93 24.2.3 Infection ....................................................................................................... 93 24.2.4 Delayed Autoimmune Diseases ................................................................... 93 24.2.5 Phlebotomy .................................................................................................. 94 24.2.6 Leukapheresis .............................................................................................. 94 24.2.7 MRI .............................................................................................................. 94 24.3 Allergic Reactions to Contrast Agents ......................................................... 94 24.4 GM-CSF and G -CSF Risks .......................................................................... 95 24.5 Unknown Risks ............................................................................................ 96 24.6 Confidentiality ............................................................................................. 96 24.7 Treatment Alternatives & Financial Reimbursement .................................. 96 25. KEY STUDY PERSONNEL ...................................................................................96 25.1 Key Study Personnel External Sites ............................................................ 99 25.2 Principal Investigator Leadership Plan ...................................................... 100 26. WITHDRAWAL FROM THE PROTOCOL .....................................................101 27. MODIFICATIONS TO THE PROTOCOL ........................................................101 28. CONTINUING REVIEW AND FINAL REPORT .............................................101 29. REFERENCES .......................................................................................................102 30. APPENDICES ........................................................................................................104 30.1 Referenced Documents .............................................................................. 104 31. ADDENDUM A ......................................................................................................106 31.1 Single Patient- Specific Protocol (UF Site Only) ....................................... 106 Re-MATC H Protocol Page 21 of 106 Version: 20180628 1. STUDY TITLE Re-MATCH : Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor Adoptive T Cell Therapy during Recovery from Myeloablative C hemotherapy and H ematopoietic Stem Cell Transplantation 2. DESCRIPTION OF CLINI CAL TRIAL This is a dual -arm, prospective Phase II clinical trial of adoptive cellular therapy targeting recurrent medulloblastoma (MB) and recurrent supratentorial primitive neuroectodermal tumors (PNETs). Group A will consist of patients undergoing hematopoietic recovery from high- dose chemotherapy and autologous per ipheral blood stem cell transplant. Group B will consist of patients undergoing non- myeloablative salvage chemotherapy and autologous peripheral blood stem cell transplant The 12 -month progression- free survival (PFS) rate of all patients will be compare d collectively to a historical cohort, as patients did not have statistically different survival outcomes in the historical data set whether they received myeloablative (MA) or non -myeloablative (NMA) chemotherapy for recurrent disease. The PFS and OS in each arm will be analyzed descriptively to explore whether therapeutic outcomes may differ on the two treatment arms in this study. 2.1 Study Synopsis Title: Re-MATCH: Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor Adoptive T Cell Therapy during Recovery from Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation Study Drug: Total tumor mRNA -pulsed autologous Dendritic Cells (DCs) (TTRNA -DCs) and tumor -specific ex vivo expanded autologous lymphocyte transfer (TTRNA -xALT) Rationale: Vaccination and adoptive T cell strategies targeting unfractionated tumor antigens in humans in other contexts have been safe and effective. DC vaccinations targeting tumor antigens in children with MB and PNETs and other brain tum ors have been shown to be feasible and safe. The prognosis for patients with recurrent MB/PNETs (reMB/PNET), particularly for those who have failed prior definitive focal +/ - craniospinal irradiation, is dismal. High Dose Chemotherapy (HDC) + PBSCT have b een used as a standard of care in recent years in recurrent disease but are seldom curative. MA and NMA chemotherapy induces a profound lymphopenia that would be predicted to prevent the induction of effective immune response to anti -tumor vaccination. Ho wever, recent studies have shown, somewhat counterintuitively, that vaccination during recovery from profound but transient lymphopenia or the adoptive transfer of tumor -specific lymphocytes into lymphodepleted hosts leads to dramatic in vivo T cell expans ion and potent immunologic and clinical responses to immunotherapy. The use of TTRNA -pulsed DCs to expand tumor -specific lymphocytes ex vivo may provide a source of lymphocytes that preferentially expand in this lymphopenic environment and serve as a sourc e of responder cells to subsequent DC vaccination. We and others have successfully employed the use of DCs loaded with total tumor RNA as an innovative strategy to induce cellular immune responses against the repertoire of, as yet, largely uncharacterized antigens present in malignant brain tumors. Tumor cells from MB/PNETs are often limited and cannot be reliably isolated or propagated in sufficient quantity to serve directly as a source of antigen for use in human vaccination protocols. We have, howeve r, been able to reproducibly amplify the RNA content from as few as 500 isolated tumor cells using RT -PCR (Reverse Transcriptase- Polymerase Chain Reaction) and in vitro transcription from amplified cDNA (complimentary Deoxyribonucleic Acid) templates to ge nerate RNA libraries in sufficient Re-MATC H Protocol Page 22 of 106 Version: 20180628 quality and quantity for clinical scale immunotherapy trials. We have also demonstrated that subtractive hybridization of RNA from normal brain can be used to enrich for antigens expressed exclusively within malignant br ain tumor cells and possibly increase the specificity and safety profile of total tumor RNA directed immunotherapy. Primary Objective: Phase II: 1. To determine if DC + xALT therapy extends progression- free survival compared to historical benchmarks during recovery from HDC + PBSCT (Group A) or salvage chemotherapy (Group B) in pediatric patients with reMB/PNETs . Secondary Objectives: 1. To determine the objective radiographic response rate of MA and NMA chemotherapy coupled with DC + xALT therapy in patients with residual disease 2. To determine if magnitude and persistence of anti -tumor humoral or cellular immunity correlates with clinical outcome 3. To evaluate changes in cytokine profile and Toll -Like Receptor (TLR) activation status in pediatric patients with reMB/PNETs after HDC (Group A) or salvage chemotherapy (Group B) and during DC + xALT therapy 4. To characterize the immunologic phenotype of lym phocyte subsets (naïve, effector, memory, regulatory) and NK cells in patients with reMB/PNETs at diagnosis and during experimental therapy 5. To identify potential tumor specific antigens as vaccine candidates through characterizing the frequency of expressi on of the top 40 tumor associated antigens (TAA 40) identified in common malignancies in recurrent MB/PNETs 6. To determine the progression- free survival and overall survival rate in pediatric patients with recurrent MB/PNETs receiving DC + xALT therapy after HDC plus PBSCT (Group A) compared to a historical benchmark 7. To determine the progression- free survival and overall survival rate in pediatric patients with recurrent MB/PNETs receiving DC + xALT therapy after salvage chemotherapy (Group B) compared to a historical benchmark 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 subsequentl y 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 reMB/PNET that is a first relapse/progression after completion of definitive focal +/- 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 (KPS) of > 50% (KPS for > 16 years of age) or Lansky performance Score (L PS) of ≥ 50 (LPS for ≤ 16 years of age) assessed within 2 weeks prior to registration and documented in the medical record or on SDW -UFBTIP -004. Patients who are Re-MATC H Protocol Page 23 of 106 Version: 20180628 unable to walk because of paralysis but who are up in a wheel chair will be considered ambula tory for the purposes of the performance score. • Bone Marrow: - ANC (Absolute neutrophil count) ≥ 1000/µl (unsupported)* - Platelets ≥ 100,000/µl (unsupported)* - Hemoglobin > 8 g/dL (may be supported) *Patients on Group B with ANC < 1000/µL and/or platele t count < 100,000/µL prior to NMA will be allowed to get vaccine and ALT infusion; however, NMA conditioning will be withheld. • Renal: -Serum creatinine ≤ upper limit of institutional normal • Hepatic: - Bilirubin ≤ 1.5 times upper limit of normal for age. - SGPT (Serum Glutamic Oxaloacetic Transaminase) (ALT) ≤ 3 times institutional upper limit of normal for age. - SGOT (AST) ≤ 3 times institutional upper limit of normal for age. • Patients of childbear ing 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 PBSC and/or bone marrow harvest following registration if PBSC or bone marrow (CD34 count of at least 2x106/kg) has not been previously stored and available for use. • Signed informed consent according to institutional guidelines must be obtained prior to registration. Additional Eligibility Requirements Prior to Initiation of Consolidation or NMA Chemotherapy : • Renal - GFR of at least 70 ml/min/1.73m2 (Group A only). • Cardiac: - ECHO cardiogram with an ejection fraction of > 45% or Multiple Gated Acquisition (MUGA) scan within normal limits (Group A only). Patients in Group B will be eligible if the ejection fraction is < or equal to 45% but will receive Fludarabine only during NMA conditioning prior to vaccine + ALT infusion. - EKG without clinically significant arrhythmias (Group A only). • Pulmonary - DLCO, FEV1, FEC (diffusion capacity) > 50% of predicted (corrected for hemoglobin and alveolar volume). (Group A only) - Crying Vital Capacity if too young to perform pulmonary function tests (Group A only). - Chest X -ray without significant abnormalities and a pulse oximetry reading of > 93% in room air at rest and following a brisk 6- minute exercise resulting in a target heart rate of at least 100/min. These two tests would be required for any patient in Group A who cannot co-operate for the DLCO test du e to neurologic deficits and for all patients in Group B. Patients in Group B who do not meet this requirement will still be eligible but will receive Fludarabine only during NMA conditioning. Exclusion Criteria: • Pregnant or need to breast feed during the study period (Negative serum pregnancy test required).