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View Clinical Trial (Medical Research Study)
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A Phase I/II Study Of Immunization With Lymphotactin And Interleukin 2 Gene Modified Neuroblastoma Tumor Cells After High-Dose Chemotherapy And Autologous Stem Cell Rescue In Patients With High Risk Neuroblastoma - NCT00703222-77030 (Clinical Trial 228518)
Permalink: http://www.ClinicalConnection.com/exp/ExpandedPatientViewStudy228518.aspx
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| City: |
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Houston |
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State:
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TX |
| Zip Code: |
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77030 |
| Conditions: |
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Neuroblastoma |
| Purpose: |
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We intend to test the safety, and immunologic and clinical efficacy of a combination of 2
allogeneic neuroblastoma tumor cell line vaccines, one of which has been genetically
modified to secrete the cytokine/chemokine combination of IL-2 and lymphotactin, in patients
undergoing chemotherapy for newly diagnosed, high risk neuroblastoma who receive single
autologous stem cell rescue as consolidation therapy.
This protocol will be carried out as a Phase I/IIa study to evaluate the safety and toxicity
of adding a previously unstudied, unmodified, irradiated neuroblastoma cell line (SKNLP) to
a studied, safe dose of a gene modified, IL-2/Lptn secreting neuroblastoma cell line
SJNB-JF-IL2/Lptn to be given as a vaccine to patients diagnosed with high risk
neuroblastoma.
A 3+3, phase I dose-escalation trial will be employed to assess safety of two dose levels.
3-6 patients will be enrolled at each dose level and dose-escalation rules will proceed as
specified in section 5.2. A 21-day window following the first vaccination will constitute
the time period for DLT assessment. Dose limiting toxicity will be any grade 3 or 4
non-hematologic toxicity as per the CTCAE v3.0 or a grade 3 injection site toxicity per the
CTCAE 3.0. Exception: Grade 3 rigors/chills will be tolerated for 48-72 hours if
attributable to vaccine reaction. Under the phase Iia portion, additional patients will be
accrued at the MTD from the phase I portion. Prior published studies showed a 6-fold
increase (range 2 - 10-fold) in vaccine specific cytotoxic T-lymphocyte precursors (CTLp)
from pre to post vaccination (Institutional data; manuscript in preparation). We will use
ELISPOT from blood drawn at the timepoints indicated, to assess for a change in the number
of vaccine specific CTLp from baseline to 1 year after vaccination . With a cohort of 10
patients treated at the MTD, we will have 80% power to detect an alternative hypothesis of a
3.5 fold increase in CTLp (SD = 2.4) vs. a null hypothesis of 1.0 based on a two-sided,
one-sample t-test with 5% alpha. We expect accrue 1 to 2 patients per month.
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| Study summary: |
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TREATMENT PLAN: Standard Chemotherapy for Neuroblastoma: Standard therapy for neuroblastoma
is given in 3 phases: induction, consolidation, and maintenance. For enrollment in this
vaccine study patients and their physicians must anticipate therapy that will include
consolidation with high dose chemotherapy with stem cell rescue. They will be eligible for
enrollment in the phase I or phase II trial of vaccination with gene modified and
unmodified, allogeneic neuroblastoma cell lines. Patients will receive Induction,
Consolidation, and Maintenance therapy per their institutional standards. A general
description of the therapy follows:
- Induction: Induction consists of multiple cycles of induction chemotherapy with harvest
of autologous stem cells immediately following a particular cycle of chemotherapy per
institutional standards. Local control of the tumor with radiation therapy and/or
surgery occurs following a few cycles of induction chemotherapy or immediately prior to
consolidation therapy.
- Consolidation: Consolidation must consist of high dose chemotherapy with autologous
stem cell rescue (HDT/SCR).
- Maintenance: Starting day +90 after HDT/SCR, patients will be treated with Isotretinoin
(Cis-Retinoic Acid, CRA).
VACCINE DOSING (See Schema Attachment in Section S): Vaccine components SJNB-JF-IL2 and
SJNB-JF-Lptn will each be dosed at 1x10e7 cells/m2. This will be given in conjunction with
an escalating dose of SKNLP vaccine in the phase I portion of this study. In the phase II
portion of this study, the same dose of SJNB-JF-IL2 and SJNB-JF-Lptn will be given in
conjunction with the highest dose of SKNLP determined in the phase I portion. Vaccination
will be administered on an inpatient or outpatient basis. Vaccination will be given
subcutaneously and sites of injection will be rotated on arms and legs. Patient will be
notified of which dose of vaccine cells they will receive if enrolled in the study.
Vaccination Schedule (Doses #1, 2, 3, & 4): - Vaccination #1 will occur 48 -96 hours after
completion of pre-stem cell harvest chemotherapy. - Vaccination #2 should be given 7-14 days
following infusion of autologous stem cell rescue following high dose chemotherapy. -
Vaccination #3 is to be given approximately 14 days after #2 (+/-2 days). - Vaccination #4
is to be given approximately 14 days after #3 (+/-2 days). Vaccination Schedule (Doses #5,
6, & 7): Following disease re-evaluation approximately 2 weeks after vaccination #4,
patients with no DLT and the following disease status will be eligible to receive vaccines
#5, 6, & 7: - Received vaccines #1, 2, 3, & 4 without DLT - Complete response/remission
(CR), partial response (PR) or stable disease (SD) - No additional investigational agents
Vaccination Schedule (Doses #8 then every 3 months for a maximum of 12 total doses):
Following disease re-evaluation post-vaccination #7 (approximately 6 weeks after vaccine
#7), patients who meet the following criteria may receive additional vaccinations every 3
months to a total of 12 doses: - Received vaccines #5, 6, & 7 with no DLT - CR, PR, or SD -
No additional investigational agents
Phase I Dose Escalation Component: While we do not suspect that addition of a second
irradiated, unmodified neuroblastoma tumor cell line to the previously tested SJNB-JF gene
modified cell line will affect the safety profile of the vaccine, as the SKNLP has not been
tested previously in vaccine studies, we will perform an abbreviated dose escalation study
of the combined vaccine to assess safety. We know that the vaccine we gave to the patients
whose neuroblastoma came back was safe. The vaccine that was given to those patients was
treated with the viruses to make cytokines. We have never used the 2nd cell group in
patients. Because of this, we plan to treat 3 to 6 patients at a lower dose of cells to see
if adding the second cell line is safe to give.
- Dose Level 1 (3-6 patients) 1x10e6 cells/m2/vaccination dose of SKNLP Unmodified
Neuroblastoma Cell Line Vaccine Component
- Dose Level 2 (3-6 patients) 1x10e7 cells/m2/vaccination dose of SKNLP Unmodified
Neuroblastoma Cell Line Vaccine Component
- SJNB-JF-IL2 and SJNB-JF-Lptn cells are each dosed at 1x10e7 cells/m2/vaccination
Vaccine Dose (Phase I) and Criteria to Move to Phase IIa: While we do not anticipate finding
a "maximum tolerated dose" (MTD) of the SKNLP cell line, we will treat 3 patients on each
dose level of the phase I portion of the study as per table 3 below. If dose limiting
toxicity (DLT) is observed in 1 of 3 patients after vaccination #1, an additional 3 patients
will be enrolled at that dose level. If 2 of 6 patients have DLT, we will enroll 3 people at
1x10e5 cells/m2. If further dose de-escalation is deemed necessary, an amendment to the
protocol will be discussed. If no DLT is observed in patients at dose level #1 (1x10e6
cell/m2) following vaccination #1, then 3 patients will be enrolled at dose level #2 (1x10e7
cells/m2). If no DLT is observed in three patients treated at dose level #2 following
vaccination #1, the study will move on to the phase IIa component. If DLT is seen in 1 of 3
patients, another 3 patients will be enrolled. If 2 of 6 experience DLT, the previous dose
level will be considered the MTD and the study will move on to phase IIa. If 1 of 6
experience DLT, 1x10e7 cell/m2 will be considered the MTD.
Eligibility to continue vaccination: Patients on the phase I portion of this study who do
not experience a dose limiting toxicity at their respective dose, will be eligible to
continue with vaccinations at the same dose (of the phase I study).
Duration of Therapy: In the absence of treatment delays due to adverse events, treatment may
continue with immunizations per the treatment plan up to12 vaccinations or until one of the
following criteria applies: - Disease progression - Intercurrent illness that prevents
further administration of treatment - Unacceptable adverse events(s) including but not
limited to grade 3-4 non-hematologic toxicity according to CTCAE v3.0. Grade 3 rigors/chills
will be tolerated for 48-72 hours if attributed to vaccination. - Patient decides to
withdraw from the study - General or specific changes in the patient's condition render the
patient unacceptable for further treatment in the judgement of the investigator.
CRITERIA FOR REMOVAL FROM STUDY: - Dose Limiting Toxicity (DLT): DLT grade 3 or 4
non-hematologic toxicity as per the CTCAE v3.0 or a grade 3 injection site toxicity per the
CTCAE 3.0. Exception: Grade 3 rigors/chills will be tolerated for 48-72 hours if
attributable to vaccine reaction.
CORRELATIVE STUDIES PHASE I/IIA: - Disease Re-evaluation: Patients with disease measurable
by routine scans/biopsy material (MIBG/bone scan, CT/MRI, bone marrow aspirate) will have
serial measurements of such indicator lesions which will be considered for response
according to the definitions in Appendix E of Full Protocol prior to vaccination #1 and stem
cell harvest, prior to consolidation chemotherapy and autologous stem cell rescue, 3 weeks
post vaccination #4, or approximately 8 weeks post autologous stem cell rescue, 18-20 weeks
post autologous stem cell rescue, every 3 months as associated with vaccinations #8-12, 3
months after the last vaccination and as clinically indicated. We will utilize the following
strategy in determining patients' eligibility for vaccinations:
1. Post-vaccination #4: As per treatment schema for standard care of neuroblastoma, disease
re-evaluation will take place between 30 and 90 days post-stem cell rescue, which will be
approximately 3 weeks after vaccination #4. Proceeding to additional vaccination will be
dependent on the results of this evaluation. 2. Post-vaccination #7: Vaccination # 7 will
occur approximately 4-6 weeks after disease re-evaluation. We will therefore encourage
disease re-evaluation with appropriate radiographic modalities and bone marrow evaluation
within 6 weeks after vaccination #7.
Immune Assessment: Immune assessment studies will include. 1) Assessment of vaccine-specific
immunity based on CTL levels as measured by ELISPOT assays or tetramer assays. 2)
Phenotyping of peripheral blood T cells 3) Storage of serum for cytokine assays These
studies will be done on patients on whom the appropriate reagents are available. If the cell
count is limiting assessment of vaccine-specific immunity will be the first priority. •
Sample Collection: Peripheral blood samples of 2cc/kg, not to exceed 30cc will be collected
in sodium heparin tubes for ELISPOT assays, in red top tubes for serum and yellow top tubes
for phenotyping from a central venous line when available. If the patient has Hgb value <
8g/dL or less, the blood draw can be obtained over a 72 hour period. • Sample Collection
Schedule: Samples for ELISPOT will be collected prior to the first vaccination, prior to
consolidation high dose chemotherapy, at the 8 week post-stem cell rescue time point, at the
18 week post-stem cell rescue time point (if the patient qualifies to continue vaccinations
beyond vaccination #4), prior to any subsequent vaccinations given beyond week 18, and 3
months post the last vaccination. • Assay Variability: In order to control for inter-ELISPOT
plate variability, 3 samples for each patient will be collected prior to first assay and
multiple patient samples may be assayed at once.
Minimal Residual Disease Assessment: We will monitor for minimal residual disease, since a
high proportion of the patients studied will be in clinical remission of their disease. -
Reverse Transcriptase Polymerase Chain Reaction (RT-PCR): We will obtain pre-and post
transplant bone marrow aspirates and perform quantitative RT-PCR for a panel of
neuroblastoma genes successfully used to detect and monitor minimal residual disease. -
Sample Collection: • 3cc EDTA tubes will be used to collect marrow • 3cc EDTA tubes will be
used to collect blood preferably from a central venous catheter;
Because of the heterogeneity of NB tumors, we will screen diagnostic tissue samples
containing known tumor to discern which of these genes are expressed. Such samples are
stored for all patients originally treated at our center. - Sample Transport: Samples should
be transported at room temperature and processed within 24 hours as long as they are stored
in appropriate media/fixative. - Target Genes: These include tyrosine hydroxylase (TH) ß
1,4-N-acetylgalactosaminyltransferase (GD2 synthase) sialyltransferase (STX) and GAGE. -
Sample Collection Schedule: A 0.5-1 cc sample from the stem cell product will be collected
in an EDTA tube. Bone marrow aspirates and peripheral blood will be taken: - Immediately
prior to pre-stem cell harvest induction chemotherapy. - Prior to consolidation chemotherapy
during disease re-evaluation period. - Approximately 7-8 weeks after stem cell rescue (after
vaccine #4) - Following vaccine dose 7 (during disease re-evaluation during weeks 18-20) -
Prior to each subsequent vaccination at 3 month intervals as long as the patient is
receiving every 3 month vaccinations. - Three months after the last vaccination is
administered.
CORRELATIVE STUDIES COLLECTIONS:
Pre Stem Cell Harvest: - Immune Studies - Disease Re-eval (Scans/BMA)
Pre-Consolidation Chemotherapy: - Immune Studies - Disease Re-eval (Scans/BMA)
Week 8 disease re-evaluation: - Immune Studies - Disease Re-eval (Scans/BMA)
Week 18-20 Disease re-evaluation: - Immune Studies - Disease Re-eval (Scans/BMA)
Prior to Subsequent Vaccinations (#8-12): - Immune Studies - Disease Re-eval (Scans/BMA)
3 months post last vaccine: - Immune Studies - Disease Re-eval (Scans/BMA) |
| Criteria: |
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Inclusion Criteria:
Histological proof of high-risk neuroblastoma at diagnosis (see Appendices A and B in Full
Protocol attached in Section S.)
Anticipating single autologous stem cell rescue following high dose consolidation
chemotherapy.
Meet all eligibility criteria for high dose chemotherapy with stem cell rescue per
institutional standard
Age <21 years at time of diagnosis
HIV negative
Exclusion Criteria:
Patients must not be currently receiving any investigational agents or have received any
tumor vaccines within the previous six months.
Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic heart failure, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements
Pregnant
HIV-positive patients regardless of treatment status |
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| Study is available at: |
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Texas Children's Hospital
Houston, TX 77030
United States
Primary Contact:
Chrystal Louis, MD
Email: clouis@bcm.tmc.edu
Phone: 832-822-4809 |
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If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
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| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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March 16, 2010 |
Modifications to
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Clinical trials are medical research studies designed to test the safety and/or
effectiveness of new drugs, devices, or treatments in humans. These studies are
conducted worldwide for a range of conditions and illnesses. Learn more about
clinical research and participating in a study at
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