Clinical Trials /

LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations

NCT01726738

Description:

This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected at baseline and at progression.If a subject is removed from the study for one of a variety of reasons including, but not limited to, an inability to tolerate the combination of dabrafenib and trametinib, a need to receive other therapy or completion of 3-years of study treatment without progression, and the subject later receives, as part of his/her standard of care, the combination of dabrafenib and trametinib and progresses on the standard of care regimen, then the subject may be contacted by the treating physician to be put back on to the LCCC 1128 protocol and have a progression biopsy at this progression time point. Markers of resistance will be explored by performing near kinome-wide profiling on tumor samples, and in patients who co-enroll in institutional protocol LCCC1108, by sequencing tumors using NextGen DNA sequencing technology. Overall response rate and duration to this combination will also be assessed.

Related Conditions:
  • Melanoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

LCCC 1128: Open Label Phase II Trial of the <span class="go-doc-concept go-doc-biomarker">BRAF</span> Inhibitor (<span class="go-doc-concept go-doc-intervention">Dabrafenib</span>) and the MEK Inhibitor (<span class="go-doc-concept go-doc-intervention">Trametinib</span>) in Unresectable Stage III and Stage IV <span class="go-doc-concept go-doc-biomarker">BRAF</span> <span class="go-doc-concept go-doc-keyword">Mutant</span> <span class="go-doc-concept go-doc-disease">Melanoma</span>; Correlation of Resistance With the Kinome and Functional <span class="go-doc-concept go-doc-keyword">Mutations</span>

Title

  • Brief Title: LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations
  • Official Title: LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations
  • Clinical Trial IDs

    NCT ID: NCT01726738

    ORG ID: LCCC 1128

    Trial Conditions

    Stage III Melanoma

    Stage IV Melanoma

    Unresectable Melanoma

    BRAF Mutant Melanoma

    Trial Interventions

    Drug Synonyms Arms
    BRAF inhibitor dabrafenib and MEK inhibitor trametinib BRAF Inhibitor Dabrafenib GSK2118436, MEK Inhibitor Trametinib GSK1120212 BRAF (dabrafenib) and MEK (trametinib) inhibitors

    Trial Purpose

    This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma
    is designed to explore the mechanisms by which tumors acquire resistance to the combination
    of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected
    at baseline and at progression. Markers of resistance will be explored by performing near
    kinome-wide profiling on tumor samples, and in patients who co-enroll in institutional
    protocol LCCC1108, by sequencing tumors using NextGen DNA sequencing technology. Overall
    response rate and duration to this combination will also be assessed.

    Detailed Description

    The present phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV
    melanoma is designed to explore the mechanisms by which tumors acquire resistance to the
    combination of BRAF and MEK inhibition. Overall response rate and duration to this
    combination will also be assessed.

    Tissue will be collected at baseline and at progression (clinical or radiological).
    Patients may remain on treatment after progression (at the discretion of the investigator)
    as long as they are still experiencing clinical benefit. We anticipate that up to 50% of
    patients may continue on therapy post-progression for 2-8 weeks.

    BRF113220, the phase I/II trial of the BRAF inhibitor dabrafenib in combination with the MEK
    inhibitor trametinib is ongoing in metastatic melanoma to establish the safety of this
    combination, and to determine the recommended phase 2 doses (RP2D) for each agent.
    Expansion cohorts at the RP2D for these drugs in combination were included in the phase I to
    characterize the safety in more detail, and to explore the efficacy of this combination.
    The combination was well tolerated as described in section 1.5, with decreased frequency of
    rash compared to either agent alone and with just 1 report of cutaneous SCC.

    This proposed study will utilize the RP2D determined in the Phase I/II study: trametinib 2mg
    QD and dabrafenib 150 mg BID. Despite a very promising overall response rate of 81%, these
    patients will also likely go on to develop resistance as a result of new resistance
    mutations, and given the cooperative signaling network of kinases that sense inhibition of
    key nodal kinases and induce compensatory responses that offset pharmacological
    intervention. The study objectives are as follows: Objectives Primary Objective To identify
    kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and
    MEK (trametinib) inhibitors, and to determine a kinome signature predictive of resistance to
    BRAF/MEK inhibition in stage III/IV melanoma Secondary Objectives To explore whether
    resistance to BRAF and MEK inhibition is associated with new functional mutations in the
    approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of
    the tumors (using NextGen DNA sequencing technology) in the subset of patients who co-enroll
    in LCCC1108, with particular focus on one of five established resistance genes (BRAF, NRAS,
    MEK1, MAP3K8 or COT, and PTEN) To determine the overall response rate (ORR: complete
    response + partial response) as measured via RECISTv1.1 To estimate the duration of ORR as
    measured via RECISTv1.1 To estimate progression-free survival (PFS) as defined by RECISTv1.1
    To estimate the rate of overall survival (OS) at 1 year from day 1 of treatment

    Primary Endpoint Kinome signature pathway will be based on comparison of kinome expression
    from pre- and post-treatment biopsies using Multiplexed Inhibitor Beads (MIBs) coupled with
    mass spectrometry.

    Trial Arms

    Name Type Description Interventions
    BRAF (dabrafenib) and MEK (trametinib) inhibitors Experimental Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit. BRAF inhibitor dabrafenib and MEK inhibitor trametinib

    Eligibility Criteria

    Inclusion Criteria:

    Subject must meet all of the inclusion criteria to participate in this study:

    Age 18 years Signed written informed consent Histologically confirmed V600E BRAF mutant
    melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2

    Normal organ function as defined by the following:

    - Absolute neutrophil count >1.2 109/L

    - Hemoglobin >9 g/dL, platelets >75 109/L

    - PT/INR and PTT 1.5 x ULN (Note: subjects receiving anticoagulation treatment may
    enroll with INR established within the therapeutic range prior to D1 of treatment)

    - Albumin >2.5 g/dL

    - Total bilirubin <1.5 x ULN

    - AST and ALT < 2.5 ULN

    - CrCl 50mL/min per Cockcroft-Gault Willing to undergo biopsy for research purposes
    only Females of child-bearing potential: willing to use two forms of effective
    contraception, and to continue use for 16 weeks post last dose of study medication.
    Effective contraception is defined as any medically recommended method (or
    combination of methods) as per standard of care, including abstinence. Females of
    non-childbearing potential are those who are postmenopausal greater than 1 year or
    who have had a bilateral tubal ligation or hysterectomy. Men with a female partner of
    childbearing potential must have either had a prior vasectomy or agree to use
    effective contraception as described from D1 of treatment, throughout the treatment
    period, and for 16 weeks after the last dose of study treatment.

    In women of child-bearing potential, negative serum pregnancy test within 48 hours prior
    to day 1 of study treatment Measurable disease as defined by RECIST v1.1 Able to swallow
    and retain oral medication Left ventricular ejection fraction by ECHO institutional
    lower limit of normal

    Exclusion Criteria:

    Any subject meeting any of the following exclusion criteria at baseline will be ineligible
    for study participation:

    Patients with a history of a prior malignancy are excluded unless they have been disease
    free for 3 or more years or unless they have a completely resected non-melanoma skin
    cancer, and/or subjects with indolent second malignancies.

    Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib
    (GSK2118436), vemurafenib, and LX281/BMS-908662) or a MEK inhibitor (including but not
    limited to trametinib (GSK1120212), AZD6244, and RDEA119); NOTE: There is no limit to the
    number of other prior therapies, and patients may be previously untreated.

    Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
    chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).

    Active GI or intracranial hemorrhage

    History or evidence of cardiovascular risk including any of the following:

    - QTc 480 msec;

    - History or evidence of current clinically significant uncontrolled arrhythmias;

    o Exception: Subjects with controlled atrial fibrillation for >30 days prior to D1
    of study treatment are eligible.

    - History of acute coronary syndromes (including myocardial infarction and unstable
    angina), coronary angioplasty, or stenting within 6 months prior to study entry;

    - Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg
    and/or diastolic >90 mm Hg which cannot be controlled by anti-hypertensive therapy;

    - Patients with intra-cardiac defibrillators or permanent pacemakers;

    - Known cardiac metastases;

    - 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.

    History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency

    Brain metastases 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

    - Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in
    lesion size) for 12 weeks prior to D1 of study treatment (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 D1 of study
    treatment, AND

    - No enzyme inducing anticonvulsants for 4 weeks prior to D1 of study treatment

    NOTE: if study subject has history of brain metastasis, but currently has no evidence of
    disease in brain (NED), confirmation by two consecutive scans separated by 6 weeks prior
    to D1 of treatment is required.

    Pulmonary embolism on active therapy History of interstitial lung disease or pneumonitis
    Known HIV, Hepatitis B or C infection (with the exception of chronic or cleared HBV and
    HCV infection which will be allowed) Currently active GI disease, or prior surgery that
    may affect ability to absorb oral medications

    History or current evidence/risk of retinal vein occlusion (RVO) or central serous
    retinopathy (CSR):

    - Predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular
    hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus,
    or history of hyperviscosity or hypercoagulability syndromes)

    - Visible retinal pathology as assessed by ophthalmic exam that is considered a risk
    factor for RVO or CSR such as:

    - Evidence of new optic disc cupping

    - Evidence of new visual field defects

    - Intraocular pressure > 21 mm Hg Currently receiving cancer therapy
    (chemotherapy, radiotherapy, immunotherapy, or biologic therapy) NOTE:
    palliative radiation therapy is permitted for non-target lesions that are either
    new or present at baseline provided total dose does not exceed 30 Gy Use of
    other prohibited medications within 5 half-lives or 14 days prior to the first
    dose of study drugs or requires any of these medications while receiving
    medication on this study Pregnant or lactating female

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Kinase Expression

    Secondary Outcome Measures

    BRAF and MEK inhibition associated with new functional mutations in the approximately 150 oncogenes

    Kinome signature predictive of resistance

    Overall Response Rate (ORR)

    Duration of Overall Response Rate (ORR)

    Progression Free Survival (PFS)

    Rate of Overall Survival (OS)

    Trial Keywords

    Melanoma

    Stage III

    Stage IV

    Unresectable

    BRAF Mutant

    Dabrafenib

    Trametinib

    Kinome

    Resistance

    Sequencing

    Mutations

    Kinases

    Mechanism