Phase I/II: Decitabine/Vaccine Therapy in Relapsed/Refractory Pediatric High Grade Gliomas/Medulloblastomas/CNS PNETs

A Phase I/Pilot II Trial Combining Decitabine and Vaccine Therapy for Patients With Relapsed or Refractory Pediatric High Grade Gliomas, Medulloblastomas, and Central Nervous System Primitive Neuroectodermal Tumors (CNS PNETs)

The main purpose of this study is to determine the safety of using the combination of decitabine and a cancer vaccine plus Hiltonol. The vaccine will be made from the subject's blood cells and is designed to interact in the subject's body with cells that are programmed to fight specific tumor proteins NY-ESO-1, Melanoma Antigen Gene-A1 (MAGE-A1) and Melanoma Antigen Gene-A3 (MAGE-A3). The decitabine will be given to increase the amount and activity of these cancer proteins on the surface of tumor cells to increase the possibility that the vaccine will stimulate cells to act against the tumor cells. Subjects will be assessed to determine how these tumors respond to the treatment.

Study Overview

• Status: Terminated
• Conditions: Neuroectodermal Tumors, Primitive; Medulloblastoma; Gliomas
• Intervention / Treatment: Biological: Vaccine (autologous dendritic cells); Drug: Decitabine and Hiltonol

Detailed Description

One of the challenges of the practical application of immunotherapy for brain tumors is the lack of expression of tumor antigens as well as the down-regulation of Major Histocompatibility Complex (MHC Class I and II ) molecules, which are needed for antigen presentation. Considering the ability of 5-aza-2-deoxycytidine (DAC) to facilitate the expression of cancer/testis (CT) antigens and major histocompatibility complex molecules (MHC) and the fact that it has good blood brain barrier penetration, it is reasonable to test this approach in a vaccine study for patients who have experienced disease recurrence. The use of a combined approach to tumor immunotherapy - antigen upregulation followed by vaccination - has not been studied in this patient population, and there is a strong biologic rationale for this strategy.

Patients with pediatric brain tumors (medulloblastoma, CNS PNET, high grade glioma) who have experienced disease relapse or progressive refractory disease will be eligible. Each cycle will consist of DAC at low dose administered over a 5 day period, followed by two weekly vaccinations consisting of autologous dendritic cells pulsed with pooled, overlapping peptide mixes derived from full-length MAGE-A1, MAGE-A3, and NY-ESO-1. This dose of DAC is lower than all previously reported doses that have been safely administered in adult patients with Myelodysplastic syndromes (MDS) and Acute myeloid leukemia (AML), and was used in a previous protocol for relapsed and refractory pediatric neuroblastoma and sarcomas. A novel way of stimulating CD4 and CD8 antigen specific T cells is to use a dendritic cells (DC) vaccine approach in which the cells are pulsed with overlapping peptides derived from these antigens, so that patients from several different HLA backgrounds can be enrolled. Overlapping peptide mixes derived from full-length NY-ESO-1, MAGE-A1, or MAGE-A3 have been acquired and consists of 15-mers, with 11 amino acid overlap. The number of DC given in our study (8-10 x 106 peptide pulsed DC) is within the range of doses given in previous studies. Vaccinations are spaced at weekly intervals, based on multiple previous studies in which this approach is taken, and the fact that in vitro re-stimulation of cytolytic T lymphocyte (CTL) generally occurs on a weekly basis. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is given days 1 through 5 during vaccine weeks, to minimize leukopenia from DAC and to help facilitate antigen presenting cell function. The adjuvant poly-interstitial Cajal-like cell (ICLC; Hiltonol) will be injected immediately after and adjacent to DC vaccine site to enhance DC maturation. We will accrue 10 patients with relapsed, refractory, or progressive pediatric brain tumors over a 3 year period. Cycles will repeat every five weeks, for two cycles. Patients who do not have disease progression after two cycles may receive an additional two cycles of therapy.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
    • Louisville, Kentucky, United States, 40202
      • Pediatric Hematology/Oncology University of Louisville
    • Louisville, Kentucky, United States, 40202
      • University of Louisville, Kosair Children's Charities Pediatric Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Criteria for enrollment:

• Relapsed medulloblastoma, CNS PNET, or high grade glioma. Confirmatory biopsy is required at time of initial diagnosis.
• Because of rapid clinical progression and decline at time of relapse in patients with grade IV gliomas and diffuse intrinsic pontine gliomas (DIPGs), and the 4-6 weeks required to develop vaccine, patients with these tumors will be eligible to enroll and have DCs harvested and stored at the time of diagnosis, but will not be treated with vaccine until time of relapse.
• Age: Patients must be 2 to 25 years of age.

Criteria for treatment:

• The patient must have experienced relapsed, progressive, or refractory disease.
• The patient may have gross tumor that has been treated with chemotherapy or radiation prior to study treatment.
• The patient must have received standard therapy for their tumor.
• The patient must be at least 90 days from primary radiotherapy.
• Hematologic Function: absolute neutrophil (ANC): 1000/uL; Platelet count: 75,000/uL.
• Renal Function: Creatinine clearance or radioisotope glomerular filtration rate (GFR) 70ml/min/1.73 m2 .
• Cardiac Function: Patient must have normal cardiac function documented by:
• Ejection fraction (>55%) documented by echocardiogram or radionuclide multigated acquisition (MUGA) scan evaluation OR
• Fractional shortening (≥28%) documented by echocardiogram
• Liver Function: Total bilirubin 1.5x normal for age, and serum glutamate pyruvate transaminase (SGPT (ALT)) and serum glutamate oxaloacetate transaminase (SGOT (AST)) 3x normal for age.
• Room air pulse oximetry >94%.
• Male and female sexually active patients of reproductive age who wish to participate must agree to use acceptable contraception.
• Lansky/Karnofsky performance scale > 50, electrocorticogram (ECOG) < or = 2 (Appendix I).

Exclusion Criteria:

• Patient is pregnant.
• Patients with a positive result for any of the following diagnostic tests: Hep B Ag, Hep B Core Ab, Hep C Ab, HIV-1 Ab, HIV-2 Ab, human T-cell leukemia virus (HTLV-1 Ab), HTLV-2 Ab, rapid plasma reagin (RPR).
• Patient has a history of autoimmune disease, specifically inflammatory bowel disease, systemic lupus erythematosis, or rheumatoid arthritis.
• Patient is receiving high doses of systemic corticosteroids or concurrent chemotherapy at the time of beginning study treatment. (Maximum dose of dexamethasone allowed is 0.1mg/kg/day not to exceed 4mg/day.)
• Patient has a known systemic hypersensitivity to DAC, Hiltonol, or any vaccine component.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Decitabine/Vaccine Therapy; Biological/Vaccine: Vaccine (autologous dendritic cells) and Drug: Decitabine and Hiltonol

Biological: Vaccine (autologous dendritic cells); Prior to vaccination, DC will be thawed, washed once with normal saline containing 1% human serum albumin, and viability will be checked (must be > 70%). Peptide pulsed DC will be placed in 1 ml tuberculin syringe(s) and transferred to the study physician for vaccination; Drug: Decitabine and Hiltonol; Patients will receive DAC at a dose of 10 mg/m2/d intravenously (IV) over one hour on days 1-5 of week 1. Hiltonol will be given intramuscularly at the same site immediately following vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Tolerability (Number of Participants Without Adverse Events)	20 weeks

Collaborators and Investigators

• Sponsor: University of Louisville
• Investigators: Principal Investigator: Kenneth G Lucas, MD, University of Louisville

Publications and helpful links

General Publications

• Lang F, Liu Y, Chou FJ, Yang C. Genotoxic therapy and resistance mechanism in gliomas. Pharmacol Ther. 2021 Dec;228:107922. doi: 10.1016/j.pharmthera.2021.107922. Epub 2021 Jun 23.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: October 20, 2014
• First Submitted That Met QC Criteria: January 5, 2015
• First Posted (Estimate): January 7, 2015

Study Record Updates

• Last Update Posted (Actual): May 4, 2018
• Last Update Submitted That Met QC Criteria: May 2, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma; Medulloblastoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Interferon Inducers; Decitabine; Poly ICLC
• Other Study ID Numbers: 14.0855