Dendritic Cell Vaccines + Dasatinib for Metastatic Melanoma
Condition: Metastatic Melanoma
MeSH terms: Melanoma
Intervention: DC vaccine; Dasatinib
Intervention MeSH terms: Dasatinib; Vaccines
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: melanoma; metastatic; vaccine; BRAF

Summary:

      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.

      Note: The outcome measures and time frames (previously) described in the PRS protocol record
      have been revised and articulated in the results section, to more accurately describe and
      represent the stated per-protocol investigations and endpoints, quantitatively.
    

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/µL

               -  absolute neutrophil count ≥ 1,500/µL

               -  absolute lymphocyte count ≥ 500/µL

               -  platelets ≥ 100,000/µL

               -  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.