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Solid TumoursPhase 1NCT01767454

Study of Dabrafenib +/- Trametinib in Combination With Ipilimumab for V600E/K Mutation Positive Metastatic or Unresectable Melanoma

A Phase 1 study testing Dabrafenib, Trametinib and Ipilimumab in people with Solid Tumours, run by GlaxoSmithKline at 7 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This is an open-label, multi-center, dose-finding Phase 1 study that will enroll subjects at least 18 years old with unresectable or metastatic melanoma and BRAF V600 mutations. The primary objective of the study is to describe the safety for the doublet therapy (dabrafenib and ipilimumab) and the triplet therapy… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Solid Tumours
What is being tested?
Dabrafenib, Trametinib and Ipilimumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
38 participants
Where
7 sitesUnited States
Study dates
12 Feb 2013to 4 Sep 2015
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Signed written informed consent
  • Males and females >= 18 years of age
  • Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive by the local laboratory. Subjects with ocular or mucosal melanoma are not eligible
  • Measurable tumor by physical or radiographic examination
  • Subjects must not have had more than 1 previous treatment regimen with chemotherapy, interferon, or IL-2 for metastatic melanoma
  • All prior anti-cancer treatment-related toxicities (except alopecia) must be <= Grade 1 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 at the time of enrollment
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  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Adequate baseline organ function as defined by: absolute neutrophil count (ANC) >= 1.2 × 109/L; Hemoglobin >= 9 g/dL; Platelet count >= 100 x 109/L; prothrombin time (PT) / international normalized ratio (INR) and partial thromboplastin time (PTT) <= 1.5 x upper limit of normal (ULN); Albumin >= 2.5 g/dL; Total bilirubin <= 1.5 x ULN; aspartate aminotransferase (AST) and alanine transaminase (ALT) <= 2.0 x ULN; Creatinine <=1.5 mg/mL; Left Ventricular Ejection fraction (LVEF) >= lower limit of normal (LLN) by ECHO
  • Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization and agree to use effective contraception, during the study, and for 30 days after the last dose of study treatment
  • Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception for at least 2 weeks prior to the first dose of study treatment until 16 weeks after the last dose of study treatment to allow for clearance of any altered sperm
  • Able to swallow and retain orally administered study treatment and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

Who cannot join

  • Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119) or ipilimumab or any other agent targeting a T-cell immunomodulatory pathway (including, but not limited to CTLA-4, PD-1, 4-1BB, OX40, GITR, CD27, and CD28)
  • Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to randomization
  • Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection)
  • A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Brain metastasis are excluded unless
  • All known lesions were previously treated with surgery or stereotactic surgery (whole-brain radiation is not allowed unless given after definitive treatment with surgery or stereotactic surgery) AND
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  • Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in lesion size) for >= 6 weeks prior to randomization (stability must be confirmed with two consecutive magnetic resonance image (MRI) or computed tomography (CT) scans with contrast, AND
  • Asymptomatic with no corticosteroid requirements for >= 4 weeks prior to randomization, AND
  • No enzyme inducing anticonvulsants for >= 4 weeks prior to randomization
  • A history or evidence of cardiovascular risk including any of the following
  • LVEF < LLN for the institution
  • A corrected QT interval >=480 msec (e.g. Bazett's formula [QTcB])
  • A history or evidence of current clinically significant uncontrolled arrhythmias (exception: subjects with controlled atrial fibrillation for > 30 days prior to randomization are eligible)
  • A history (within 6 months prior to first dose of study treatment) of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty
  • A history or evidence of current >=Class II congestive heart failure as defined by the New York Heart Association (NYHA)
  • Treatment refractory hypertension defined as systolic blood pressure >140 millimetres of mercury (mmHg) and/or diastolic blood pressure >90 mmHg which cannot be controlled by antihypertensive therapy
  • Patients with intra-cardiac defibrillators
  • Abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study
  • A history or current evidence/risk of retinal vein occlusion (RVO) or Central serous retinopathy (CSR) including
  • Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes), or
  • Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as evidence of new optic disc cupping; Evidence of new visual field defects on automated perimetry; Intraocular pressure >21 mmHg as measured by tonography
  • History of any of the following diseases: inflammatory bowel disease or any other autoimmune bowel disease; systemic lupus erythematosus; rheumatoid arthritis; or any autoimmune ocular diseases. Patients with active autoimmune disease or a history of autoimmune disease other than those mentioned above must be approved by the GSK medical monitor
  • Active pneumonitis or interstitial lung disease
  • Lactating female
  • History of another malignancy (Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible)
  • Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures
  • Any prohibited medication
  • Administration of an investigational study treatment within 28 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment(s) in this study
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
  • Unwillingness or inability to follow the procedures outlined in the protocol

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

United States7 sites

  • GSK Investigational Site

    Boston, Massachusetts, 02215

  • GSK Investigational Site

    Houston, Texas, 77030

  • GSK Investigational Site

    Los Angeles, California, 90025

  • GSK Investigational Site

    Nashville, Tennessee, 37232

  • GSK Investigational Site

    New York, New York, 10065

  • GSK Investigational Site

    San Francisco, California, 94115

  • GSK Investigational Site

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: Phase 1 Study of the BRAF Inhibitor Dabrafenib +/- MEK Inhibitor Trametinib in Combination With Ipilimumab for Unresectable or Metastatic Melanoma

This is an open-label, multi-center, dose-finding Phase 1 study that will enroll subjects at least 18 years old with unresectable or metastatic melanoma and BRAF V600 mutations. The primary objective of the study is to describe the safety for the doublet therapy (dabrafenib and ipilimumab) and the triplet therapy (dabrafenib/trametinib and ipilimumab). Preliminary efficacy data will also be collected. Subjects will be assigned to receive either the doublet combination (dabrafenib and ipilimumab) or the triplet combination (dabrafenib, trametinib, and ipilimumab). Subjects will be enrolled to dose-finding cohorts in the doublet combination (dabrafenib + ipilimumab) in a sequential 3+3 fashion. Following establishment of a dose for the doublet combination, an expansion cohort will be opened. At the same time, enrollment to dose finding cohorts for the triplet combination (dabrafenib + trametinib + ipilimumab) will begin in a sequential 6+6 fashion. Enrollment into triplet cohorts will take priority when both the doublet expansion arm and the triplet dose-finding arm are open for enrollment at the same time. Approximately 9-24 subjects will be enrolled to the dose finding portion of the study. Approximately 30 subjects will be enrolled to doublet expansion cohort and 30 subjects will be enrolled in the triplet expansion cohort. A two-week run-in period without ipilimumab will be followed by 4 intravenous doses of ipilimumab at the recommended dose and schedule. Oral daily dosing of dabrafenib or dabrafenib + trametinib will continue from the two-week run-in, through combination with ipilimumab, and post-ipilimumab until no longer of clinical benefit, in the opinion of the treating physician, or until unacceptable AE or death

Conditions
Solid Tumours
Being tested
Dabrafenib, Trametinib, Ipilimumab
Keywords
BRAF V600E, Melanoma, V600K, Trametinib, Dabrafenib, Ipilimumab
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DabrafenibDrug

    Dabrafenib 100 mg or 150 mg BID orally will be administered. Capsules with unit dose strengths of 50 mg or 75 mg

  • TrametinibDrug

    Trametinib 1 mg or 2 mg once daily will be administered. Tablets with unit dose strengths of 0.5 mg or 2 mg

  • IpilimumabDrug

    Ipilimumab 3 mg/kg intravenously over 90 minutes Q3W for a total of 4 doses will be administered. Supplied as Vials of 50 mg/10 mL (5 mg/mL) and 200 mg/40 mL (5 mg/mL)

Study groups in NCT01767454
Study groupRoleWhat they receive
Doublet armExperimentalSubjects will be started with dabrafenib 150 mg twice daily (BID) orally for 2 weeks (run-in). The doublet arm will comprise 2 cohorts. Cohort A1 (Dabrafenib 150 mg BID + ipilimumab). Cohort A-1 (Dabrafenib 100 mg BID +ipilimumab). Ipilimumab will be administered as 3 mg/kg every 3 weeks (Q3W) for a total of 4 infusions over approximately 12-16 weeks. Dabrafenib will be continued through combination with ipilimumab and post-ipilimumab until no longer of clinical benefit, in the opinion of the treating physician, or until unacceptable AE or death
Receives: Drug: Dabrafenib; Drug: Ipilimumab
Triplet armExperimentalThis arm will be initiated using dabrafenib and ipilimumab doses established in the doublet dose-finding. Subjects will be started with dabrafenib and trametinib orally for 2 weeks (run-in), followed by ipilimumab 3 mg/kg Q3W for a total of 4 infusions over approximately 12-16 weeks. The triplet arm will comprise 3 planned cohorts. Cohort B-1: Dabrafenib 100 mg BID + trametinib 1 mg once daily + ipilimumab, Cohort B1: Dabrafenib 150 mg BID + trametinib 1 mg once daily+ ipilimumab, Cohort B2: Dabrafenib 150 mg BID + trametinib 2 mg once daily + ipilimumab. Dabrafenib and trametinib wil be continued through combination with ipilimumab and post-ipilimumab until no longer of clinical benefit, in the opinion of the treating physician, or until unacceptable AE or death
Receives: Drug: Dabrafenib; Drug: Trametinib; Drug: Ipilimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of subjects with Adverse Events (AEs) to assess the safety of dabrafenib +/- trametinib when administered in combination with ipilimumab

    AEs will be collected from the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment

    Measured: Follow-up up to 6 months after last subject last dose

  2. Changes in laboratory values, vital signs, and physical examinations as a measure of safety of dabrafenib +/- trametinib when administered in combination with ipilimumab

    Hematology, clinical chemistry, and urinalysis parameters to be tested. Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate. A complete physical examination will be performed at screening and every 12 months thereafter, as well as whenever clinically indicated.A brief physical examination will be performed every 3 or 4 weeks

    Measured: Follow-up up to 6 months after last subject last dose

Secondary outcomes (3)

  1. Number of subjects with AEs and changes in laboratory values, vital signs, and physical examinations to determine a recommended dose for dabrafenib +/- trametinib when administered in combination with ipilimumab

    All subjects will be evaluated for dose-limiting toxicity (DLT) from the first dose of ipilimumab until 1 week after the third dose of ipilimumab to determine a recommended dose for dabrafenib +/- trametinib when administered in combination with ipilimumab

    Measured: Up to approximately Week 9 in doublet and triplet arm

  2. Overall response rate

    Overall Response will be determined using Modified immune-related response criteria (irRC)

    Measured: Follow-up up to 6 months after last subject last dose

  3. Concentrations of trametinib, dabrafenib and its metabolites (GSK2285403, GSK2298683, and GSK2167542) in the triplet arm and dabrafenib and its metabolites in the doublet arm

    Four blood samples will be collected on the day of first dose of ipilimumab (Cycle 1) - Study Day 15. One blood sample will be obtained on the day of the second and third dose of ipilimumab (Cycles 2 and 3) - Study Days 36 and 57. Subjects will be instructed to withhold their morning dose until after they arrive at the clinic. Ipilimumab infusion should start as soon as possible after oral dosing of dabrafenib/trametinib. PK samples have a +/-30 minute window for collection.

    Measured: Day 15 (pre-dose,1, 2, and 4 hours post-dose); Day 36 and Day 57 (pre-dose only) for doublet and triplet arms

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jan 2013 (estimated)
  2. Study start12 Feb 2013
  3. Primary completion4 Sep 2015
  4. Study completion4 Sep 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
38 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01767454
Sponsor's protocol ID
115984
Status last verified
Nov 2017
First submitted
10 Jan 2013
Last updated
14 Nov 2017
Results posted
No
Data monitoring committee
Yes

Publications

  • Ackerman A, Klein O, McDermott DF, Wang W, Ibrahim N, Lawrence DP, Gunturi A, Flaherty KT, Hodi FS, Kefford R, Menzies AM, Atkins MB, Long GV, Sullivan RJ. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014 Jun 1;120(11):1695-701. doi: 10.1002/cncr.28620. Epub 2014 Feb 27.

    PubMed 24577748

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Dabrafenib, Trametinib and Ipilimumab in people with Solid Tumours, run by GlaxoSmithKline at 7 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Nov 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of subjects with Adverse Events (AEs) to assess the safety of dabrafenib +/- trametinib when administered in combination with ipilimumab (time frame: Follow-up up to 6 months after last subject last dose). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01767454, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Nov 2017.

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