimumab) is allowed.
3. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue (archival or newly obtained tumor samples) using the cobas 4800 BRAF V600 mutation test.
4. Male or female patient aged * 18 years.
5. Life expectancy * 12 weeks.
Exclusion criteria
1. History of prior RAF or MEK pathway inhibitor treatment.
2. Palliative radiotherapy within 14 days prior to the first dose of study treatment.
3. Major surgery or traumatic injury within 14 days prior to first dose of study treatment.
4. Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Patients with a previous malignancy within the past 3 years are excluded except for patients with resected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast.
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 | EUCTR2012-003008-11-NL |
| ClinicalTrials.gov | NCT01689519 |
| CCMO | NL42321.068.12 |