Dendritic Cell Vaccines + Dasatinib for Metastatic Melanoma

NCT01876212 | Completed Phase 2 Results DMC

• 3 other identifiers: 12-048R01CA169118UPCI 12-048
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Melanoma

Keywords

melanoma; metastatic; vaccine; BRAF

Outcome Measures

Primary Outcomes (1)

• Immune Response Rate

  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.

  Up to 13 months

Secondary Outcomes (19)

• Best Clinical Response

  Up to 13 months

• Objective Response Rate (ORR)

  Up to 13 months

• Worst Grade of Any Toxicity

  Up to 2 years

• Progression-free Survival (PFS)

  Up to 15 months

• Overall Survival (OS)

  Up to 30 months

Study Arms (2)

Vaccine + dasatinib

EXPERIMENTAL

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; Drug: Dasatinib

Vaccine + dasatinib from cycle 1

EXPERIMENTAL

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; Drug: Dasatinib

Interventions

DC vaccine BIOLOGICAL

Also known as: Type 1-polarized, autologous, DC vaccines incorporating tumor blood vessel antigen (TBVA)-derived peptides

Vaccine + dasatinib; Vaccine + dasatinib from cycle 1

Dasatinib DRUG

Also known as: BMS-354825, Sprycel

Vaccine + dasatinib; Vaccine + dasatinib from cycle 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Walter J. Storkus: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Related Publications (1)

• Storkus WJ, Maurer D, Lin Y, Ding F, Bose A, Lowe D, Rose A, DeMark M, Karapetyan L, Taylor JL, Chelvanambi M, Fecek RJ, Filderman JN, Looney TJ, Miller L, Linch E, Lowman GM, Kalinski P, Butterfield LH, Tarhini A, Tawbi H, Kirkwood JM. Dendritic cell vaccines targeting tumor blood vessel antigens in combination with dasatinib induce therapeutic immune responses in patients with checkpoint-refractory advanced melanoma. J Immunother Cancer. 2021 Nov;9(11):e003675. doi: 10.1136/jitc-2021-003675.

  PMID: 34782430 DERIVED

MeSH Terms

Conditions

Melanoma; Neoplasm Metastasis

Interventions

lentiviral minigene vaccine of COVID-19 coronavirus; Dasatinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Results Point of Contact

• Title: Barbara Stadterman, MPH MCCR
• Organization: UPMC Hillman Cancer Center

stadtermanbm@upmc.edu

412-647-5554

Study Officials

• John Kirkwood, MD

  University of Pittsburgh Cancer Institute (UPCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Medicine, Clinical & Translational Science

Study Record Dates

• First Submitted: June 10, 2013
• First Posted: June 12, 2013
• Study Start: May 16, 2014
• Primary Completion: July 11, 2018
• Study Completion: July 31, 2019
• Last Updated: August 22, 2019
• Results First Posted: August 6, 2019

Record last verified: 2019-08

Locations

US (1)