Dendritic Cell Vaccines + Dasatinib for Metastatic Melanoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by University of Pittsburgh
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Hussein Tawbi, University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01876212
First received: June 10, 2013
Last updated: March 21, 2014
Last verified: March 2014
  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 (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.


Condition Intervention Phase
Metastatic Melanoma
Biological: DC vaccine
Drug: Dasatinib
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • Increase of CD8+ T cell response from addition of dasatinib [ Time Frame: Change from Baseline at weeks 2 & 4 for at least 6 cycles. ] [ Designated as safety issue: No ]
    Translation and clinical vaccine trials have demonstrated that DC/peptide-based vaccines effectively activate specific CD8+ T cells in tumor-bearing hosts that may be detected in peripheral blood, and that individuals that exhibit objective clinical response to such vaccine therapies tend to derive from the cohort of patients that display detectable increases in T cell responses post-vaccination. Our own pre-clinical studies support the effectiveness of DC1/peptide vaccination to elicit protective/therapeutic T cell-mediated immunity in melanoma models in vivo, supporting the hypothesis that DC1/peptide vaccination of advanced stage melanoma patients will result in increased quantities of specific CD8+ T cells in patient peripheral blood and that those individuals in which improved response to many peptides can be observed are those that are more likely to demonstrate clinical benefit.


Secondary Outcome Measures:
  • Number of participants with adverse events [ Time Frame: at least 6 cycles (24 weeks) ] [ Designated as safety issue: Yes ]
  • Tumor response [ Time Frame: every 8 weeks ] [ Designated as safety issue: No ]
    Although objective tumor response is not the primary endpoint of this trial, patients with measurable disease will be assessed by standard criteria. For the purposes of this study, patients should be re-evaluated every 8 weeks. In addition to a baseline scan, confirmatory scans will also be obtained ≥ 4 weeks following initial documentation of an objective response.

  • PF and overall survival [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Patients will be followed for 1 year after removal from study treatment or until death, whichever occurs first.

  • Number of CD8+ T cells infiltrating into melanoma lesions [ Time Frame: Week 1 of cycles 2, 4, & 6. ] [ Designated as safety issue: No ]
    Tumor progression is believed to be linked to the accumulation of suppressor cell populations (both MDSC and Treg) and strong pro-angiogenic signals, as well as, "prevention" of Type-1 T cell recruitment within the tumor microenvironment. Our preliminary data in murine melanoma models support the ability of dasatinib (particularly when combined with DC1/peptide vaccines) to counteract these biologic endpoints in vivo. We hypothesize that such changes may also be evidenced in effectively treated melanoma patients by analyzing melanoma biopsies taken post- versus pre-treatment and that the greatest "normalization" of the tumor microenvironment will be observed after treatment with combined dasatinib + vaccine therapy.

  • Number of suppressor cell populations and blood vessels in melanoma tumor biopsies [ Time Frame: Week 1 of cycles 2, 4, & 6. ] [ Designated as safety issue: No ]
    Tumor progression is believed to be linked to the accumulation of suppressor cell populations (both MDSC and Treg) and strong pro-angiogenic signals, as well as, "prevention" of Type-1 T cell recruitment within the tumor microenvironment. Our preliminary data in murine melanoma models support the ability of dasatinib (particularly when combined with DC1/peptide vaccines) to counteract these biologic endpoints in vivo. We hypothesize that such changes may also be evidenced in effectively treated melanoma patients by analyzing melanoma biopsies taken post- versus pre-treatment and that the greatest "normalization" of the tumor microenvironment will be observed after treatment with combined dasatinib + vaccine therapy.

  • Number of suppressor cell populations in patients peripheral blood [ Time Frame: Change from Baseline at weeks 2 & 4 for at least 6 cycles. ] [ Designated as safety issue: No ]
    Cancer patients have commonly also been shown to have elevated populational frequencies of Treg (based on the CD4+Foxp3+ phenotype) circulating in the peripheral blood. Alternate TKI, such as sunitinib, have been shown capable of reducing peripheral blood Treg levels within the first 4 week cycle of drug administration, in concert with a rebound in Type-1 T cell numbers and function in PBMC (59). Based on our pre-clinical data (Fig. 1), we hypothesize that dasatinib with provide a similar effect in melanoma patients and that those patients exhibiting the greatest degree of Treg reduction post-therapy will be more likely to respond favorably against the peptide epitopes contained in the vaccine formulation.

  • Level of EphA2 protein expression in tumor biopsies [ Time Frame: Week 1 of cycles 2, 4, & 6. ] [ Designated as safety issue: No ]
    We have previously shown that drug treatments (including dasatinib in vitro) that promote the proteasome-dependent degradation of the tumor (and tumor vascular endothelial) cell-associated protein EphA2 lead to improved recognition by specific CD8+ T cells. We hypothesize that administration of dasatinib to melanoma patients will promote the loss of EphA2 protein within the tumor lesion, leading to an enhancement in the sensitivity of EphA2+ cells in the tumor microenvironment to EphA2-specific CD8+ T cells that have been activated as a consequence of DC1/peptide-based vaccination.

  • Serum concentration of the T cell-recruiting chemokine CXCL10/IP-10 [ Time Frame: Change from Baseline at weeks 2 & 4 for at least 6 cycles. ] [ Designated as safety issue: No ]
    We and others have recently shown that therapeutic CD8+ T cells require the production of CXCR3 ligand chemokines within the tumor microenvironment in order to effectively home to these disease sites. Two recent clinical trials, including our DC1/glioma peptide vaccination trial in patients with brain tumors strongly support CXCL10 (aka IP-10) as a chemokine associated with superior clinical outcome to immune-based therapy. We hypothesize that this will also be the case in our DC1/TBVA peptide vaccinated patients with melanoma where Type-1 CXCR3+ responder T cells require a gradient of CXCL10/IP-10 (as detected in serum) in order to traffick to tumor sites in vivo.


Estimated Enrollment: 28
Study Start Date: November 2013
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vaccine + dasatinib

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.

Biological: DC vaccine
Other Name: Type 1-polarized, autologous, DC vaccines incorporating tumor blood vessel antigen (TBVA)-derived peptides
Drug: Dasatinib
Other Names:
  • BMS-354825
  • Sprycel
Experimental: Vaccine + dasatinib

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.

Biological: DC vaccine
Other Name: Type 1-polarized, autologous, DC vaccines incorporating tumor blood vessel antigen (TBVA)-derived peptides
Drug: Dasatinib
Other Names:
  • BMS-354825
  • Sprycel

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01876212

Contacts
Contact: Hussein Tawbi, MD, PhD 412-648-6466 tawbhx@upmc.edu
Contact: Carrie Muniz, RN, BSN 412-623-6121 munizca@upmc.edu

Locations
United States, Pennsylvania
Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
Hussein Tawbi
Investigators
Principal Investigator: Hussein Tawbi, MD University of Pittsburgh Cancer Institute (UPCI)
  More Information

No publications provided

Responsible Party: Hussein Tawbi, Assistant Professor of Medicine, Clinical & Translational Science, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01876212     History of Changes
Other Study ID Numbers: 12-048, R01CA169118, UPCI 12-048
Study First Received: June 10, 2013
Last Updated: March 21, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Pittsburgh:
melanoma
metastatic
vaccine
BRAF

Additional relevant MeSH terms:
Melanoma
Nevi and Melanomas
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Dasatinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 20, 2014