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Dendritic Cell Vaccines + Dasatinib for Metastatic Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01876212
Recruitment Status : Completed
First Posted : June 12, 2013
Results First Posted : August 6, 2019
Last Update Posted : August 22, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Walter J. Storkus, University of Pittsburgh

Brief 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.


Condition or disease Intervention/treatment Phase
Metastatic Melanoma Biological: DC vaccine Drug: Dasatinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Actual Study Start Date : May 16, 2014
Actual Primary Completion Date : July 11, 2018
Actual Study Completion Date : July 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma
Drug Information available for: Dasatinib

Arm Intervention/treatment
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 from cycle 1

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




Primary Outcome Measures :
  1. Immune Response Rate [ Time Frame: Up to 13 months ]

    Immune Response is defined as improved peripheral blood CD8+ T cell responses against 3 or more peptide epitopes after active vaccination with Type I-polarized autologous dendritic cell (αDC1) vaccine incorporating 6 tumor blood vessel-associated antigen (TBVA)-derived peptides.

    The measure of Immune Response for this study is expressed as a proportion of responders: The number of HLA-A2+ melanoma patients with improved peripheral blood CD8+ T cell responses (responders) divided by the total number of evaluable patients.



Secondary Outcome Measures :
  1. Best Clinical Response [ Time Frame: Up to 13 months ]
    The number of treated patients by best clinical response achieved (tumor measurements via radiologic evaluation) using RECIST 1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

  2. Objective Response Rate (ORR) [ Time Frame: Up to 13 months ]

    The proportion of evaluable patients that achieved either partial or complete responses. Calculation: The number of patients who experienced a Partial Response (PR) + the number of patients who experienced a Complete Response (CR) / total number of response-evaluable patients.

    Per RECIST v1.1, Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.


  3. Worst Grade of Any Toxicity [ Time Frame: Up to 2 years ]
    Number of participants and severity grades for treatment-relatedness scores of possibly, probably, or definitely.

  4. Progression-free Survival (PFS) [ Time Frame: Up to 15 months ]
    The length of time after study treatment that a patient lives with disease but the disease does not progress. Patients were followed for 1 year after removal from study treatment or until death, whichever occurs first. Per RECIST 1.1, Progressive Disease is defined as a ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

  5. Overall Survival (OS) [ Time Frame: Up to 30 months ]
    The length of time from the start of study treatment, that patients remain alive.

  6. T Cell-recruiting Chemokine CXCL10/IP-10 [ Time Frame: At baseline (prior to treatment) ]
    Circulating serum concentration (levels) of T cell-recruiting chemokine CXCL10/IP-10 analyzed via ELISA assay. Higher levels of T cell-recruiting chemokine CXCL10/IP-1 correlate with patients exhibiting objective clinical response immunotherapy.

  7. T Cell-recruiting Chemokine CXCL10/IP-10 [ Time Frame: At between 5 and 7 weeks, post treatment ]
    Circulating serum concentration (levels) of T cell-recruiting chemokine CXCL10/IP-10 analyzed via ELISA assay. Higher levels of T cell-recruiting chemokine CXCL10/IP-1 correlate with patients exhibiting objective clinical response immunotherapy.

  8. Treg CD4FoxP3 Suppressor Cells [ Time Frame: At baseline (prior to treatment) ]
    Percentage of Treg CD4FoxP3 suppressor cells in patients' peripheral blood. The accumulation of Treg CD4FoxP3 suppressor cell populations correlates with tumor progression (disease progression) and negative prognosis.

  9. Treg CD4FoxP3 Suppressor Cells [ Time Frame: At between 4 and 6 weeks, post treatment ]
    Percentage of Treg CD4FoxP3 suppressor cells in patients' peripheral blood. The accumulation of Treg CD4FoxP3 suppressor cell populations correlates with tumor progression (disease progression) and negative prognosis.

  10. Treg CD4FoxP3 Suppressor Cells [ Time Frame: At between 7 and 10 weeks, post treatment ]
    Percentage of Treg CD4FoxP3 suppressor cells in patients' peripheral blood. The accumulation of Treg CD4FoxP3 suppressor cell populations correlates with tumor progression (disease progression) and negative prognosis.

  11. Monocytic Myeloid Derived Suppressor Cells (M-MDSC) [ Time Frame: At baseline (prior to treatment) ]
    Percentage of Monocytic Myeloid Derived Suppressor Cells (M-MDSC) present in patients' peripheral blood. The accumulation of M-MDSC populations correlates with tumor progression (disease progression) and negative prognosis.

  12. Monocytic Myeloid Derived Suppressor Cells (M-MDSC) [ Time Frame: At between 4 and 6 weeks, post treatment ]
    Percentage of Monocytic Myeloid Derived Suppressor Cells (M-MDSC) present in patients' peripheral blood. The accumulation of M-MDSC populations correlates with tumor progression (disease progression) and negative prognosis.

  13. Monocytic Myeloid Derived Suppressor Cells (M-MDSC) [ Time Frame: At between 7 and 10 weeks, post treatment ]
    Percentage of Monocytic Myeloid Derived Suppressor Cells (M-MDSC) present in patients' peripheral blood. The accumulation of M-MDSC populations correlates with tumor progression (disease progression) and negative prognosis.

  14. Polymorphonucler Myeloid-derived Suppressor Cells (PMN-MDSC) [ Time Frame: At baseline (prior to treatment) ]
    Percentage of Polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) present in patients' peripheral blood. The accumulation/increase of M-MDSC populations correlates with tumor progression (disease progression) and negative prognosis.

  15. Polymorphonucler Myeloid-derived Suppressor Cells (PMN-MDSC) [ Time Frame: At between 4 and 6 weeks, post treatment ]
    Percentage of Polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) present in patients' peripheral blood. The accumulation/increase of M-MDSC populations correlates with tumor progression (disease progression) and negative prognosis.

  16. Polymorphonucler Myeloid-derived Suppressor Cells (PMN-MDSC) [ Time Frame: At between 7 and 10 weeks, post treatment ]
    Percentage of Polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) present in patients' peripheral blood. The accumulation/increase of M-MDSC populations correlates with tumor progression (disease progression) and negative prognosis.

  17. EphA2 Protein Expression in Tumor Biopsies [ Time Frame: Up to 6 months ]
    Level of EphA2 protein expression in tumor tissue biopsies.

  18. Suppressor Cell Populations and Blood Vessels in Melanoma Tumor Biopsies [ Time Frame: Up to 6 months ]
    Percentage of suppressor cell populations and blood vessels in melanoma tumor biopsies.

  19. CD8+ T Cells Infiltration [ Time Frame: Up to 6 months ]
    Percentage of CD8+ T cells infiltrating into melanoma lesions (tumor tissues).



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01876212


Locations
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United States, Pennsylvania
Hillman Cancer Center
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
Walter J. Storkus
National Cancer Institute (NCI)
Investigators
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Principal Investigator: John Kirkwood, MD University of Pittsburgh Cancer Institute (UPCI)
  Study Documents (Full-Text)

Documents provided by Walter J. Storkus, University of Pittsburgh:

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Responsible Party: Walter J. Storkus, Associate Professor of Medicine, Clinical & Translational Science, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01876212    
Other Study ID Numbers: 12-048
R01CA169118 ( U.S. NIH Grant/Contract )
UPCI 12-048 ( Other Identifier: University of Pittsburgh Cancer Institute )
First Posted: June 12, 2013    Key Record Dates
Results First Posted: August 6, 2019
Last Update Posted: August 22, 2019
Last Verified: August 2019
Keywords provided by Walter J. Storkus, University of Pittsburgh:
melanoma
metastatic
vaccine
BRAF
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Dasatinib
Vaccines
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action