ANBL12P1,Pilot Study Using Myeloablative Busulfan/Melphalan (BuMel) Consolidation Following Induction Chemotherapy for Patients with Newly Diagnosed High-Risk Neuroblastoma

Study ID
STU 042013-006

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

  • Children's Medical Center-Dallas

Contact
Sarmistha Sen
214-456-0437
sarmistha.sen@childrens.com

Principal Investigator
Tanya Watt

Summary

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 BuMel regimen following induction therapy has been shown in a randomized european trial to have superior outcome over carboplatin, etoposide and melphalan (CeM). Though the regimen has been used in SioP-en neuroblastoma studies, it has not been studied within the framework of a CoG induction platform. 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 patterned after recent high-risk neuroblastoma studies (anBL02P1, anBL0532 and anBL09P1) but will give 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. Busulfan pharmacokinetics will be examined and adjustments made for an auC above 5500 (micromole/liter)*minute. Following recovery from BuMel Consolidation chemotherapy, patients who achieve end of induction primary site complete response (CR) will receive 21.6 Gy external beam radiation therapy (eBRT) to the primary site (standard dose) while patients achieving [Less Than] CR at the primary site will receive an additional boost of 14.4 Gy for a total dose of 36 Gy eBRT delivered to gross residual primary site disease, as per CoG anBL0532. 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. Data from CoG a3973 indicate that Curie scoring carries prognostic significance, with post-induction Curie scores able to identify patients at high-risk for subsequent relapse or disease progression.1 The current study will examine our ability to perform aLK gene testing prospectively, within 4 to 6 weeks of diagnosis, 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.2 The current study (anBL12P1) will test our ability to obtain tumor samples prospectively and identify molecular profiles within 6-8 weeks of diagnosis which may also impact future clinical trial design.

Participant Eligibility

1. Age
Patients must be <= 30 years of age at the time of initial diagnosis.

2. Diagnosis
Patients must have a diagnosis of neuroblastoma (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.
2.1
Patients with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following:
a. MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or
b. Age > 18 months (> 547 days) regardless of biologic features or
c. 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.
2.2
Patients with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following:
a. MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features or
b. Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status.
2.3
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.
2.4
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.
2.5
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.

3. Prior Therapy
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.

4. Organ Function Requirements
4.1 Adequate Renal Function
4.2 Adequate Liver Function
4.3 Adequate Cardiac Function
4.4 Ability to tolerate PBSC collection: