Clinical Trials /

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

NCT01767454

Description:

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

Related Conditions:
  • Melanoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Study of <span class="go-doc-concept go-doc-intervention">Dabrafenib</span> +/- <span class="go-doc-concept go-doc-intervention">Trametinib</span> in Combination With <span class="go-doc-concept go-doc-intervention">Ipilimumab</span> for V600E/K <span class="go-doc-concept go-doc-keyword">Mutation</span> Positive Metastatic or Unresectable <span class="go-doc-concept go-doc-disease">Melanoma</span>

Title

  • Brief Title: Study of Dabrafenib +/- Trametinib in Combination With Ipilimumab for V600E/K Mutation Positive Metastatic or Unresectable Melanoma
  • Official Title: Phase 1 Study of the BRAF Inhibitor Dabrafenib +/- MEK Inhibitor Trametinib in Combination With Ipilimumab for V600E/K Mutation Positive Metastatic or Unresectable Melanoma
  • Clinical Trial IDs

    NCT ID: NCT01767454

    ORG ID: 115984

    Trial Conditions

    Solid Tumours

    Trial Interventions

    Drug Synonyms Arms
    Dabrafenib Triplet arm, Doublet arm
    Trametinib Triplet arm
    Ipilimumab Triplet arm, Doublet arm

    Trial Purpose

    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

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Doublet arm Experimental Subjects 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 Dabrafenib, Ipilimumab
    Triplet arm Experimental This 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 Dabrafenib, Trametinib, Ipilimumab

    Eligibility Criteria

    Inclusion Criteria:

    - 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

    - 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

    Exclusion Criteria:

    - 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

    1. 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

    2. 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

    3. Asymptomatic with no corticosteroid requirements for >= 4 weeks prior to
    randomization, AND

    4. No enzyme inducing anticonvulsants for >= 4 weeks prior to randomization

    - A history or evidence of cardiovascular risk including any of the following

    1. LVEF < LLN for the institution

    2. A corrected QT interval >=480 msec (e.g. Bazett's formula [QTcB])

    3. A history or evidence of current clinically significant uncontrolled arrhythmias
    (exception: subjects with controlled atrial fibrillation for > 30 days prior to
    randomization are eligible)

    4. A history (within 6 months prior to first dose of study treatment) of acute
    coronary syndromes (including myocardial infarction or unstable angina),
    coronary angioplasty

    5. A history or evidence of current >=Class II congestive heart failure as defined
    by the New York Heart Association (NYHA)

    6. 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

    7. Patients with intra-cardiac defibrillators

    8. 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

    1. 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

    2. 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

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

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

    Secondary Outcome Measures

    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

    Overall response rate

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

    Trial Keywords

    Trametinib

    Dabrafenib

    BRAF V600E

    Ipilimumab

    V600K

    Melanoma