Clinical Trial: Dendritic Cell Vaccines + Dasatinib for Metastatic Melanoma

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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 Wit

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 cycl

Detailed Summary:
Sponsor: Walter J. Storkus

Current Primary Outcome: Increase of CD8+ T cell response from addition of dasatinib [ Time Frame: Change from Baseline at weeks 1 & 3 for at least 6 cycles. ]

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.


Original Primary Outcome: Increase of CD8+ T cell response from addition of dasatinib [ Time Frame: Change from Baseline at weeks 2 & 4 for at least 6 cycles. ]

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.


Current Secondary Outcome:

  • Number of participants with adverse events [ Time Frame: at least 6 cycles (24 weeks) ]
  • Tumor response [ Time Frame: every 8 weeks ]
    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 ]
    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. ]
    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. ]
    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 1 & 3 for at least 6 cycles. ]
    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. ]
    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 1 & 3 for at least 6 cycles. ]
    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 traffic to tumor sites in vivo.


Original Secondary Outcome:

  • Number of participants with adverse events [ Time Frame: at least 6 cycles (24 weeks) ]
  • Tumor response [ Time Frame: every 8 weeks ]
    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 ]
    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. ]
    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. ]
    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. ]
    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. ]
    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. ]
    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.


Information By: University of Pittsburgh

Dates:
Date Received: June 10, 2013
Date Started: November 2013
Date Completion: July 2018
Last Updated: October 24, 2016
Last Verified: October 2016