A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain

• Register: ClinicalTrials.gov
• Last refreshed on: 19 October 2017
• Main ID: NCT01266967
• Date of registration: 02/12/2010
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain Break MB
• Scientific title: BRF113929: An Open-Label, Two-Cohort, Multicentre Study of GSK2118436 as a Single Agent in Treatment Naïve and Previously Treated Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain
• Date of first enrolment: February 2011
• Target sample size: 172
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT01266967
• Study type: Interventional
• Phase: Phase 2

Countries of recruitment

Australia, Canada, France, Germany, Italy, United States

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion criteria

Inclusion Criteria:

- Cohort A:

- No prior local therapy for brain metastases.

- Subjects who are receiving concomitant corticosteroids must be on a stable or
decreasing dose for at least 3 weeks prior to first dose of study treatment.

- No prophylactic or preventive anti-epileptic therapy. Exception: anti-epileptic
therapy indicated in order to prevent neurologic symptoms caused by a pre-existing
condition and not related to brain metastasis is allowed.

- Cohort B:

- Subjects must have received at least one local therapy for brain metastases including
but not restricted to brain surgery, Whole Brain Radiotherapy or Stereotactic
Radiosurgery (e.g. gamma knife, linear-accelerated-based radiosurgery, charged
particles, and CyberKnife). Multiple local therapies or combinations of local
therapies are allowed. For subjects receiving local therapy to all brain lesions
(including WBRT), progression of pre-existing lesions based on RECIST 1.1 (> 20%
increase in longest diameter on baseline scan) or new measurable lesions are required.
For subjects receiving local therapy for some but not all lesions, disease progression
based on RECIST 1.1 is not required as long as there are remaining brain lesions that
are measurable and not previously treated.

- Subjects who are receiving concomitant corticosteroids must be on a stable or
decreasing dose for at least 2 weeks prior to first dose of study treatment.

- Prophylactic or preventive anti-epileptic therapy is allowed.

- General:

- Must sign written informed consent.

- Must be at least 18 years of age.

- Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600E- or
V600K-mutation.

- Up to two previous treatment regimens for extracranial metastatic melanoma including
chemo-, cytokine-, immuno-, biological- and vaccine-therapy.

- At least one measurable intracranial target lesion for which all of the following
criteria have to be met:

- previously untreated or progressive according to RECIST 1.1 (greater than or equal to
20% increase in longest diameter on baseline scan) after previous local therapy

- immediate local therapy clinically not indicated or patient is not a suitable
candidate to receive immediate local therapy

- largest diameter of greater than or equal to 0.5cm but less than or equal to 4 cm as
determined by contrast-enhanced MRI

- for target lesions (for definition see Section 6.1.1) with diameter of greater than
0.5 cm but less than or equal to 1 cm documented measurement by a neuroradiologist is
required.

- for all lesions with diameter of greater than or equal to 3 cm but less than or equal
to 4 cm documented measurement by a neuroradiologist is required.

- Time interval between last day of previous anti-tumour systemic treatment and first
dose of GSK2118436:

- 14 days elapsed from last treatment with surgery, SRS or gamma knife

- 28 days elapsed from last treatment with WBRT

- Greater than or equal to 28 days or five half-lives (whichever is longer) have elapsed
from last dose of approved or investigational chemo-, cytokine-, immune-, biological-,
or vaccine-therapy.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

- Adequate organ function.

- Women with child-bearing potential and men with reproductive potential must be willing
to practice acceptable methods of birth control during the study.

- Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to the first dose of study treatment.

Exclusion Criteria:

- Neurological symptoms related to brain metastasis.

- Previous treatment with a BRAF or MEK inhibitor.

- Current or expected use of a prohibited medication during treatment with GSK2118436.

- Presence of leptomeningeal disease or primary dural metastases.

- Known allergies against contrast agents required for magnetic resonance imaging (MRI)
of intracranial lesions.

- Current use of therapeutic warfarin. NOTE: Low molecular weight heparin and
prophylactic low-dose warfarin are permitted.

- Unresolved toxicity of National Cancer Institute Common Terminology Criteria for
Adverse Events, version 4.0 (NCI v4.0) Grade 2 or higher from previous anti-cancer
therapy, except alopecia.

- Presence of active gastrointestinal disease or other condition that will interfere
significantly with the absorption of drugs.

- A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or
Hepatitis C Virus (HCV) infection.

- Acute infection requiring intravenous antibiotics

- History of another malignancy. Exception: (a) Subjects who have been disease-free for
5 years, (b) a history of completely resected non-melanoma skin cancer, (c)
successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent
prostate cancer requiring no or only anti-hormonal therapy with histologically
confirmed tumour lesions that can be clearly differentiated from melanoma target and
non-target lesions are eligible.

- Certain cardiac abnormalities.



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Melanoma and Brain Metastases

Intervention(s)

Drug: GSK2118436

Primary Outcome(s)

Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator [Time Frame: From the time of the Baseline assessment until disease progression or end of study treatment (average of 18.3 weeks)]

Secondary Outcome(s)

Overall Survival of V600E Mutation-positive Participants [Time Frame: Time from the first dose of study medication until death due to any cause (average of 35 weeks)]

Number of Participants With a Worst-case on Therapy Change to Grade 3 and Grade 4, or With Any Grade Increase (AGI), From Baseline Grade for Clinical Chemistry Parameters [Time Frame: From Screening until the conclusion of the study (up to 103 weeks)]

Number of Participants With V600K Mutation-positive Melanoma With OIR, as Assessed by the Investigator [Time Frame: From the time of the Baseline assessment until disease progression or end of study treatment (average of 16 weeks)]

Composite of Pharmacokinetic Parameters of GSK2118436 in a Subset of Participants Receiving Dexamethasone [Time Frame: Day 15]

Duration of Intracranial Response for the Subset of V600K Mutation-positive Participants [Time Frame: Time from the first documented evidence of intracranial CR or PR until the time of the first documented intracranial disease progression or death due to any cause (average of 31 weeks)]

Progression-free Survival in V600K Mutation-positive Participants [Time Frame: Time from the first dose of study medication to the earliest of death or progression (average of 17 weeks)]

Duration of Overall Response for the Subset of V600E Mutation-positive Participants [Time Frame: Time from the first documented evidence of CR or PR until the time of the first documented disease progression or death due to any cause (average of 28 weeks)]

Median Concentrations of GSK2118436 and Its Metabolites Including GSK2285403, GSK2298683, and GSK2167542 [Time Frame: Week 4 (pre-dose and 1-3 hours post-dose) and Weeks 8, 16, 24, and 32 (either pre-dose in the morning or in the afternoon at 4-8 hours post-dose)]

Duration of Intracranial Response for the Subset of V600E Mutation-positive Participants [Time Frame: Time from the first documented evidence of intracranial CR or PR until the time of the first documented intracranial disease progression or death due to any cause (average of 27 weeks)]

Duration of Overall Response for the Subset of V600K Mutation-positive Participants [Time Frame: Time from the first documented evidence of CR or PR until the time of the first documented disease progression or death due to any cause (average of 31 weeks)]

Mean Blood Pressure at Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36 [Time Frame: Baseline; Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36]

Number of Participants With V600E Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator [Time Frame: From the time of the Baseline assessment until disease progression or end of study treatment (average of 24 weeks)]

Number of Participants With V600K Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator [Time Frame: From the time of the Baseline assessment until disease progression or end of study treatment (average of 17 weeks)]

Number of Participants With Abnormal Echocardiograms (ECHO) at Weeks 4 and 12 [Time Frame: Weeks (W) 4 and 12]

Number of Participants With a Worst-case On-therapy Increase From Baseline in Bazett's QTc Reading in the 12-lead Electrocardiogram (ECG) [Time Frame: Baseline; Weeks 4, 12, 20, 28, 40, 52, and 64]

Number of Response Genetics Incorporated (RGI) Investigational Use Only (IUO) Assay Mutation Positive Participants and THxID BRAF Assay Mutation Positive Participants With the Indicated Best Intracranial Response [Time Frame: Screening]

Overall Survival in V600K Mutation-positive Participants [Time Frame: Time from the first dose of study medication until death due to any cause (average of 26 weeks)]

Number of Participants With a Worst-case on Therapy Change to Grade 3 and Grade 4, or With Any Grade Increase (AGI), From Baseline Grade for Hematology Parameters [Time Frame: From Screening until the conclusion of the study (up to 103 weeks)]

Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) [Time Frame: From Screening until the conclusion of the study (up to 103 weeks)]

Number of Participants With the Indicated Hepatobiliary Laboratory Abnormalities [Time Frame: From Screening until the conclusion of the study (up to 103 weeks)]

Progression-free Survival in V600E Mutation-positive Participants [Time Frame: Time from the first dose of study medication to the earliest of death or progression (average of 23 weeks)]

Secondary ID(s)

113929

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 05/03/2014
• URL: https://clinicaltrials.gov/ct2/show/results/NCT01266967