Clinical Trials /

Akt Inhibitor GSK2141795, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer

NCT01902173

Description:

This phase I/II trial studies the side effects and the best dose of Akt inhibitor GSK2141795 when given together with dabrafenib and trametinib and to see how well they work in treating patients with stage IIIC-IV cancer. Akt inhibitor GSK2141795, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving Akt inhibitor GSK2141795 with dabrafenib and trametinib may be a better treatment for cancer.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Suspended

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">GSK2141795</span>, <span class="go-doc-concept go-doc-intervention">Dabrafenib</span>, and <span class="go-doc-concept go-doc-intervention">Trametinib</span> in Treating Patients With Stage IIIC-IV Cancer

Title

  • Brief Title: GSK2141795, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer
  • Official Title: Phase I/II Study of the Safety and Efficacy of the AKT Inhibitor GSK2141795 in Combination With Dabrafenib and Trametinib in Patients With BRAF Mutant Cancer
  • Clinical Trial IDs

    NCT ID: NCT01902173

    ORG ID: NCI-2013-01320

    NCI ID: NCI-2013-01320

    Trial Conditions

    Adult Solid Neoplasm

    Recurrent Colon Carcinoma

    Recurrent Melanoma

    Recurrent Ovarian Carcinoma

    Recurrent Ovarian Germ Cell Tumor

    Stage IIIC Colon Cancer

    Stage IIIC Ovarian Cancer

    Stage IIIC Ovarian Germ Cell Tumor

    Stage IIIC Skin Melanoma

    Stage IV Skin Melanoma

    Trial Interventions

    Drug Synonyms Arms
    Akt Inhibitor GSK2141795 GSK2141795, Oral Akt Inhibitor GSK2141795 Treatment (Akt inhibitor GSK2141795, dabrafenib, trametinib)
    Dabrafenib BRAF Inhibitor GSK2118436, DABRAFENIB, GSK-2118436A, GSK2118436, Tafinlar Treatment (Akt inhibitor GSK2141795, dabrafenib, trametinib)
    Trametinib GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist, TRAMETINIB Treatment (Akt inhibitor GSK2141795, dabrafenib, trametinib)

    Trial Purpose

    This phase I/II trial studies the side effects and the best dose of Akt inhibitor GSK2141795
    (GSK2141795) when given together with dabrafenib and trametinib and to see how well they
    work in treating patients with stage IIIC-IV cancer. Akt inhibitor GSK2141795, dabrafenib,
    and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for
    cell growth. Giving Akt inhibitor GSK2141795 with dabrafenib and trametinib may be an
    effective treatment for cancer.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To assess the safety of dabrafenib in combination with GSK2141795 and select the optimal
    dose of GSK2141795 for the phase II portion in patients with v-raf murine sarcoma viral
    oncogene homolog B1 (BRAF) mutant cancer. (This trial will not proceed to the Phase II study
    of dabrafenib and GSK2141795, but will move to an evaluation of triple therapy) (Phase I)
    II. To assess the safety of dabrafenib and trametinib and GSK2141795 in combination and
    select the optimal dose of the combination for the Phase II Portion in patients with BRAF
    mutant cancer. (Phase I) III. To evaluate the objective response rate (confirmed and
    unconfirmed, complete and partial responses) in patients with BRAF^V600 mutant metastatic
    melanoma who have previously progressed on BRAF^V600 inhibitor-based therapy (BRAFi), or
    BRAFi + MEK inhibitor-based therapy (MEKi). (Phase II)

    SECONDARY OBJECTIVES:

    I. To estimate overall survival and progression-free survival. II. To assess the toxicity
    profile of the recommended phase II dose. III. To assess response (complete and partial,
    confirmed and unconfirmed) of patients enrolled on each phase I portion).

    TERTIARY OBJECTIVES:

    I. To explore the molecular mechanisms of acquired resistance to BRAF inhibitor therapy
    using available biopsies of lesions that progressed during prior BRAF inhibitor-based
    therapy.

    II. To explore potential drug-drug interactions between dabrafenib and GSK2141795 leading to
    changes in the expected exposure with either agent compared to prior experience. (Phase I)

    OUTLINE: This is a phase I, dose-escalation study of Akt inhibitor GSK2141795 followed by a
    phase II study. Dose escalation of dabrafenib, trametinib, and Akt inhibitor GSK2141795 will
    be initiated after completion of the dabrafenib + GSK2141795 phase I dose escalation.

    Dabrafenib and Akt inhibitor GSK2141795: Patients receive dabrafenib orally (PO) twice daily
    (BID) and Akt inhibitor GSK2141795 PO once daily (QD) on days 1-28. Courses repeat every 28
    days in the absence of disease progression or unacceptable toxicity.

    Dabrafenib, trametinib, and Akt inhibitor GSK2141795: Patients receive dabrafenib PO BID,
    trametinib PO QD, and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28
    days in the absence of disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up every 3 months for 1 year and
    then every 6 months for 2 years.

    Trial Arms

    Name Type Description Interventions
    Treatment (Akt inhibitor GSK2141795, dabrafenib, trametinib) Experimental Dabrafenib and Akt inhibitor GSK2141795: Patients receive dabrafenib PO BID and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Dabrafenib, trametinib, and Akt inhibitor GSK2141795: Patients receive dabrafenib PO BID, trametinib PO QD, and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity Akt Inhibitor GSK2141795, Dabrafenib, Trametinib

    Eligibility Criteria

    Inclusion Criteria:

    - PHASE I PORTION ELIGIBILITY CRITERIA

    - Patients must have BRAF^V600 mutant metastatic cancer irrespective of the histology
    or prior therapy; BRAF^V600 mutant status must be documented by a Clinical Laboratory
    Improvement Amendments (CLIA)-certified laboratory; use of an Food and Drug
    Administration (FDA)-approved test is preferred although other BRAF tests at a
    CLIA-certified laboratory may also be accepted

    - Patients must have locally advanced unresectable stage IIIC or metastatic stage IV
    cancer with either progression to prior therapy or a newly diagnosed cancer that does
    not have an available treatment with curative intent

    - Patients must have a complete physical examination and medical history within 28 days
    prior to registration

    - Patients must have measurable or non-measurable disease; all measurable lesions must
    be assessed (by physical examination, computed tomography [CT], or magnetic resonance
    imaging [MRI] scan) within 28 days prior to registration; tests to assess
    non-measurable disease must be performed within 42 days prior to registration; all
    disease must be assessed and documented on the baseline tumor assessment form
    (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)

    - All patients must undergo a CT or MRI of the brain within 42 days prior to
    registration; patients with asymptomatic brain metastases or previously treated brain
    metastases that are stable (i.e. not requiring corticosteroids) at the time of
    registration will be eligible

    - Patients may have received prior systemic therapy (chemotherapy, immunotherapy,
    biologic therapy, or combination regimens); all adverse events associated with prior
    treatment must have resolved to =< grade 1 prior to registration

    - Patients progressing on a prior BRAF inhibitor-based therapy will be eligible, as are
    patients nave to BRAF inhibitor therapy; resistance to BRAF inhibitor-based therapy
    will be defined as progressive disease by RECIST 1.1 criteria while receiving therapy
    with a BRAF inhibitor (vemurafenib or dabrafenib, alone or in combination with a
    mitogen-activated protein kinase [MEK] inhibitor); this may be innate resistance
    (patients who never achieved a tumor response while on BRAF inhibitor therapy) or
    acquired resistance (progression after having a tumor response to BRAF inhibitor
    therapy); there will not be a period of break between progression on the prior BRAF
    inhibitor-based therapy and the start of dabrafenib and GSK2141795

    - Patients may have received prior surgery (for both the primary and stage IV disease);
    all adverse events associated with prior surgery must have resolved to =< grade 1
    prior to registration

    - Patients may have received prior radiation therapy; all adverse events associated
    with prior radiation therapy must have resolved to =< grade 1 prior to registration

    - Patients must be willing to submit blood for pharmacokinetics; sites must order S1221
    pharmacokinetic (PK) kit immediately after registration; the Southwest Oncology Group
    (SWOG) patient identification (ID) number must be provided on the S1221 PK Kit
    request form

    - Patients must have available and be willing to submit baseline tissue taken at the
    time of disease progression to prior BRAF inhibitor-based therapy (either fresh
    frozen [preferred], or paraffin-embedded tumor blocks) OR must have a site of disease
    that can be biopsied within this study for translational medicine studies; tissue may
    be from an archival biopsy or a new biopsy after the patient has been registered to
    the protocol; since patients are referred to this protocol after progression on prior
    BRAF inhibitor-based therapy, the biopsy taken at the time of progression will be
    used as the baseline biopsy for this study; patients must be willing to submit plasma
    and whole blood for translational medicine studies

    - Patients must have Zubrod performance status =< 1

    - Absolute neutrophil count (ANC) >= 1,200/ul

    - Platelets >= 100,000/ul

    - Hemoglobin >= 9 g/dL

    - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x ULN
    for patients with Gilbert's syndrome)

    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or
    < 5 x IULN for patients with known liver metastases)

    - Serum albumin >= 2.5 g/dL

    - Serum creatinine =< 1.5 mg/dL OR measured or calculated creatinine clearance >= 50
    mL/min

    - Patient must have a left ventricular ejection fraction >= institutional lower limit
    of normal (LLN) by echocardiogram (ECHO) or multigated acquisition (MUGA) within 28
    days prior to registration

    - Patients must not have a corrected QT (QTc) interval >= 480 msecs within 28 days
    prior to registration

    - Patients must not have a history of acute coronary syndromes (including unstable
    angina), myocardial infarction within 6 months, coronary angioplasty, or stenting
    within the past 24 weeks; class II, III, or IV heart failure as defined by the New
    York Heart Association (NYHA) functional classification system; or history of known
    cardiac arrhythmias (such as atrial fibrillation) unless it has been stably
    controlled for > 30 days prior to registration; 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 are not eligible

    - Patients with melanoma must have a serum lactate dehydrogenase (LDH) test performed
    within 28 days prior to registration

    - Patients with human immunodeficiency virus (HIV) are eligible if they are not on
    antiviral agents and have adequate cluster of differentiation (CD)4 counts (>= 500
    mm^3)

    - Patients receiving anticoagulation treatment are allowed to participate with
    international normalized ratio (INR) established within the therapeutic range

    - At the time of registration, patients must not be receiving any medications or
    substances that are strong inhibitors or inducers of cytochrome P450, family 3,
    subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8
    (CYP2C8); patients must not be planning to use herbal remedies (e.g., St. John's
    wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer
    resistance protein 1 (Bcrp1)

    - Women of childbearing potential must have a negative pregnancy test within 14 days of
    registration

    - Patients must not be pregnant or nursing; women/men of reproductive potential must
    have agreed to use an effective contraceptive method; a woman is considered to be of
    "reproductive potential" if she has had menses at any time in the preceding 12
    consecutive months; in addition to routine contraceptive methods, "effective
    contraception" also includes heterosexual celibacy and surgery intended to prevent
    pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
    bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
    previously celibate patient chooses to become heterosexually active during the time
    period for use of contraceptive measures outlined in the protocol, he/she is
    responsible for beginning contraceptive measures

    - Patient must not have uncontrolled intercurrent illness including, but not limited
    to, ongoing or active infection, previously diagnosed type 1 diabetes mellitus/type 2
    diabetes, psychiatric illness/social situations, symptomatic congestive heart
    failure, unstable angina pectoris, cardiac arrhythmia, that would limit compliance
    with study requirements; patients must not have any evidence of mucosal or internal
    bleeding; patients must not have received any major surgery within four weeks prior
    to registration

    - Patients must not have an active hepatitis B virus (HBV) or hepatitis C virus (HCV)
    infection

    - Patients must not have a history of allergic reactions attributed to compounds of
    similar chemical or biologic composition to dabrafenib or other agents used in this
    study including dimethyl sulfoxide (DMSO)

    - Patients must be able to 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; patients who have
    feeding tubes can enroll in the study provided that the capsules do not need to be
    modified

    - Patients or their legally authorized representative must be informed of the
    investigational nature of this study and must sign and give written informed consent
    in accordance with institutional and federal guidelines

    - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
    treating institution's identity is provided in order to ensure that the current
    (within 365 days) date of institutional review board approval for this study has been
    entered in the system

    - Patients must have a serum albumin >= 2.5 g/dL within 28 days prior to registration

    - Patients with known history or current evidence of retinal vein occlusion (RVO) are
    not eligible:

    - History of RVO, or predisposing factors to RVO (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 such as:

    - Evidence of new optic disc cupping

    - Evidence of new visual field defects

    - Intraocular pressure > 21 mmHg

    - NOTE: Ophthalmic exam is required for all patients; exam must be obtained
    within 28 days prior to registration

    - Patients must not have uncontrolled hypertension (defined as systolic blood pressure
    > 140 mm Hg and/or diastolic blood pressure > 90 mm Hg which cannot be controlled by
    anti-hypertensive therapy)

    - PHASE II PORTION ELIGIBILITY CRITERIA

    - Patients must have histologically confirmed melanoma with BRAF^V600 mutation;
    patients must have stage IIIC or stage IV disease

    - Patients must have received prior BRAF inhibitor therapy (e.g. dabrafenib,
    vemurafenib) within 56 days prior to registration; prior trametinib therapy is
    permitted; patients are not required to interrupt BRAF or MEK inhibitor therapy prior
    to the initiation of three agent combination therapy on study

    - Patients must have measurable disease; all measurable lesions must be assessed (by
    physical examination, CT, or MRI scan) within 28 days prior to registration; tests to
    assess non-measurable disease must be performed within 42 days prior to registration;
    patients whose only measurable disease is within a previous radiation therapy port
    must demonstrate clearly progressive disease (in the opinion of the treating
    investigator) prior to registration; all disease must be assessed and documented on
    the baseline tumor assessment form (RECIST 1.1)

    - Patients must have Zubrod performance status =< 2

    - No other prior malignancy is allowed except for the following: adequately treated
    basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
    stage I or II cancer from which the patient is currently in complete remission, or
    any other cancer from which the patient has been disease free for five years;
    patients with history of RAS mutation-positive tumors are not eligible regardless of
    interval from the current study; Note: Prospective RAS testing is not required;
    however, if the results of previous RAS testing are known, they must be used in
    assessing eligibility

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum-tolerated dose (MTD) of Akt inhibitor GSK2141795, determined according to incidence of dose-limiting toxicity, graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)

    Objective response rate (confirmed and unconfirmed, complete and partial responses) as assessed by RECIST version 1.1 (Phase II)

    Secondary Outcome Measures

    Overall survival (Phase II)

    Progression-free survival as assessed by RECIST version 1.1 (Phase II)

    Toxicity rate graded by the NCI CTCAE version 4.0 (Phase II)

    Trial Keywords