Clinical Trials /

Dendritic Cell Vaccines + Dasatinib for Metastatic Melanoma

NCT01876212

Description:

Current therapeutic approaches available for patients with advanced-stage melanoma remain inadequate, and existing approaches including those involving immunotherapy with cytokines and/or targeted strategies have resulted in disappointingly low rates of durable and complete responses. Correcting immune dysfunction in advanced-stage melanoma patients using tyrosine-kinase inhibitor (TKI) such as dasatinib is proposed to relicense the patient's immune system to respond optimally to specific immunization. The integration of antigens expressed by tumor-associated blood vessel cells provides a means to selectively target the genetically-/antigenically-heterogeneous population of tumor cells in the advanced-stage melanoma patient. This is a single-center, prospective randomized Phase 2 trial evaluating the activity, safety and immune effects of dasatinib given in combination with an autologous type-1 polarized Dendritic Cell (αDC1) vaccine. The current trial represents a randomized Phase 2 study to determine the activity and safety of intradermal (id) administration of αDC1s loaded with a mixture of six TBVA-derived peptides at the time of, or immediately after, an initial therapy cycle with the TKI dasatinib. Dasatinib will be administered at the standard dose and schedule recommended by the FDA (70 mg BID). The autologous type-I DC vaccine will be administered either prior to, or concomitant with, the initiation of dasatinib administration. All patients will receive dasatinib at a starting dose of 70 mg twice daily by mouth in the outpatient setting approximately every 12 hours, at the same time each day. The DC vaccine will be administered by a single intradermal injection of approximately 10e7 cells, with all the DCs being administered on days 1 and 15 of every cycle on an outpatient basis in the University of Pittsburgh Clinical and Translational Research Center (UPCI-CTRC). Patients on Arm A will start dasatinib administration on cycle 2, day 1 (week 5), while those patients in Arm B will start dasatinib administration on cycle 1, day 1 (week 1). Men and women at least 18 years of age must be HLA-A2+ and have histologically confirmed melanoma that is metastatic (Stage IV) or unresectable Stage IIIB/C and for which standard curative or palliative measures do not exist or are no longer effective.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Dendritic Cell Vaccines + <span class="go-doc-concept go-doc-intervention">Dasatinib</span> for Metastatic <span class="go-doc-concept go-doc-disease">Melanoma</span>

Title

  • Brief Title: Dendritic Cell Vaccines + Dasatinib for Metastatic Melanoma
  • Official Title: A Randomized Phase 2 Pilot Study of Type I-Polarized Autologous Dendritic Cell Vaccines Incorporating Tumor Blood Vessel Antigen (TBVA)-Derived Peptides in Combination With Dasatinib in Patients With Metastatic Melanoma
  • Clinical Trial IDs

    NCT ID: NCT01876212

    ORG ID: 12-048

    NCI ID: R01CA169118

    Trial Conditions

    Metastatic Melanoma

    Trial Interventions

    Drug Synonyms Arms
    Dasatinib BMS-354825, Sprycel Vaccine + dasatinib, Vaccine + dasatinib

    Trial Purpose

    Current therapeutic approaches available for patients with advanced-stage melanoma remain
    inadequate, and existing approaches including those involving immunotherapy with cytokines
    and/or targeted strategies have resulted in disappointingly low rates of durable and
    complete responses. Correcting immune dysfunction in advanced-stage melanoma patients using
    tyrosine-kinase inhibitor (TKI) such as dasatinib is proposed to relicense the patient's
    immune system to respond optimally to specific immunization. The integration of antigens
    expressed by tumor-associated blood vessel cells provides a means to selectively target the
    genetically-/antigenically-heterogeneous population of tumor cells in the advanced-stage
    melanoma patient.

    This is a single-center, prospective randomized Phase 2 trial evaluating the activity,
    safety and immune effects of dasatinib given in combination with an autologous type-1
    polarized Dendritic Cell (DC1) vaccine. The current trial represents a randomized Phase 2
    study to determine the activity and safety of intradermal (id) administration of DC1s
    loaded with a mixture of six TBVA-derived peptides at the time of, or immediately after, an
    initial therapy cycle with the TKI dasatinib.

    Dasatinib will be administered at the standard dose and schedule recommended by the FDA (70
    mg BID). The autologous type-I DC vaccine will be administered either prior to, or
    concomitant with, the initiation of dasatinib administration. All patients will receive
    dasatinib at a starting dose of 70 mg twice daily by mouth in the outpatient setting
    approximately every 12 hours, at the same time each day.

    The DC vaccine will be administered by a single intradermal injection of approximately 10e7
    cells, with all the DCs being administered on days 1 and 15 of every cycle on an outpatient
    basis in the University of Pittsburgh Clinical and Translational Research Center
    (UPCI-CTRC).

    Patients on Arm A will start dasatinib administration on cycle 2, day 1 (week 5), while
    those patients in Arm B will start dasatinib administration on cycle 1, day 1 (week 1).

    Men and women at least 18 years of age must be HLA-A2+ and have histologically confirmed
    melanoma that is metastatic (Stage IV) or unresectable Stage IIIB/C and for which standard
    curative or palliative measures do not exist or are no longer effective.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Vaccine + dasatinib Experimental Patients will start vaccine on cycle 1, day 1 and dasatinib on cycle 2, day 1 (week 5). All patients will receive dasatinib at a starting dose of 70 mg twice daily by mouth in the outpatient setting. Dasatinib will be supplied as 50 mg and 20 mg tablets. Patients will take 1 of the 50 mg tablets and 1 of the 20 mg tablets twice daily, approximately every 12 hours, at the same time each day. The DC vaccine will be administered by a single intradermal injection of approximately 10e7 cells, with all the DCs being administered on days 1 and 15 of each cycle. The intradermal administration will be in the vicinity of the four nodal drainage groups of the four extremities. Dasatinib
    Vaccine + dasatinib Experimental Patients will start vaccine on cycle 1, day 1 and dasatinib on cycle 1, day 1. All patients will receive dasatinib at a starting dose of 70 mg twice daily by mouth in the outpatient setting. Dasatinib will be supplied as 50 mg and 20 mg tablets. Patients will take 1 of the 50 mg tablets and 1 of the 20 mg tablets twice daily, approximately every 12 hours, at the same time each day. The DC vaccine will be administered by a single intradermal injection of approximately 10e7 cells, with all the DCs being administered on days 1 and 15 of each cycle. The intradermal administration will be in the vicinity of the four nodal drainage groups of the four extremities. Dasatinib

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must be HLA-A2+ and have histologically confirmed melanoma that is
    metastatic (Stage IV) or unresectable Stage IIIB/C and for which standard curative or
    palliative measures do not exist or are no longer effective.

    - Patients must have measurable disease by RECIST 1.1, 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 CT scan, MRI, or calipers by
    clinical exam. See Section 11 for the evaluation of measurable disease.

    - Patients should have at least 2 subcutaneous, intracutaneous, and accessible tumor
    deposits, lymph node or other site available for biopsy purposes. Patients that have
    one biopsiable site that can be amenable to 2 biopsies (pre- and post-) will be
    considered eligible.

    - Prior chemotherapy, immunotherapy, or targeted therapy is allowed as long as it did
    not include dasatinib.

    - Age > 18 years. Because no dosing or adverse event data are currently available on
    the use of dasatinib in patients < 18 years of age, children are excluded from this
    study, but will be eligible for future pediatric trials.

    - ECOG performance status < 2 (Karnofsky > 60%, see Appendix A).

    - Life expectancy of greater than 12 weeks.

    - Patients must have normal organ and marrow function as defined below:

    - Leukocytes 3,000/L

    - absolute neutrophil count 1,500/L

    - absolute lymphocyte count 500/L

    - platelets 100,000/L

    - total bilirubin within normal institutional limits

    - AST(SGOT)/ALT(SGPT) 2.5 X institutional upper limit of normal

    - Creatinine 2.0 X institutional upper limit of normal

    - Serum magnesium, potassium and adjusted (or ionized) calcium the institutional
    lower limit of normal. (Supplementation of electrolytes prior to screening is
    allowed).

    - Sexually active women and men of childbearing potential must agree to use an
    effective method of birth control during the course of the study and for up to 3
    months following the last dose of the study drug, in a manner such that risk of
    pregnancy is minimized. Surgical sterilization, intrauterine device or barrier method
    (e.g. condom and/or diaphragm with spermicidal agents) are acceptable forms of birth
    control. Women of childbearing potential must have a negative pregnancy test (serum)
    within 7 days prior to treatment. A pregnancy test is not required for registration.
    Women who have not menstruated for more than 2 years will be considered
    postmenopausal, thus not of childbearing potential.

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

    Exclusion Criteria:

    - Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
    nitrosoureas or mitomycin C) prior to entering the study or those who have not
    recovered from adverse events due to agents administered more than 4 weeks earlier.

    - Patients with documented c-KIT mutations.

    - Patients who are receiving any other investigational agents.

    - Patients with known active brain metastases should be excluded. Patients with treated
    brain metastases with documented stability for 4 weeks are eligible.

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to dasatinib or any of the components of the vaccine being administered
    as part of this study.

    - Women who are pregnant or nursing/breastfeeding.

    - History of significant bleeding disorder unrelated to cancer, including:

    - Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

    - Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor
    VIII antibodies)

    - Patients currently taking medications that inhibit platelet function (i.e., aspirin,
    dipyridamole, epoprostenol, eptifibatide, clopidogrel, cilostazol, abciximab,
    ticlopidine, and any non-steroidal anti-inflammatory drug) because of a potential
    increased risk of bleeding from dasatinib.

    - Patients currently taking anticoagulants (warfarin, heparin/low molecular weight
    heparin [e.g., danaparoid, dalteparin, tinzaparin, enoxaparin]) because of a
    potential increased risk of bleeding from dasatinib.

    - Diagnosis of unstable angina or myocardial infarction within 6 months of study entry.

    - Patients currently taking one or more of the following drugs that are generally
    accepted to have a risk of causing Torsades de Pointes:

    - quinidine, procainamide, disopyramide

    - amiodarone, sotalol, ibutilide, dofetilide

    - erythromycins, clarithromycin

    - chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

    - cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone,
    halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.

    - Diagnosed or suspected congenital long QT syndrome.

    - Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec) within 30 days
    prior to study registration.

    - Any history of clinically significant ventricular arrhythmias (such as ventricular
    tachycardia, ventricular fibrillation, or Torsades de pointes)

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

    - HIV-positive patients on combination antiretroviral therapy are ineligible because of
    the potential for pharmacokinetic interactions with dasatinib. In addition, these
    patients are at increased risk of lethal infections when treated with
    marrow-suppressive therapy. Appropriate studies will be undertaken in patients
    receiving combination antiretroviral therapy when indicated.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Increase of CD8+ T cell response from addition of dasatinib

    Secondary Outcome Measures

    Number of participants with adverse events

    Tumor response

    PF and overall survival

    Number of CD8+ T cells infiltrating into melanoma lesions

    Number of suppressor cell populations and blood vessels in melanoma tumor biopsies

    Number of suppressor cell populations in patients peripheral blood

    Level of EphA2 protein expression in tumor biopsies

    Serum concentration of the T cell-recruiting chemokine CXCL10/IP-10

    Trial Keywords

    melanoma

    metastatic

    vaccine

    BRAF