Neuroblastoma Protocol 2008: Therapy for Children With Advanced Stage High Risk Neuroblastoma

A Phase II study of temsirolimus in combination with standard chemotherapy (irinotecan; cyclophosphamide, doxorubicin and etoposide (CAE); cisplatin and etoposide (HiPE) and topotecan (TPT) followed by and additional six courses of induction chemotherapy and then intensification with autologous hematopoietic stem cell transplantation. The first five courses of induction chemotherapy will also evaluate the feasibility of combining weekly temsirolimus with these standard chemotherapy combinations. This will be followed by 16 months of oral maintenance therapy with eight months of 13-cis-retinoic acid and then eight months of oral topotecan.

Study Overview

• Status: Terminated
• Conditions: Neuroblastoma
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Cisplatin; Drug: Etoposide; Radiation: Radiation Therapy; Drug: Doxorubicin; Drug: Temsirolimus; Drug: Irinotecan; Procedure: Surgical Resection of Primary Tumor; Drug: Topotecan; Procedure: PBSC; Drug: 13-cis-retinoic acid

Detailed Description

All children will receive fixed doses of intravenous temsirolimus (50 mg/m2 weekly 6 times ) concomitantly with two courses of fixed dosages of irinotecan (20 mg/m2 intravenously daily 5 times ,2 days off, repeated daily 5 times .If these initial dosages are not tolerable then subsequent patients will be given a reduced dosage of temsirolimus (25 mg/m2 weekly 6 times) with 20 mg/m2 of irinotecan.If this dosage combination is not tolerable, the irinotecan dosage will be decreased to 15 mg/m2 .If this dosage combination is not tolerable then further enrollment to the initial six week treatment will be terminated.The second course of irinotecan will begin on day 22 and response will be determined after six weeks (two courses). Resection of primary tumor will be attempted after this initial therapy, whenever possible.

Following initial treatment children will undergo alternating courses of induction chemotherapy with cyclophosphamide, doxorubicin, etoposide, topotecan, and cisplatin (Block 2). The first cohort of 17 patients will receive Block 2 with temsirolimus (50mg/m2) for all three courses, weekly 2 times. If this is not tolerated subsequent patients will receive Block 2 chemotherapy with reduced dosages of temsirolimus (25mg/m2).

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients <18 years old with newly diagnosed, advanced stage, high-risk neuroblastoma defined as one of the following:

  • Children < 1 yo with International Neuroblastoma Staging System (INSS) stage 2a, 2b, 3, 4 or 4S disease and MYCN amplification (>10 copies, or greater than four-fold increase in MYCN signal as compared to reference signal)
  • INSS 2a or 2b disease and MYCN amplification, regardless of age or additional biologic features

  • INSS stage 3 and:

    1. MYCN amplification (>10 copies, or greater than four-fold increase in MYCN signal as compared to reference signal, regardless of age or additional biologic features
    2. Age > 18 mo (> 547 days) with unfavorable pathology, regardless of MYCN status

  • INSS stage 4 and:

    1. MYCN amplification, regardless of age or additional biologic features
    2. Age > 18 months (> 547 days) regardless of biologic features
    3. Age 12 - 18 months (365 - 547 days) with any of the following three unfavorable biologic features (MYCN amplification, unfavorable pathology and/or DNA index =1) or any biologic feature that is indeterminant/unknown
  • Children less than or equal to 365 days initially diagnosed with: INSS stage 1, 2, 4S who progressed to a stage 4 without interval chemotherapy.
• Histologic proof of neuroblastoma or positive bone marrow for tumor cells with increased urine catecholamines.
• Adequate renal and hepatic function (serum creatinine <3 x upper limit of normal for age, (AST) aspartate aminotransferase < 3 x upper limit of normal).
• No prior therapy, unless an emergency situation requires local tumor treatment (discuss with PI)
• Written, informed consent according to institutional guidelines

Exclusion Criteria:

• Any evidence, as judged by the investigator, of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease).
• Pregnant or breast feeding (women of child-bearing potential).
• Children with INSS 4 disease, age <12 months with all 3 favorable biologic features (non-amplified MYCN, favorable pathology and DNA index >1).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 1; Fixed doses of IV temsirolimus concomitantly with two courses of fixed dosages of irinotecan, 2 days off, repeated daily 5 times.If initial dosages are not tolerable, subsequent patients will be given a reduced dosage of temsirolimus with irinotecan.If this dosage combination is not tolerable,irinotecan dosage will be decreased.If this dosage combination is not tolerable.Further enrollment to initial six week treatment will be terminated.Second course of irinotecan will begin on day 22, response will be determined after six weeks. Resection of primary tumor will be attempted after initial therapy.Following initial treatment children will undergo alternating courses of induction chemotherapy with cyclophosphamide,doxorubicin,etoposide,topotecan, and cisplatin.First cohort of 17 patients will receive Block 2 with temsirolimus for all three courses, weekly 2 times.If this is not tolerated subsequent patients will receive Block 2 chemotherapy with reduced dosages of temsirolimus.

Drug: Cyclophosphamide; Cyclophosphamide; Drug: Cisplatin; Cisplatin; Drug: Etoposide; Etoposide; Radiation: Radiation Therapy; Radiation Therapy; Drug: Doxorubicin; Doxorubicin; Drug: Temsirolimus; Temsirolimus; Drug: Irinotecan; Irinotecan; Procedure: Surgical Resection of Primary Tumor; Surgical Resection of Primary Tumor; Drug: Topotecan; Topotecan; Procedure: PBSC; Peripheral Blood Stem Cell Harvest; Drug: 13-cis-retinoic acid; 13-cis-retinoic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response Plus Partial Response	The objective was to measure the efficacy and feasability of Temsirolimus and Irinotecan as measured by the objective response rate and toxicity rate.	10 years

Collaborators and Investigators

• Sponsor: St. Jude Children's Research Hospital
• Investigators: Principal Investigator: Wayne L Furman, MD, St. Jude Children's Research Hospital

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: December 11, 2008
• First Submitted That Met QC Criteria: December 15, 2008
• First Posted (Estimate): December 16, 2008

Study Record Updates

• Last Update Posted (Actual): May 30, 2017
• Last Update Submitted That Met QC Criteria: April 24, 2017
• Last Verified: May 1, 2010

More Information

Terms related to this study

• Keywords: Neuroblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Keratolytic Agents; Topoisomerase I Inhibitors; Cyclophosphamide; Etoposide; Cisplatin; Irinotecan; Doxorubicin; Topotecan; Sirolimus; Tretinoin; Isotretinoin
• Other Study ID Numbers: NB2008