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.
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.
