Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Biomarker/Laboratory analysis, Treatment	Active	Under 21	Other	22053 NCT00703222

Trial Description

Summary

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.

Further Study Information

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. At the time of diagnosis, the patient will receive 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: 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 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) - Stable Disease - 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 - Complete response/remission (CR) - Stable Disease - 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. 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 to vaccination #1 and stem cell harvest, prior to consolidation chemotherapy and autologous stem cell rescue, 2 weeks post vaccination #4, or approximately 7 weeks post autologous stem cell rescue, 18-20 weeks post autologous stem cell rescue, and then every 3 months during the first year following autologous stem cell rescue. We will utilize this 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 2 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.

• Vaccine Specific Cytotoxic T-Lymphocyte Precursor (CTLp) Assessment: 1. ELISPOT assay: Provides the ability to quantify vaccine specific CTLp's at time points pre and post-vaccination according to the study calendar. Previous vaccine trials at our institution have made use of ELISPOT assay for determination of changes in numbers of vaccine/tumor specific CTLp frequency pre and post-vaccination. • Sample Collection: Peripheral blood samples of 2cc/kg, not to exceed 30cc will be collected in sodium heparin tubes from a central venous line when available. If the patient has < 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 chemotherapy cycle number 4 during tumor re-staging, prior to consolidation high dose chemotherapy, at the 8 week post-stem cell rescue time point, at the 16 week post-stem cell rescue time point (if the patient qualifies to continue vaccinations beyond vaccination #4), and prior to any subsequent vaccinations given beyond week +16. • 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. - Target Genes: These include tyrosine hydroxylase (TH) ß 1,4-N-acetylgalactosaminyltransferase (GD2 synthase) sialyltransferase (STX) and GAGE. - Sample Collection Schedule: Bone marrow aspirates and peripheral blood will be taken prior to the pre-stem cell harvest chemotherapy cycle (per standard therapy) and thus prior to stem cell harvest and vaccine #1, prior to consolidation chemotherapy and thus prior to autologous transplant, prior to vaccination #2 (approximately day +7 after stem cell rescue), at the 8 week post-stem cell rescue follow up, at the 16 week post-autologous stem cell transplant time-point (if the patient qualifies to continue vaccinations beyond vaccination #4), and in peripheral blood only prior to each subsequent vaccination at 3 month intervals as long as the patient is receiving every 3 month vaccinations. Additional samples, such as bone marrow, will be taken when clinically indicated and available.

CORRELATIVE STUDIES COLLECTIONS:

Prior to Pre Stem Cell Harvest Injection: - Immune Studies - Disease Re-eval (Scans/BMA/bx) - Min Residual Disease Studies

Prior to Pre Stem Cell Rescue/Consolidation Chemotherapy: - Immune Studies - Disease Re-eval (Scans/BMA/bx) - Min Residual Disease Studies

Prior to Day + 7 Injection (Vaccine #2): - Min Residual Disease Studies

14 Days Post Vaccine # 4: - Immune Studies - Disease Re-eval (Scans/BMA/bx) - Min Residual Disease Studies

Prior to Subsequent Vaccinations: - Immune Studies - Min Residual Disease Studies

Q3 months until 1 year: - Immune Studies - Disease Re-eval (Scans/BMA/bx) - Min Residual Disease Studies

Eligibility Criteria

Inclusion Criteria:

• Histologically proven, 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

• 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

Trial Contact Information

Trial Lead Organizations/Sponsors

Dan L. Duncan Cancer Center at Baylor College of Medicine

Chrystal Louis, MD

Principal Investigator

Chrystal Louis, MD		Ph: 832-822-4809
		Email: clouis@bcm.tmc.edu

Malcolm Brenner, MB, PhD		Ph: 832-824-4671
		Email: mkbrenne@txccc.org

U.S.A.
Texas
	Houston
	Texas Children's Hospital
		Chrystal Louis, MD	Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00703222
Information obtained from ClinicalTrials.gov on March 18, 2009