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A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Anti-Cancer Activity of Trametinib in Combination With Palbociclib in Subjects With Solid Tumors

NCT02065063

Description:

This is a dose-escalation, Phase I/II, open-label, three-part study. Part 1 is designed to determine the recommended dose and schedule for the orally administered MEK inhibitor trametinib, given together with the CDK4/6 inhibitor palbociclib in subjects with solid tumors. Multiple dose levels of each inhibitor will be tested to determine the recommended dose and schedule. Part 2 will evaluate the effect of the combination on tumor biomarkers safety, and anti-cancer activity in subjects with cutaneous melanoma that do not have a change at BRAFV600. Approximately 100-200 subjects will be enrolled. All subjects will receive trametinib and/or palbociclib until disease progression, death, consent withdrawal or unacceptable adverse event (AE). Data was only collected and analyzed for the Phase I component of the study, the Phase II component of the study was terminated without data collection

Related Conditions:
  • Malignant Solid Tumor
  • Melanoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Anti-<span class="go-doc-concept go-doc-disease">Cancer</span> Activity of <span class="go-doc-concept go-doc-intervention">Trametinib</span> in Combination With <span class="go-doc-concept go-doc-intervention">Palbociclib</span> in Subjects With Solid Tumors

Title

  • Brief Title: A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Anti-Cancer Activity of Trametinib in Combination With Palbociclib in Subjects With Solid Tumors
  • Official Title: A Dose-Escalation, Phase I/II, Open-Label, Three-Part Study of the MEK Inhibitor, Trametinib, Combined With the CDK4/6 Inhibitor, Palbociclib, To Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Anti-Cancer Activity in Subjects With Solid Tumors
  • Clinical Trial IDs

    NCT ID: NCT02065063

    ORG ID: 200344

    Trial Conditions

    Cancer

    Trial Interventions

    Drug Synonyms Arms
    Trametinib Part 1, Part 2, Part 3
    Palbociclib Part 1, Part 2, Part 3

    Trial Purpose

    This is a dose-escalation, Phase I/II, open-label, three-part study. Part 1 is designed to
    determine the recommended dose and schedule for the orally administered MEK inhibitor
    trametinib, given together with the CDK4/6 inhibitorpalbociclib in subjects with solid
    tumors. Multiple dose levels of each inhibitor will be tested to determine the recommended
    dose and schedule. Part 2 will evaluate the effect of the combination on tumor biomarkers
    safety, and anti-cancer activity in subjects with cutaneous melanoma that do not have a
    change at BRAFV600. Approximately 100-200 subjects will be enrolled. All subjects will
    receive trametinib and/or palbociclib until disease progression, death, consent withdrawal
    or unacceptable adverse event (AE).

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Part 1 Experimental Part 1 is a dose finding phase in which subjects will be initially administered 75 milligram (mg) of palbociclib (21 days on/7 days off) and 1.5 mg of trametinib (once daily continuous dosing) in each 28-day cycle. Dose escalations will continue based on predefined parameters until the RCR is identified. The RCR will not exceed the maximum tolerated dose (MTD). Trametinib, Palbociclib
    Part 2 Experimental Once the MTD and schedule have been determined, two expansion cohorts of up to 20 subjects each will be enrolled. The cohorts will enroll subjects with BRAF-WT (wild type) cutaneous melanoma that are either NRAS-WT or NRAS-MUT (mutated). Subjects will be dosed at or below the RCR to determine the inhibition of selected tumor biomarkers at each dose level. Trametinib, Palbociclib
    Part 3 Experimental Part 3 will be a randomized Phase II study in which subjects will be administered the RCR as previously identified. Part 3 will be initiated only if an RCR is identified, and sufficient anticancer activity is observed in Parts 1 and 2. Trametinib, Palbociclib

    Eligibility Criteria

    Inclusion Criteria:

    - Inclusion Criteria for Part 1 and Part 2

    - Subjects >=18 years old.

    - Signed written informed consent.

    - All prior anti-cancer treatment-related toxicities (except alopecia and laboratory
    values as listed in the protocol) must be <=grade 1 according to the Common
    Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of
    randomization.

    - Able to swallow and retain oral medication and must not have any clinically
    significant gastrointestinal abnormalities that may alter absorption such as
    malabsorption syndrome or major resection of the stomach or bowels.

    - Women of childbearing potential must have a negative serum pregnancy test within 7
    days of first dose of study treatment and agree to use effective contraception as
    defined in the protocol.

    - Men with a female partner of childbearing potential must have either had a prior
    vasectomy or agree to use effective contraception as described in the protocol.

    - An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

    - Adequate baseline organ function as defined in the protocol.

    - Other Inclusion criteria for Part 1

    - Histologically or cytologically confirmed diagnosis of solid tumor malignancy that is
    not responsive to standard therapies or for which there is no approved or curative
    therapy.

    - Subjects with cutaneous melanoma must provide either a fresh or archived tumor sample
    for genetic analysis including determination of or confirmation of BRAF and NRAS
    genetic status based on local laboratory results. To ensure prompt delivery of tumor
    samples, tissue shipment tracking information must be provided before administration
    of study treatment can be initiated.

    - Other Inclusion criteria for Part 2

    - Measurable disease (i.e., present with at least one measurable lesion per RECIST,
    version 1.1).

    - Histologically or cytologically confirmed diagnosis of advanced or metastatic
    cutaneous melanoma that is determined to be BRAFV600 wild type and either NRAS wild
    type or NRAS mutation type. Note: Subjects with a melanoma of unknown primary origin
    may be allowed to enrol if all other types of melanoma (e.g., uveal, mucosal, or
    acral) can be reasonably ruled out.

    - Must provide either a fresh or archived tumor sample for genetic analysis.

    - Accessible tumor for biopsy and willingness to provide pre-dose tumor biopsies on
    Days 1 and Day 15.

    - Inclusion Criteria for Part 3

    - The inclusion criteria for Part 3 will be based on emerging data from Parts 1 and 2
    and will be specified in an amendment.

    Exclusion Criteria:

    - Prior treatment with a MEK inhibitor or a CDK4/6 inhibitor.

    - BRAFV600 mutation positive.

    - For Part 1, subjects may have had any number of prior systemic anti-cancer
    treatments, but may not have received more than 2 schedules of myeloablative
    chemotherapy. For Parts 2 and 3, more than two prior systemic anti-cancer treatment
    (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational
    treatment) for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma are not
    permitted. Prior systemic treatment in the adjuvant setting is allowed. (Note:
    Ipilimumab treatment must end at least 8 weeks prior to Study Day 1 (Parts 1 and 2)
    or randomization (Part 3.)

    - Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
    biologic therapy, or immunotherapy within 21 days prior to Study Day 1 (Parts 1 and
    2) or randomization (Part 3), or daily or weekly chemotherapy without the potential
    for delayed toxicity within 14 days prior to Study Day 1 (Parts 1 and 2) or
    randomization (Part 3).

    - Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days),
    whichever is shorter, prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3).

    - Current use of a prohibited medication as described in the protocol.

    - History of another malignancy (Part 3 only). Exception: Subjects who have been
    disease-free for 3 years, or subjects with a history of completely resected,
    non-melanoma skin cancer, or subjects with indolent second malignancies are eligible.
    T1a melanoma and melanoma in situ are permitted. Consult GlaxoSmithKline (GSK)
    Medical Monitor if unsure whether second malignancies meet requirements specified
    above.

    - Any serious or unstable pre-existing medical conditions (aside from malignancy
    exceptions specified above), psychiatric disorders, or other conditions that could
    interfere with the subject's safety, obtaining informed consent, or compliance with
    study procedures.

    - Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
    Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV
    infection will be permitted).

    - History of leptomeningeal disease or spinal cord compression secondary to metastasis.

    - Brain metastasis, unless previously treated with surgery or stereotactic radiosurgery
    and the disease has been confirmed stable (i.e., no increase in lesion size, and
    stable or decreased doses of corticosteroids) for at least 6 weeks with two
    consecutive scans prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3).
    (Enzyme inducing anticonvulsants are not allowed while subjects are on study
    treatment. Prior whole-brain radiation as adjuvant treatment is allowed.)

    - A history or evidence of cardiovascular risk including any of the following: A QT
    interval corrected for heart rate using the Fridericia's formula (QTcF) >=480
    millisecond (msec); A history or evidence of current clinically significant
    uncontrolled arrhythmias; Exception: Subjects with atrial fibrillation controlled for
    >30 days prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3); History of
    acute coronary syndromes (including myocardial infarction and unstable angina),
    coronary angioplasty, or stenting within 6 months prior to Study Day 1 (Parts 1 and
    2) or randomization (Part 3); A history or evidence of current >=Class II congestive
    heart failure as defined by the New York Heart Association (NYHA) guidelines;
    Treatment refractory hypertension defined as a blood pressure of systolic>140
    millimeters of mercury (mmHg) and/or diastolic >90 mmHg which cannot be controlled by
    anti-hypertensive therapy; Patients with intra-cardiac defibrillators or permanent
    pacemakers; Known cardiac metastases.

    - A history or current evidence/risk of Retinal Vein Occlusion (RVO) or Central Serous
    Retinopathy (CSR) including: History of RVO or CSR, or predisposing factors to RVO or
    CSR (e.g. uncontrolled glaucoma or ocular hypertention, uncontrolled systemic disease
    such as hypertension, diabetes mellitus, or 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; Intraocular pressure >21
    mmHg as measured by tonography.

    - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
    chemically related to the study treatments, their excipients, and/or dimethyl
    sulfoxide (DMSO).

    - History of interstitial lung disease or pneumonitis.

    - Females who are nursing.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Part 1: Change from baseline in vital signs

    Part 1: Change from baseline in physical examination findings

    Part 1: Change from baseline in 12-lead electrocardiograms (ECG) assessment

    Part 1: Change from baseline in echocardiogram (ECHO) or Multi Gated Acquisition (MUGA) scans assessment

    Part 1: Change from baseline in chemistry and hematology laboratory values

    Part 1: Number of subjects with adverse events (AEs)

    Part 1: Composite of pharmacokinetic (PK) parameters following trametinib and palbociclib administration

    Part 1: Number of subjects with anti-cancer activity

    Part 2: Change from baseline in tumor biomarkers

    Secondary Outcome Measures

    Part 1: GSK1120212 and PD-0332991 PK parameters following repeat-dose administration of trametinib and palbociclib

    Part 1 and Part 2: Number of subjects with response rate

    Part 1 and Part 2 : Number of subjects with Duration of response (DOR)

    Part 1 and Part 2: Number of subjects with Progression-free survival (PFS)

    Part 2 : Change from baseline in vital signs

    Part 2: Change from baseline in physical examination findings

    Part 2: Change from baseline in 12-lead electrocardiograms (ECG) assessment

    Part 2: Change from baseline in echocardiogram (ECHO) or Multi Gated Acquisition (MUGA) scans assessment

    Part 2 : Change from baseline in chemistry and hematology laboratory values

    Part 2 : Number of subjects with adverse events (AEs)

    Part 2: Composite of pharmacokinetic (PK) parameters following trametinib and palbociclib administration

    Trial Keywords

    BRAFV600 wild type

    trametinib

    NRAS mutant

    MEK inhibitor

    GSK1120212

    NRAS wild type

    PD-0332991

    cutaneous melanoma

    CDK4/6 inhibitor

    palbociclib