Busulfan, Melphalan, and Stem Cell Transplant After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma | RxWiki

Busulfan, Melphalan, and Stem Cell Transplant After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma

Overview[ - collapse ][ - ]

Purpose	This pilot clinical trial studies busulfan, melphalan, and stem cell transplant after chemotherapy in treating patients with newly diagnosed high-risk neuroblastoma. Giving chemotherapy to the entire body before a stem cell transplant stops the growth of tumor cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy or radiation therapy is given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.
Condition	Neuroblastoma
Intervention	Drug: Cisplatin Drug: Cyclophosphamide Drug: Doxorubicin Drug: Etoposide Drug: Topotecan Drug: Vincristine Radiation: external beam radiation therapy Procedure: PBSC Procedure: ASCT: autologous stem cell transplant (busulfan, melphalan) Drug: Busulfan Drug: Melphalan Drug: Mesna
Phase	N/A
Sponsor	Children's Oncology Group
Responsible Party	Children's Oncology Group
ClinicalTrials.gov Identifier	NCT01798004
First Received	January 6, 2013
Last Updated	February 5, 2014
Last verified	February 2014

Tracking Information[ + expand ][ + ]

First Received Date	January 6, 2013
Last Updated Date	February 5, 2014
Start Date	April 2013
Estimated Primary Completion Date	Not Provided
Current Primary Outcome Measures	Number of patients who experience one or more unacceptable toxicities (severe sinusoidal obstruction syndrome [SOS] or grade 4-5 pulmonary toxicity per Common Toxicity Criteria [CTC] v.4.0) during the consolidation phase of therapy [Time Frame: Up to 28 days post-consolidation therapy] [Designated as safety issue: Yes]The primary study endpoint is the tolerability of the BuMel regimen, which will be quantified as the number of patients who experience one or more unacceptable toxicities (severe SOS (Sinusoidal obstruction syndrome) or Grade 4-5 pulmonary toxicity per CTCv.4.0) during the Consolidation phase of therapy.
Current Secondary Outcome Measures	Response Rates [Time Frame: Up to 5 years] [Designated as safety issue: No]Will be assessed by determining the response rates for high-risk neuroblastoma patients undergoing Induction therapy followed by Consolidation with BuMel and local radiotherapy. Response will be determined using the International Response Criteria. Event Free Survival [Time Frame: Up to 5 years] [Designated as safety issue: No]Will be assessed by determining the event-free survival rates for high-risk neuroblastoma patients undergoing Induction therapy followed by Consolidation with BuMel and local radiotherapy. Overall Survival [Time Frame: Up to 5 years] [Designated as safety issue: No]Will be assessed by determining the overall survival rates for high-risk neuroblastoma patients undergoing Induction therapy followed by Consolidation with BuMel and local radiotherapy. Incidence of non-hematologic organ toxicity (grade 3 and higher) and all cause mortality graded according to the National Cancer Institute (NCI) CTC v3.0 [Time Frame: Up to 180 days] [Designated as safety issue: Yes]Will be assessed by a descriptive analysis of the relationship between busulfan pharmacokinetics with the occurrence of non-hematologic toxicities. In addition, the association between busulfan exposure levels as measured by the area under the curve (AUC) and event-free survival and overall survival will be examined using Cox proportional hazards models. Both the first dose AUC and the average daily AUC for busulfan will be required to perform the comparative analyses with non-hematologic toxicity, event-free and overall survival. First dose area under the curve (AUC) and average daily AUC for busulfan [Time Frame: Within 28 days following Consolidation] [Designated as safety issue: No]Relationship with occurrence of non-hematologic toxicities assessed by a descriptive analysis. Association between busulfan exposure levels as measured by the area under the curve (AUC) and event-free survival and overall survival will be examined using Cox proportional hazards models. Concordance between central reviewers and institutional reviewers with Curie scoring for consistency. [Time Frame: Up to week 12 (cycle 4 of induction therapy)] [Designated as safety issue: No]Will be assessed by calculating the percentage of MIBG scans receiving institutionally and centrally reviewed Curie scores within 1 unit of each other, at diagnosis and after Cycle 4 of Induction therapy. Up to 138 MIBG scans are expected at diagnosis and up to 124 MIBG scans from the 90% of patients estimated to be MIBG avid are projected post-Cycle 4 of Induction therapy, for a total of up to 262 MIBG scans. Correlate melphalan pharmacokinetics with non-hematologic toxicity measured by average daily area under the curve (AUC) [Time Frame: Within 28 days following completion of Consolidation therapy] [Designated as safety issue: No]Will be assessed by a descriptive analysis of the relationship between melphalan pharmacokinetics and the combination of busulfan and melphalan AUC with the occurrence of non-hematologic toxicities. In addition, the association between melphalan exposure levels as measured by the AUC and event-free survival and overall survival will be examined using Cox proportional hazards models. Feasibility of performing Curie scores in "real time" [Time Frame: Within 21 days of Cycle 4] [Designated as safety issue: No]Will be assessed by calculating the percentage of centrally reviewed post-Cycle 4 MIBG scans reporting a Curie score which will be considered to have been determined in "real time." The date of scan acquisition is defined as the date of completion of the MIBG scan. The central review process will be deemed acceptable if ≥ 90% of submitted post-Cycle 4 MIBG scans complete the central review process within 21 days of scan acquisition Proportion of high-risk neuroblastoma patients for whom ALK status can be obtained [Time Frame: Within 6 weeks of diagnosis] [Designated as safety issue: No]Will be assessed by calculating the proportion of high-risk neuroblastoma patients for whom ALK status can be obtained within 4-6 weeks of diagnosis. Proportion of high-risk neuroblastoma patients with MYCN non-amplified tumors for whom molecular profiling results can be obtained [Time Frame: Within 8 weeks of diagnosis] [Designated as safety issue: No]Will be assessed by determining the proportion of high-risk neuroblastoma patients with MYCN non-amplified tumors for whom molecular profiling results can be obtained within 6-8 weeks of diagnosis.

Descriptive Information[ + expand ][ + ]

Brief Title	Busulfan, Melphalan, and Stem Cell Transplant After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma
Official Title	Pilot Study Using Myeloablative Busulfan/Melphalan (BuMel) Consolidation Following Induction Chemotherapy for Patients With Newly Diagnosed High-Risk Neuroblastoma
Brief Summary	This pilot clinical trial studies busulfan, melphalan, and stem cell transplant after chemotherapy in treating patients with newly diagnosed high-risk neuroblastoma. Giving chemotherapy to the entire body before a stem cell transplant stops the growth of tumor cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy or radiation therapy is given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.
Detailed Description	This groupwide pilot study examines the toxicity profile of the Busulfan-Melphalan (BuMel) myeloablative preparative regimen in children and young adults with newly diagnosed high-risk neuroblastoma. The primary objective of the proposed study will be to examine the toxicity profile of this regimen in the context of COG therapy, with specific focus on the incidence and severity of pulmonary and hepatic toxicity. The Induction regimen will be 5 cycles of Induction. Consolidation therapy will consist of 4 doses of busulfan IV given once daily followed by a single dose of melphalan with a rest day prior to and following the melphalan dose. After recovery from Consolidation radiation therapy, patients will be encouraged to participate in clinical trials of ch14.18 immunotherapy (ie, ANBL0032 or other). Additional examinations will include pharmacokinetic measurements of busulfan and melphalan that will be collected and correlated with toxicity and survival. We will examine the ability to perform Curie scoring in real time, within 21 days of scan acquisition. This will be the first prospective use of Curie scoring in a cooperative group setting. This study will examine our ability to perform ALK gene testing prospectively, within 4 to 6 weeks of sample acquisition, by a centralized lab. Aberrations of the ALK gene in neuroblastoma tumors have been reported by multiple investigators, with potential therapeutic implications. Potential targeted inhibitors of ALK aberrations are now available, and may impact future clinical trial designs. In addition, molecular profiling of MYCN non-amplified tumors with a 14-gene signature panel will be performed. This study will test our ability to obtain tumor samples prospectively and identify molecular profiles within 6-8 weeks of sample acquisition which may also impact future clinical trial design.
Study Type	Interventional
Study Phase	N/A
Study Design	Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Condition	Neuroblastoma
Intervention	Drug: Cisplatin Cycle 3 and 5: CISplatin: IV over 1 hour Dose: 50 mg/m2/dose. For patients ≤ 12 kg the dose is 1.67 mg/kg/dose. Days: 1-4. Other Names: NSC# 119875Drug: Cyclophosphamide Cycle 1: IV over 15-30 mins - 400 mg/m2/dose or 13.3 mg/kg/dose if pt ≤ 12 kg Cycle 2: IV over 15-30 mins - 400 mg/m2/dose or 13.3 mg/kg/dose if pt ≤ 12 kg Cycle 4: IV over 1- 6 hours - 2100 mg/m2/dose or 70 mg/kg/dose if pt ≤ 12 kg Other Names: NSC# 26271Drug: Doxorubicin IV over 24 hours Dose: 25 mg/m2/dose. For patients ≤ 12 kg the dose administered is 0.83 mg/kg/dose. Days: 1-3 Continuous infusions require administration through a central venous access. Protect diluted solution from sun light. Other Names: NSC# 123127Drug: Etoposide IV over 1- 2 hours Dose: 200 mg/m2/dose. For patients ≤ 12 kg the dose is 6.67 mg/kg/dose. Days: 1-3 Infuse diluted solution (concentration ≤ 0.4 mg/mL) over at least 1-2 hours; slow rate of administration if hypotension occurs. The use of an in-line filter during the infusion is suggested. Other Names: NSC # 141540Drug: Topotecan IV over 30 minutes Dose: 1.2 mg/m2/dose Days: 1-5 Topotecan dosing is based on BSA regardless of age or weight. Other Names: NSC# 609699Drug: Vincristine IV push over 1 minute or infusion via minibag as per institutional policy. Age-based dosing: Age (in months) < 12 Dose 0.017 mg/kg/dose. Age (in months) ≥ 12 and weight > 12 kg Dose 0.67 mg/m2/dose or 0.022 mg/kg/dose [whichever is lower] Age (in months) ≥ 12 and weight ≤ 12 kg Dose 0.022 mg/kg/dose Note: Total dose may NOT exceed 2 mg in 72 hours or 0.67 mg/day for any patient. Administer prior to start of DOXOrubicin infusion and then daily for 3 total doses. Other Names: NSC# 67574Radiation: external beam radiation therapy Radiation will be given after recovery from BuMel transplant. Treatment volumes will be based on post-Induction imaging (MIBG, CT and/or MRI) and operative reports. Organ toxicity within the radiation field should have resolved. It is desirable to start radiation therapy no sooner than Day +28 and by Day +42 following ASCR of the BuMel transplant. Other Names: EBRTProcedure: PBSC Stem cells will be infused on Day 0 of Consolidation therapy. Where the DMSO volume in the stem cell product would exceed accepted level for infusion within a 24 hour period, stem cell products may be infused over 2 days to meet this standard Other Names: PBSC harvest: Peripheral blood stem cell harvest.Procedure: ASCT: autologous stem cell transplant (busulfan, melphalan) Chemotherapy also destroys healthy bone marrow. The blood stem cells that were stored during the Induction phase are given back to the patient after the high-dose chemotherapy. When these cells are given back, the procedure is called an Autologous Stem Cell Transplant (ASCT). Drug: Busulfan Consolidation therapy will consist of 4 doses of busulfan IV given once daily Other Names: NSC#50 BuMel Drug: Melphalan Short IV infusion to be completed in not more than 30 minutes Other Names: NSC#8806Drug: Mesna Mesna is a supportive care drug which is given to help protect your bladder from the side effects of chemotherapy. Induction Cycle 4 (Weeks 10-12) - Mesna: IV over 15 - 30 minutes or by continuous infusion. Other Names: sodium 2-mercaptoethane sulfonate UCB 3983 Mesnex NSC #113891
Study Arm (s)	Experimental: Treatment (induction therapy, consolidation therapy, ASCT) INDUCTION THERAPY: COURSES 1-2: Cyclophosphamide IV over 15-30 mins and topotecan hydrochloride IV over 30 mins on days 1-5. Day 6 Filgrastim dose. Treatment repeats every 3 wks for 2 courses. COURSES 3 & 5: Cisplatin IV over 1 hr on days 1-4 and etoposide IV over 1-2 hrs on days 1-3. Treatment repeats every 3 wks for 2 courses. COURSE 4: Cyclophosphamide IV over 1-6 hrs days 1-2, vincristine sulfate IV over 1 min days 1-3, & doxorubicin hydrochloride IV over 24 hrs days 1-3. MESNA after chemo. Treatment repeats every 3 wks for 1 course. Treatment continues in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: 4-8 wks following the 5th course of induction therapy, busulfan IV over 3 hrs days -6 to -3 & melphalan IV day -1. Radiation Therapy & ASCT: autologous stem cell transplant (busulfan, melphalan) day 0. PBSC infusion 24 hrs after melphalan infusion. Some patients undergo external beam radiation therapy (EBRT) after induction & consolidation.

Recruitment Information[ + expand ][ + ]

Recruitment Status	Recruiting
Estimated Enrollment	138
Estimated Completion Date	Not Provided
Estimated Primary Completion Date	January 2015
Eligibility Criteria	Inclusion Criteria: - Patients must have a diagnosis of neuroblastoma (International Classification of Diseases for Oncology [ICD-O] morphology 9500/3) or ganglioneuroblastoma (nodular or intermixed) verified by histology or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites; patients with the following disease stages at diagnosis are eligible, if they meet the other specified criteria - Patients with newly diagnosed neuroblastoma with International Neuroblastoma Staging System (INSS) stage 4 are eligible with the following: - MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features - Age > 18 months (> 547 days) regardless of biologic features - Age 12-18 months (365-547 days) with any of the following 3 unfavorable biologic features (MYCN amplification, unfavorable pathology and/or DNA index = 1) or any biologic feature that is indeterminate/unsatisfactory/unknown - Patients with newly diagnosed neuroblastoma with INSS stage 3 are eligible with the following: - MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features - Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status - Patients with newly diagnosed neuroblastoma with INSS stage 2A/2B with MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features - Patients with newly diagnosed neuroblastoma with INSS Stage 4S with MYCN amplification (> 4-fold increase in MYCN expression signals as compared to reference signals), regardless of additional biologic features - Patients >= 365 days initially diagnosed with neuroblastoma INSS stage 1, 2, 4S who progressed to a stage 4 without interval chemotherapy; these patients must have been enrolled on ANBL00B1; study enrollment on ANBL12P1 must occur within 4 weeks of progression to stage 4 for INSS stage 1, 2, 4S - Patients must not have had prior systemic therapy except for localized emergency radiation to sites of life-threatening or function-threatening disease and/or no more than 1 cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (as per P9641, A3961, ANBL0531, or similar) prior to determination of MYCN amplification status and histology - Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows: - Age 1 month to < 6 months: 0.4 mg/dL - Age 6 months to < 1 year: 0.5 mg/dL - Age 1 to < 2 years: 0.6 mg/dL - Age 2 to < 6 years: 0.8 mg/dL - Age 6 to < 10 years: 1 mg/dL - Age 10 to < 13 years: 1.2 mg/dL - Age 13 to < 16 years: 1.5 mg/dL (males), 1.4 mg/dL (females) - Age >= 16 years: 1.7 mg/dL (males), 1.4 mg/dL (females) - Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and - Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN for age - Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by radionuclide evaluation - No known contraindication to peripheral blood stem cell (PBSC) collection; examples of contraindications might be a weight or size less than that determined to be feasible at the collecting institution, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure. Exclusion Criteria: - Patients that are 12-18 months of age with INSS stage 4 and all 3 favorable biologic features (ie, nonamplified MYCN, favorable pathology, and DNA index > 1) are not eligible - Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events - Lactating females are not eligible unless they have agreed not to breastfeed their infants - Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained - Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation.
Gender	Both
Ages	N/A
Accepts Healthy Volunteers	No
Contacts	Contact: Meera Raman, MS, PMP, CCRP (626) 241-1532 mraman@childrensoncologygroup.org
Location Countries	United States

Administrative Information[ + expand ][ + ]

NCT Number	NCT01798004
Other Study ID Numbers	ANBL12P1
Has Data Monitoring Committee	Yes
Information Provided By	Children's Oncology Group
Study Sponsor	Children's Oncology Group
Collaborators	National Cancer Institute (NCI)
Investigators	Study Chair: Meaghan Granger, MD Cook Children's Medical Center
Verification Date	February 2014

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