Clinical Trials /

Ipilimumab With or Without Dabrafenib, Trametinib, and/or Nivolumab in Treating Patients With Melanoma That Is Metastatic or Cannot Be Removed by Surgery

NCT01940809

Description:

This randomized phase I trial studies the side effects and best way to give ipilimumab with or without dabrafenib, trametinib and/or nivolumab in treating patients with melanoma that has spread to other parts of the body (metastatic) or cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may interfere with the ability of cancer cells to grow and spread. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether ipilimumab works better with or without dabrafenib, trametinib, and/or nivolumab in treating melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Ipilimumab</span> With or Without <span class="go-doc-concept go-doc-intervention">Dabrafenib</span>, and/or <span class="go-doc-concept go-doc-intervention">Trametinib</span> in Treating Patients With <span class="go-doc-concept go-doc-disease">Melanoma</span> That Is Metastatic or Cannot Be Removed by Surgery

Title

  • Brief Title: Ipilimumab With or Without Dabrafenib, and/or Trametinib in Treating Patients With Melanoma That Is Metastatic or Cannot Be Removed by Surgery
  • Official Title: A Sequential Safety and Biomarker Study of BRAF-MEK Inhibition on the Immune Response in the Context of CTLA-4 Blockade for BRAF Mutant Melanoma
  • Clinical Trial IDs

    NCT ID: NCT01940809

    NCT Alias ID: NCT01938703

    ORG ID: NCI-2013-01703

    NCI ID: NCI-2013-01703

    Trial Conditions

    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, DABRAFENIB, GSK-2118436A, GSK2118436, Tafinlar Arm A (ipilimumab, dabrafenib, trametinib), Arm C (ipilimumab, dabrafenib)
    Trametinib GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist, TRAMETINIB Arm A (ipilimumab, dabrafenib, trametinib), Arm B (ipilimumab, trametinib)

    Trial Purpose

    This randomized phase I trial studies the side effects and best way to give ipilimumab with
    or without dabrafenib and/or trametinib in treating patients with melanoma that has spread
    to other parts of the body (metastatic) or cannot be removed by surgery. Monoclonal
    antibodies, such as ipilimumab, may interfere with the ability of cancer cells to grow and
    spread. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the
    enzymes needed for cell growth. It is not yet known whether ipilimumab works better with or
    without dabrafenib and/or trametinib in treating melanoma.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To evaluate the safety and tolerability of ipilimumab following lead-in of v-raf murine
    sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK)
    inhibitors, either alone or in combination, in patients with BRAFV600 mutant melanoma.

    SECONDARY OBJECTIVES:

    I. To determine the response rate to ipilimumab after BRAF and MEK inhibitors, either alone
    or in combination, compared to no prior kinase inhibitor treatment.

    II. To determine the safety and tolerability of dabrafenib and trametinib combination in the
    setting of prior ipilimumab alone or ipilimumab proceeded by BRAF and MEK inhibitors, either
    alone or in combination.

    III. To determine the response rate to dabrafenib and trametinib in the setting of prior
    ipilimumab alone or ipilimumab proceeded by BRAF and MEK inhibitors, either alone or in
    combination.

    IV. To obtain peripheral blood and tumor tissue for biomarker analysis. V. To describe the
    immune impact of kinase inhibitor therapy on the immune response associated with ipilimumab
    treatment.

    VI. To observe and record anti-tumor activity.

    OUTLINE: Patients are randomized to 1 of 4 treatment arms.

    ARM A: Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once
    daily (QD) for 25 days. Patients then receive ipilimumab intravenously (IV) over 90 minutes.
    Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease
    progression or unacceptable toxicity.

    ARM B: Patients receive trametinib PO QD for 25 days. Patients then receive ipilimumab IV
    over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the
    absence of disease progression or unacceptable toxicity.

    ARM C: Patients receive dabrafenib PO BID for 25 days. Patients then receive ipilimumab IV
    over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the
    absence of disease progression or unacceptable toxicity.

    ARM D: Patients receive ipilimumab IV over 90 minutes. Treatment repeats every 3 weeks for 4
    courses in the absence of disease progression or unacceptable toxicity.

    After 12 weeks of treatment with ipilimumab, all patients may continue to receive dabrafenib
    PO BID and trametinib PO QD in the absence of disease progression.

    After completion of study treatment, patients are followed up for 4 weeks.

    Trial Arms

    Name Type Description Interventions
    Arm A (ipilimumab, dabrafenib, trametinib) Experimental Patients receive dabrafenib PO BID and trametinib PO QD for 25 days. Patients then receive ipilimumab IV over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Dabrafenib, Trametinib
    Arm B (ipilimumab, trametinib) Experimental Patients receive trametinib PO QD for 25 days. Patients then receive ipilimumab IV over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Trametinib
    Arm C (ipilimumab, dabrafenib) Experimental Patients receive dabrafenib PO BID for 25 days. Patients then receive ipilimumab IV over 90 minutes. Treatment with ipilimumab repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Dabrafenib
    Arm D (ipilimumab) Experimental Patients receive ipilimumab IV over 90 minutes Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

    Inclusion Criteria:

    - Study participants must have histologically or cytologically confirmed unresectable
    or metastatic malignant melanoma

    - Study participants 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

    - Study participants must have completed any prior treatment at least 3 weeks prior to
    treatment on this protocol; prior treatments may have included chemotherapy however
    may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2,
    ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy;
    prior treatment with interferon in the adjuvant setting is allowed, though prior
    treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is
    allowed though must have included no more than 3000 centigray (cGy) to fields
    including substantial marrow

    - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

    - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L

    - Hemoglobin >= 9 g/dL

    - Platelets >= 100 x 10^9/L

    - Albumin >= 2.5 g/dL

    - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects
    with known Gilbert's syndrome

    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
    institutional ULN

    - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault
    formula) >= 50 mL/min

    - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
    time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment
    may be allowed to participate with INR established within the therapeutic range prior
    to randomization

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

    - 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

    - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug
    Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments
    (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA
    approved method, information about the assay must be provided

    - 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

    - Women of child-bearing potential must agree to use adequate contraception (barrier
    method of birth control, or abstinence; hormonal contraception is not allowed) for
    the duration of study participation, and for at least 2 weeks after treatment with
    dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a
    woman become pregnant or suspect she is pregnant while she is participating in this
    study, she should inform her treating physician immediately

    - All prior treatment-related toxicities must be Common Terminology Criteria for
    Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of
    randomization

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

    Exclusion Criteria:

    - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive
    radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the
    last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks
    preceding the first dose of study treatment

    - Use of other investigational drugs within 28 days (or five half-lives, whichever is
    shorter; with a minimum of 14 days from the last dose) preceding the first dose of
    study treatment and during the study

    - Study participants with a history of prior treatment with BRAF or MEK inhibitors or
    immunotherapy (such as ipilimumab, anti-PD 1 antibody, cluster of differentiation
    [CD]137 agonist or other immune activating therapy, excluding vaccines, interferon or
    interleukin [IL]-2)

    - Autoimmune disease: study participants with a history of inflammatory bowel disease,
    including ulcerative colitis and Crohn's disease, are excluded from this study, as
    are patients with a history of symptomatic disease (e.g., rheumatoid arthritis,
    systemic progressive sclerosis [scleroderma], systemic lupus erythematosus,
    autoimmune vasculitis [e.g., Wegener's granulomatosis]); central nervous system (CNS)
    or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome
    and myasthenia gravis, multiple sclerosis)

    - Study participants with known immune impairment who may be unable to respond to
    anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody

    - Study participants with brain metastases are excluded unless these have been
    definitively treated and are radiographically stable for at least 1 month; the study
    participant must also demonstrate a stable physical exam and must have discontinued
    systemic steroids for treatment of edema related to brain metastases or treatment for
    over 24 hours

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

    - 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

    - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
    therapy are ineligible

    - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the
    exception of cleared HBV and HCV infection, which will be allowed)

    - Patients with history of rat sarcoma (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

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

    - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec

    - History of acute coronary syndromes (including myocardial infarction or unstable
    angina), coronary angioplasty, or stenting within the past 24 weeks prior to
    randomization

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

    - Intra-cardiac defibrillators

    - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (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 or evidence of current clinically significant uncontrolled cardiac
    arrhythmias; clarification: subjects with atrial fibrillation controlled for >
    30 days prior to dosing are eligible

    - 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

    - Any condition which in the investigator's opinion makes the subject unsuitable for
    study participation

    - History of retinal vein occlusion (RVO)

    - History of interstitial lung disease or pneumonitis

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Proportion of patients with grade 3 or higher immune-related adverse events (irAEs), graded according to the National Cancer Institute (NCI) CTCAE v4.0

    Secondary Outcome Measures

    Disease-control rate

    Proportion of patients receiving dabrafenib and trametinib with grade 3 or higher irAEs after disease progression on ipilimumab, according to the NCI CTCAE v4.0

    Response rate for the total treatment period according to Response Evaluation Criteria in Solid Tumors v1.1

    Trial Keywords