Medulloblastoma, Neuroectodermal Tumor
Conditions
Keywords
Medulloblastoma, Primitive Neuroectodermal Tumor
Brief summary
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. Approximately 35 patients with first recurrence of medulloblastoma (reMB)/supratentorial primitive neuroectodermal tumors (PNETs) will be treated with tumor-specific immune cells and dendritic cell vaccines to see what impact they have on the tumor.
Detailed description
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. 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. In this study, the investigators will treat patients with first recurrence reMB/PNETs after completion of definitive radiation therapy with autologous tumor-specific T cell immunotherapy (TTRNA-xALT) plus TTRNA-loaded dendritic cell vaccine. Following surgical resection, biopsy, or cytology examination with confirmatory pathologic diagnosis, patients will be enrolled into Group A (high-dose chemotherapy or HDC) or Group B (non-myeloablative or NMA salvage chemotherapy) based on eligibility for HDC. Patients with localized relapse and have not failed HDC+ peripheral blood stem cell transplant (PBSCT) previously will be enrolled into Group A. Patients with disseminated disease, have previously failed HDC+PBSCT, or are otherwise considered poor candidates for HDC based on overall health status, but otherwise meet eligibility criteria, will be enrolled into Group B. All patients will receive DC + xALT therapy.
Interventions
BIOLOGICALTTRNA-xALT
TTRNA-xALT 3 x 10\^7/kg by intravenous injection once.
BIOLOGICALTTRNA-DCs
TTRNA-DCs 1 x 10\^7 by intradermal injection every 2 weeks for 3 total doses.
Sponsors
University of Florida
United States Department of Defense
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Years
Healthy volunteers
No
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 (\> 101.5F) 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 12 Month Progression-free Survival (PFS-12) | up to 12 months | PFS-12 is the number of participants (%) with PFS at 12 months. PFS is defined as time interval from date of first DC vaccine to date of progression (death is also treated as progression) or censoring, whichever happens first. The PFS-12 of Historical Benchmark is 33%. The granular PFS of Historical Bechmark is 4,16, 5, 12, 14, 7, 5, 5, 12, 9, 24 and 13 months (Gururangan et al,. Neuro Oncol. 2008, Table 3) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Radiographic Response Rate | Baseline MRI (prior to Adoptive Cellular Therapy (ACT)) compared to post-ACT MRI (approximately 8 weeks post-baseline MRI) | Objective Response Rate (ORR), defined as the proportion of subjects who show partial or complete response (CR+PR) to therapy, SD (stable disease), and PD (progressive disease) or not assessable, using RECIST criteria based on their best overall response over 8 weeks when comparing pre-ACT vs. post-ACT MRI. |
| Change in Cytokine Profile for IFNg | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure serum cytokines in peripheral blood pre and post ACT therapy for patients in Arm A and Arm B. We will compare baseline (pre-ACT) to post treatment (both TTRNA-xALT and TTRNA-DCs vaccines administered) changes for each arm. Longitudinal difference baseline to Day 14 and 28 with each patient serving as own control using mixed linear effect model. |
| Overall Survival (OS) Rate | baseline up to 12 months | 12-month OS calculated based on benchmark. OS-12 is the proportion of participants with OS at 12 months. |
| Change in Type 1 Interferon | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure change in cellular immunity in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to Day 28 (including Day 14) with each patient. OS Univariable Cox Regression with Change in Cellular Immunity was applied. The Hazard Ratio with 95% CI reported. |
| Change in Type 2 Interferon | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure change in cellular immunity in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to Day 28 (including Day 14) with each patient. OS Univariable Cox Regression with Change in Cellular Immunity was applied. The Hazard Ratio with 95% CI reported. |
| Change in Percentage of CD8 Naive T Cells in PBMC | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure change in lymphocyte phenotype in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline (pre-treatment) to 28 days with each patient serving as own control using mixed linear effect model. |
| Change in Cytokine Profile for IL10 | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure serum cytokines in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to Day 14 and 28 with each patient serving as own control using mixed linear effect model. |
| Change in Cytokine Profile for IL12p70 | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure serum cytokines in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to Day 14 and 28 with each patient serving as own control using mixed linear effect model. |
| Change in Cytokine Profile for IL2 | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure serum cytokines in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to Day 14 and 28 with each patient serving as own control using mixed linear effect model. |
| Change in Cytokine Profile for IL4 | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure serum cytokines in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to Day 14 and 28 with each patient serving as own control using mixed linear effect model. |
| Change in Cytokine Profile for IL6 | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure serum cytokines in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to Day 14 and 28 with each patient serving as own control using mixed linear effect model. |
| Change in Cytokine Profile for TNFa | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure serum cytokines in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to Day 14 and 28 with each patient serving as own control using mixed linear effect model. |
| Change in TLR Activation Status | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure change in TLR activation status in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to Day 14 and 28 with each patient serving as own control using mixed linear effect model. We quantified pathway activity using GSVA applied to normalized RNA-seq expression data. The enrichment score for each sample was defined as the maximum deviation from zero of this running sum, yielding a dimensionless GSVA score that represents the relative coordinated up- or down-regulation of TLR pathway genes within that sample compared to the background transcriptome. Higher GSVA score represents upregulation and lower GSVA score represents downregulation. There is no clinical relevance threshold. |
| Change in Percentage of CD8 Memory T Cells in PBMC | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure change in lymphocyte phenotype in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to 28 days with each patient serving as own control using mixed linear effect model. |
| Change in Percentage of CD4 Naive T Cells in PBMC | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure change in lymphocyte phenotype in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to 28 days with each patient serving as own control using mixed linear effect model. |
| Change in Percentage of CD4 Memory T Cells in PBMC | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure change in lymphocyte phenotype in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to 28 days with each patient serving as own control using mixed linear effect model. |
| Change in Percentage of Treg T Cells in PBMC | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure change in lymphocyte phenotype in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to 28 days with each patient serving as own control using mixed linear effect model. |
| Change in Percentage of NK Cells in PBMC | baseline prior to immunotherapy to 28 days post-vaccine #1 (both TTRNA-xALT and TTRNA-DCs vaccines administered) | We will measure change in lymphocyte phenotype in peripheral blood pre and post therapy for patients in Arm A and Arm B. We will compare baseline to post treatment changes for each arm. Longitudinal difference baseline to 28 days with each patient serving as own control using mixed linear effect model. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDuane Mitchell, MD, PhD
University of Florida
Participant flow
Pre-assignment details
Thirty-six patients were assessed for eligibility in the Phase II trial. Ten subjects were excluded; eight did not meet eligibility and two declined participation prior to allocation to intervention arm. Twenty-two patients received adoptive cellular therapy, DC plus ALT.
Participants by arm
| Arm | Count |
|---|---|
| Group A High dose chemotherapy plus peripheral blood stem cell transplant followed by TTRNA-xALT and TTRNA-DCs.
TTRNA-xALT: TTRNA-xALT 3 x 10\^7/kg by intravenous injection once.
TTRNA-DCs: TTRNA-DCs 1 x 10\^7 by intradermal injection every 2 weeks for 3 total doses. | 7 |
| Group B NMA Salvage chemotherapy plus peripheral blood stem cell transplant followed by TTRNA-xALT and TTRNA-DCs.
TTRNA-xALT: TTRNA-xALT 3 x 10\^7/kg by intravenous injection once.
TTRNA-DCs: TTRNA-DCs 1 x 10\^7 by intradermal injection every 2 weeks for 3 total doses. | 15 |
| Total | 22 |
Baseline characteristics
| Characteristic | Group A | Total | Group B |
|---|---|---|---|
| Age, Continuous | 15 years | 12.5 years | 10 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 19 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 16 Participants | 9 Participants |
| Region of Enrollment United States | 7 Participants | 22 Participants | 15 Participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 15 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 7 | 18 / 19 |
| other Total, other adverse events | 7 / 7 | 19 / 19 |
| serious Total, serious adverse events | 4 / 7 | 5 / 19 |
Outcome results
Primary
12 Month Progression-free Survival (PFS-12)
PFS is defined as time interval from date of first DC vaccine to date of progression (death is also treated as progression) or censoring, whichever happens first.
Time frame: up to 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A | 12 Month Progression-free Survival (PFS-12) | 215 Days |
| Group B | 12 Month Progression-free Survival (PFS-12) | 69 Days |
Comparison: Based on published literature, PFS-12 for patients with recurrent disease after initiating treatment with HDC + PBSCT or standard salvage therapy was 33% (95% confidence interval of 10%, 59%). The study was designed to differentiate between a PFS-12 rate of 33% (null hypothesis) and 55% (alternative hypothesis). If 35 patients enrolled, this assessment has 90% power assuming a type I error rate of 0.10. We assume that PFS of historical controls follows exponential distribution.p-value: 0.92790% CI: [0.107, 0.764]Log Rank
Comparison: Based on published literature, PFS-12 for patients with recurrent disease after initiating treatment with HDC + PBSCT or standard salvage therapy was 33% (95% confidence interval of 10%, 59%). The study was designed to differentiate between a PFS-12 rate of 33% (null hypothesis) and 55% (alternative hypothesis). If 35 patients enrolled, this assessment has 90% power assuming a type I error rate of 0.10. We assume that PFS of historical controls follows exponential distribution.p-value: <0.001Log Rank
p-value: <0.00190% CI: [0.03, 0.276]Log Rank
Secondary
Characterize Immunologic Phenotype of Lymphocyte Subsets and NK Cells
We will conduct flow cytometry from patient samples. Blood will be obtained for immunologic monitoring prior to non-mobilized leukapheresis, prior to immunotherapy, 1 day post Vaccine #1, 4 (+/- 1) days post Vaccine #1, weekly post Vaccine #1 for six weeks.
Time frame: baseline compared to 6 weeks post vaccine #1 and longitudinal measures through overall survival (up to 60 months)
Secondary
Correlate Magnitude and Persistence of Anti-tumor Humoral or Cellular Immunity With Clinical Outcome
Peripheral blood will be used to compare pre-therapy lymphocyte function to defined intervals after each immunization. Blood will be obtained for immunologic monitoring prior to non-mobilized leukapheresis, prior to immunotherapy, 1 day post Vaccine #1, 4 (+/- 1) days post Vaccine #1, weekly post Vaccine #1 for six weeks.
Time frame: baseline compared to 6 weeks post vaccine #1 and longitudinal measures through overall survival (up to 60 months)
Secondary
Determine of Overall Survival Rate
Kaplan-Meier estimator will be used to describe length of overall survival from initiation of vaccine #1 for both Groups A and B.
Time frame: up to 60 months
Secondary
Evaluate Changes in Cytokine Profile and Toll-Like Receptor Activation Status
We will measure serum cytokines pre and post therapy. Blood will be obtained for immunologic monitoring prior to non-mobilized leukapheresis, prior to immunotherapy, 1 day post Vaccine #1, 4 (+/- 1) days post Vaccine #1, weekly post Vaccine #1 for six weeks.
Time frame: baseline compared to 6 weeks post vaccine #1 and longitudinal measures through overall survival (up to 60 months)
Secondary
Objective Radiographic Response Rate
Radiographic response will be assessed as a percentage change in tumor size from pre-treatment (baseline) MRI scans of the brain and spine obtained with and without contrast. Evaluation will be based on the NCI-endorsed, World Health Organization RECIST criteria and using a modified version of the MacDonald criteria (complete response, partial response, stable disease, progressive disease or not assessible).
Time frame: best overall radiographic response through duration on study (up to 60 months)