Clinical Trials /

Onalespib, Dabrafenib, and Trametinib in Treating Patients With BRAF-Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

NCT02097225

Description:

This phase I trial studies the side effects and best dose of onalespib when given together with dabrafenib and trametinib in treating patients with BRAF-mutant melanoma or solid tumors that have spread to another place in the body (metastatic) or cannot be removed by surgery. Onalespib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Hsp90 Inhibitor AT13387, Dabrafenib, and <span class="go-doc-concept go-doc-intervention">Trametinib</span> in Treating Patients With Recurrent <span class="go-doc-concept go-doc-disease">Melanoma</span> or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

Title

  • Brief Title: Hsp90 Inhibitor AT13387, Dabrafenib, and Trametinib in Treating Patients With Recurrent Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
  • Official Title: Phase I Study of AT13387 in Combination With Dabrafenib and Trametinib in With BRAF-Mutant Melanoma and Other Solid Tumors
  • Clinical Trial IDs

    NCT ID: NCT02097225

    ORG ID: NCI-2014-00615

    NCI ID: NCI-2014-00615

    Trial Conditions

    Recurrent Melanoma

    Solid Neoplasm

    Stage IIIA Skin Melanoma

    Stage IIIB Skin Melanoma

    Stage IIIC Skin Melanoma

    Stage IV Skin Melanoma

    Trial Interventions

    Drug Synonyms Arms
    Dabrafenib BRAF Inhibitor GSK2118436, GSK-2118436A, GSK2118436 Treatment (dabrafenib, trametinib, Hsp90 inhibitor AT13387)
    Hsp90 Inhibitor AT13387 AT13387 Treatment (dabrafenib, trametinib, Hsp90 inhibitor AT13387)
    Trametinib GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist Treatment (dabrafenib, trametinib, Hsp90 inhibitor AT13387)

    Trial Purpose

    This phase I trial studies the side effects and best dose of heat shock protein (Hsp)90
    inhibitor AT13387 when given together with dabrafenib and trametinib in treating patients
    with melanoma or solid tumors that have spread to another place in the body (metastatic) or
    cannot be removed by surgery and have come back after previous treatment (recurrent). Hsp90
    inhibitor AT13387, dabrafenib, and trametinib may stop the growth of tumor cells by blocking
    some of the enzymes needed for cell growth.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To determine the maximum tolerated dose (MTD), toxicity, and safety profile of AT13387
    (Hsp90 inhibitor AT13387) given weekly in combination with dabrafenib and trametinib in
    patients with v-raf murine sarcoma viral oncogene homolog B (BRAF)-mutant metastatic or
    unresectable solid tumors.

    SECONDARY OBJECTIVES:

    I. To obtain preliminary estimates of the objective response rate (ORR) and progression-free
    survival (PFS) and document the 6-month PFS and 1-year overall survival (OS) of patients
    with BRAF-mutant metastatic or unresectable melanoma treated with AT13387 given weekly in
    combination with dabrafenib and trametinib.

    II. To describe the pharmacokinetics of treatment with dabrafenib, trametinib, and AT13387.

    OUTLINE: This is a dose-escalation study of Hsp90 inhibitor AT13387.

    Patients receive dabrafenib orally (PO) twice daily (BID), trametinib PO once daily (QD) on
    days 1-28, and Hsp90 inhibitor AT13387 intravenously (IV) over 1 hour on days 1, 8, and 15.
    Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up at 28 days.

    Trial Arms

    Name Type Description Interventions
    Treatment (dabrafenib, trametinib, Hsp90 inhibitor AT13387) Experimental Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and Hsp90 inhibitor AT13387 IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Dabrafenib, Hsp90 Inhibitor AT13387, Trametinib

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have histologically confirmed, BRAF-mutant (V600E/K) solid tumor (dose
    escalation) (molecularly confirmed using Cobas assay or a comparable Food and Drug
    Administration [FDA]-approved assay) that is metastatic or unresectable, have
    received and tolerated prior BRAF or BRAF and mitogen-activated protein kinase (MEK)
    inhibitor (BRAF targeted) therapy at full dose or not previously received BRAF
    targeted therapy, and for which standard curative or palliative measures do not exist
    or are no longer effective; for the dose expansion cohort, patients will be required
    to have BRAF-mutant melanoma as otherwise defined above

    - If test at Clinical Laboratory Improvement Amendments (CLIA)-certified
    laboratory (lab) used a non-FDA approved method, information about the assay
    must be provided; (FDA approved tests for BRAF V600 mutations in melanoma
    include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test)

    - Patients must have measurable disease, defined as at least one lesion that can be
    accurately measured in at least one dimension (longest diameter to be recorded for
    non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional
    techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic
    resonance imaging (MRI), or calipers by clinical exam

    - Prior therapy is allowed; patients may have received any number of prior lines of
    therapy, including treatment with a BRAF and/or MEK inhibitor; all prior anti-cancer
    treatment-related toxicities must be less than or equal to grade 1 according to the
    Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; National
    Cancer Institute [NCI], 2009) at the time of enrollment

    - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

    - Life expectancy of greater than 3 months

    - Leukocytes >= 3,000/mcL

    - Absolute neutrophil count >= 1,200/mcL

    - Hemoglobin >= 9 g/dl (patients may be transfused to this level)

    - Platelets >= 100,000/mcL

    - Total bilirubin < 1.5 x institutional upper limit of normal OR > 1.5 x institutional
    upper limit of normal allowed if direct bilirubin is within normal range

    - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
    [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
    =< 2.5 x institutional upper limit of normal

    - Prothrombin time (PT) < 1.3 x upper limit of normal (ULN)

    - International normalized ratio (INR) < 1.3 x ULN

    - Partial thromboplastin time (PTT) < 1.3 x ULN

    - Serum creatinine =< 1.5 mg/dL OR creatinine clearance >= 50 mL/min/1.73 m^2

    - Potassium > 3 and < 5.5 mEq/L

    - Magnesium > 1.2 and < 2.5 mEq

    - Left ventricular >= institutional lower limit of normal (LLN) by echocardiogram
    (ECHO) ejection fraction

    - Women of child-bearing potential must have a negative serum pregnancy test within 14
    days prior to randomization and agree to use effective contraception (barrier method
    of birth control, or abstinence; hormonal contraception is not allowed) from 14 days
    prior to randomization, throughout the treatment period, and for 4 months after the
    last dose of study treatment; should a woman become pregnant or suspect she is
    pregnant while she is participating in this study, she should inform her treating
    physician immediately

    - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by
    the site; exposure may be decreased due to enzyme induction when on treatment, thus
    warfarin dosing may need to be adjusted based upon PT/INR; consequently, when
    discontinuing dabrafenib, warfarin exposure may be increased and thus close
    monitoring via PT/INR and warfarin dose adjustments must be made as clinically
    appropriate; prophylactic low dose warfarin may be given to maintain central catheter
    patency

    - Ability to understand and the willingness to sign a written informed consent document

    - 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

    Exclusion Criteria:

    - Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
    nitrosoureas or mitomycin C) prior to day 1 of cycle 1, or prior systemic anti-cancer
    therapy (chemotherapy with delayed toxicity, extensive radiation therapy,
    immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks prior to
    day 1 of cycle 1; patients are permitted to be on dabrafenib and trametinib standard
    of care at start of therapy without wash-out period prior to day 1 of cycle 1; dosing
    will change to protocol determined dose levels on day 1 of cycle 1

    - Patients must not have received prior HSP90 inhibitor therapy

    - Patients who are receiving any other investigational agents; patients who have taken
    an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever
    is shorter, prior to randomization

    - Patients with history of activating rat sarcoma (RAS) mutation positive tumors
    regardless of interval from current study

    - Patients must have no clinical evidence of leptomeningeal or brain metastasis causing
    spinal cord compression that are symptomatic or untreated or not stable for >= 4
    weeks (must be documented by imaging) or requiring corticosteroids; subjects on a
    stable dose of corticosteroids > 1 month or who have been off of corticosteroids for
    at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation
    Program (CTEP) medical monitor; subjects must also be off of enzyme-inducing
    anticonvulsants for > 4 weeks

    - History of known immediate or delayed hypersensitivity reactions attributed to
    compounds of similar chemical or biologic composition to AT13387, dabrafenib, or
    trametinib, or excipients or to dimethyl sulfoxide (DMSO)

    - Uncontrolled intercurrent illness including, but not limited to, ongoing or active
    serious infection, symptomatic congestive heart failure, unstable angina pectoris,
    cardiac arrhythmia, uncontrolled diabetes, or psychiatric illness/social situations
    that would limit compliance with study requirements

    - Pregnant women are excluded from this study; breastfeeding should be discontinued
    prior to the mother being treated with the study drugs

    - Patients known to be human immunodeficiency virus (HIV)-positive patients and on
    combination antiretroviral therapy are ineligible

    - History of another malignancy other than the study indication under this trial within
    5 years of study enrollment

    - Exception: patients with history of RAS mutation-positive tumors are not
    eligible regardless of interval from the current study; prospective RAS testing
    is not required; however, if the results of previous RAS testing are known, they
    must be used in assessing eligibility

    - History of interstitial lung disease or pneumonitis

    - History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment
    epithelial detachment (RPED):

    - History of RVO or RPED, or predisposing factors to RVO or RPED (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 RPED such as evidence of new optic disc cupping, evidence
    of new visual field defects, and intraocular pressure > 21 mm mercury (Hg)

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

    - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 460
    msec

    - History or evidence of current clinically significant uncontrolled arrhythmias
    (exception: patients with controlled atrial fibrillation for > 30 days prior to
    randomization are eligible)

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

    - History or evidence of current >= class II congestive heart failure as defined
    by the New York Heart Association (NYHA) functional classification system

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

    - 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

    - Prior placement of an implantable defibrillator

    - History of or identification on screening imaging of intracardiac metastases

    - No known active infection with hepatitis B virus (HBV), or hepatitis C virus (HCV);
    patients with chronic or cleared HBV infection and HCV infection are eligible

    - Current use of a prohibited medication; the following medications or non-drug
    therapies are prohibited:

    - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if
    used as an appetite stimulant is allowed)

    - Concurrent treatment with bisphosphonates is permitted; however, treatment must
    be initiated prior to the first dose of study therapy; prophylactic use of
    bisphosphonates in patients without bone disease is not permitted, except for
    the treatment of osteoporosis

    - The concurrent use of all herbal supplements is prohibited during the study
    (including, but not limited to, St. John's wort, kava, ephedra [ma huang],
    ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)

    - Current use of a prohibited medication; patients 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) are ineligible; current use of, or intended ongoing treatment with:
    herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of
    P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also
    be excluded

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    MTD of Hsp90 inhibitor AT13387 in combination with dabrafenib and trametinib, defined as the highest dose level at which 0 or 1 of six patients has experienced a dose limiting toxicity

    Secondary Outcome Measures

    Disease-free survival

    ORR, defined as the proportion of patients with complete or partial response as their best response to therapy assessed according to Response Evaluation Criteria in Solid Tumors version 1.1

    OS

    PFS

    PFS

    Trial Keywords