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Vaccine Immunotherapy for Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor (Re-MATCH)

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ClinicalTrials.gov Identifier: NCT01326104
Recruitment Status : Recruiting
First Posted : March 30, 2011
Last Update Posted : September 14, 2018
Sponsor:
Collaborator:
United States Department of Defense
Information provided by (Responsible Party):
University of Florida

July 22, 2010
March 30, 2011
September 14, 2018
April 2010
March 2019   (Final data collection date for primary outcome measure)
  • Evaluate safety of TTRNA-DCs and TTRNA-xALT [ Time Frame: 28 Days ]
  • Determine progression-free survival [ Time Frame: 12 Months ]
  • Establishing the safety and DLT of DC + xALT therapy in this patient population with TTRNA-xALT and TTRNA-DCs will be the primary goal in the Phase I portion of the trial. [ Time Frame: 44 months ]
    A 3+3 Phase I study design with 3 lymphocyte (xALT) dose levels will be used to assess the safety of DC + xALT therapy, and to determine the maximum tolerated dose (MTD) for DC + xALT. An escalating total dose of TTRNA-xALT (3 x 10^6/Kg, 3 x 10^7/Kg, and 3 x 10^8/Kg) with TTRNA-DCs (2 x 10^7) will be evaluated in separate cohorts of 3 to 6 patients each for the purpose of establishing a MTD and a DLT in this patient population.
  • For the Phase II portion of the trial, the primary efficacy endpoint will be 12-month progression-free survival (PFS-12) rate after treatment with DC + xALT therapy as a surrogate for overall survival. [ Time Frame: 48 months ]
    The Phase II portion of this study will assess the clinical impact of DC + xALT therapy among pediatric patients with reMB/PNETs. The basis for making this assessment will be the proportion of patients who survive 12 months without disease progression (PFS-12) as a surrogate clinical marker for OS in this patient population. Progression-free survival will be measured from the initiation of HDC for comparison to our historical experience of HDC + PBSCT in this patient population.
Complete list of historical versions of study NCT01326104 on ClinicalTrials.gov Archive Site
  • Determine Objective Radiographic Response Rate [ Time Frame: 24 Months ]
  • Correlate magnitude and persistence of anti-tumor humoral or cellular immunity with clinical outcome [ Time Frame: 12 Months ]
  • Evaluate changes in cytokine profile and Toll-Like Receptor activation status [ Time Frame: 12 Months ]
  • Characterize the immunologic phenotype of lymphocyte subsets (naïve, effector, memory, regulatory) and natural killer cells [ Time Frame: 12 Months ]
  • Identify potential tumor specific antigens as vaccine candidates [ Time Frame: 12 Months ]
  • Determine the progression-free survival and overall survival rate [ Time Frame: 36 Months ]
Not Provided
Not Provided
Not Provided
 
Vaccine Immunotherapy for Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor
Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor Adoptive T Cell Therapy During Recover From Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation

Immunotherapy is a specific approach to treating cancer that has shown promise in adult patients for the treatment of melanoma, malignant brain tumors, and other cancers. The study investigators will use the experience they have gained from these studies to try to improve the outcome for children affected by a recurrent brain tumor.

This study will have two phases.

During Phase I, approximately 9 patients will be treated with increasing doses of tumor-specific immune cells to determine the safety of this treatment. Phase I patients will also receive dendritic cell vaccines to help boost the function of these immune cells and maintain their growth.

During Phase II, approximately 35 patients will be treated with tumor-specific immune cells and dendritic cell vaccines to see what impact they have on the tumor.

Malignant brain tumors now represent the most frequent cause of cancer death in children. Despite aggressive and highly toxic multi-modality therapy including surgery, craniospinal radiation, and high-dose chemotherapy coupled with peripheral blood stem cell transplantation, almost half the children diagnosed with the most common malignant brain tumors, medulloblastoma (MB) and primitive neuroectodermal tumors (PNET), will still die from recurrent disease. Furthermore, survivors are often left with severe and lifelong treatment-associated cognitive and motor deficits. The development of more effective and tumor-specific therapies that will not add further toxicity to existing treatments is paramount in improving clinical outcomes for children affected by MB/PNETs. Immunotherapy targeting tumor-specific antigens expressed within brain tumors is a modality potentially capable of meeting this clear and urgent need.

Despite considerable advancements and promising clinical results observed in immunotherapy trials directed against adult malignant brain tumors, efforts in the immunologic treatment of pediatric brain tumors have been limited to relatively few notable studies. This is due, at least in part, to the often limited viable tumor tissue available for tumor cell-based vaccine preparations, and the lack of identification of consistently expressed tumor-specific antigens within these cancers.

The use of total tumor RNA (TTRNA)-loaded dendritic cells (DCs) was pioneered at Duke University, as a novel platform for inducing potent immunologic responses against the variety of uncharacterized and patient-specific antigens present within malignant tumor cells. Duke demonstrated that sufficient RNA for clinical vaccine preparations can be amplified with high fidelity using existing molecular technologies from as few as 500 isolated pediatric and adult brain tumor cells, thus allowing vaccine preparation from surgical biopsies and even microdissected archival tumor specimens. In this study, the investigators will treat recurrent MB/PNETs during hematopoietic recovery from chemotherapy.

Immunotherapy administered during recovery from chemotherapy may have tremendous advantages, as adoptive cellular therapy following lymphodepletive conditioning regimens has emerged as the most effective treatment strategy for advanced and refractory melanoma. Our hypothesis is that DC + ex vivo expanded Autologous Lymphocyte Transfer (xALT) therapy targeting recurrent MB/PNETs during recovery from myeloablative chemotherapy will be safe and will prolong survival in children and young adults with recurrent MB/PNETs.

Interventional
Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Medulloblastoma
  • Neuroectodermal Tumor
  • Biological: TTRNA-xALT
    TTRNA-xALT 3 x 10^7/kg by intravenous injection once.
  • Biological: TTRNA-DCs
    TTRNA-DCs 1 x 10^7 by intradermal injection every 2 weeks for 3 total doses.
Experimental: TTRNA-xALT & TTRNA-DCs
TTRNA-xALT 3 x 10^7/kg by intravenous injection once. TTRNA-DCs 1 x 10^7 by intradermal injection every 2 weeks for 3 total doses.
Interventions:
  • Biological: TTRNA-xALT
  • Biological: TTRNA-DCs
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
35
64
March 2020
March 2019   (Final data collection date for primary outcome measure)

Inclusion Criteria:

Screening:

  • Age ≤ 30 years of age.
  • Suspected first recurrence/progression of MB/PNET since completion of definitive focal +/- craniospinal irradiation. Disease progression prior to receiving definitive focal +/- craniospinal irradiation will not disqualify patients from enrollment if they have subsequently failed definitive radiotherapy and are at first recurrence/progression at time of enrollment. Patients who are unable to receive radiation therapy due to genetic disorders that put them at significant risk for radiation-induced secondary malignancies (i.e. Gorlin's syndrome or NF1 mutation) are eligible for enrollment at first disease recurrence/progression.

Re-MATCH Protocol:

  • Patients must have histologically confirmed recurrent MB/PNET that is a first relapse/progression after completion of definitive radiotherapy +/- craniospinal irradiation. Patients with a first relapse/progression who are unable to receive radiation therapy due to genetic disorders that put them at significant risk for radiation-induced secondary malignancies (ie. Gorlin's syndrome or NF1 mutation) are eligible for enrollment.
  • Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration.
  • Karnofsky Performance Status of ≥ 50% or Lansky Performance Score of ≥ 50.
  • Absolute Neutrophil Count (ANC) ≥ 1000/µl (unsupported).
  • Platelets ≥ 100,000/µl (unsupported).
  • Hemoglobin > 8 g/dL (may be supported).
  • Serum creatinine ≤ upper limit of institutional normal
  • Bilirubin ≤ 1.5 times upper limit of normal for age.
  • Serum Glutamic Oxaloacetic Transaminase (ALT) ≤ 3 times institutional upper limit of normal for age.
  • Serum Glutamic Oxaloacetic Transaminase (AST) ≤ 3 times institutional upper limit of normal for age.
  • Patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study.
  • Patient or patient guardian consent to peripheral blood stem cell (PBSC) and/or bone marrow harvest following registration if PBSC or bone marrow (CD34 count of at least 2x10^6/kg) has not been previously stored and available for use.
  • Signed informed consent according to institutional guidelines must be obtained prior to registration.

Exclusion Criteria:

  • Pregnant or need to breast feed during the study period.
  • Active infection requiring treatment or an unexplained febrile (> 101.5o F) illness.
  • Known immunosuppressive disease, human immunodeficiency virus infection, or carriers of Hepatitis B or Hepatitis C virus.
  • Patients with active renal, cardiac (congestive cardiac failure, myocardial infarction, myocarditis), or pulmonary disease.
  • Patients receiving concomitant immunosuppressive agents for medical condition.
  • Patients who need definitive radiotherapy for treatment of recurrent MB/PNET. Focal boost radiotherapy may be delivered prior to immunotherapy if required for local control.
  • Patients receiving any other concurrent anticancer or investigational drug therapy.
  • Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction).
  • Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.
Sexes Eligible for Study: All
up to 30 Years   (Child, Adult)
No
Contact: Marcia Hodik, RN 352-273-6971 marcia.hodik@neurosurgery.ufl.edu
United States
 
 
NCT01326104
IRB201500502
W81XWH-10-1-0089 ( Other Grant/Funding Number: Department of Defense )
CDMRP-PRO93877 ( Other Identifier: Department of Defense )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: Undecided
University of Florida
University of Florida
United States Department of Defense
Principal Investigator: Duane Mitchell, MD, PhD University of Florida
University of Florida
September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP