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Administration of High Dose Thiotepa and Melphalan With Autologous Hematopoietic Stem Cell Transplant in Children and Adolescents With Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00607984
Recruitment Status : Unknown
Verified January 2008 by Rabin Medical Center.
Recruitment status was:  Recruiting
First Posted : February 6, 2008
Last Update Posted : February 6, 2008
Information provided by:
Rabin Medical Center

Brief Summary:
The prognosis of children and adolescents with high risk tumors of the central nervous system and other miscellaneous solid tumors is poor despite modern treatment protocols. Frequently, physicians suggest additional therapy with high dose chemotherapy after a good initial response to standard doses of treatment has been obtained, so as to reduce the chance that the tumor will recur. We propose a regimen of high dose thiotepa and melphalan followed by rescue of the patient's previously stored hematopoietic (blood manufacturing) system with blood stem cells. The aim of this study is to prove that this therapy is tolerable in children and adolescents, that it results in tolerable levels of toxicity, and that it improves the survival of this group of children as compared to standard therapy given in the past

Condition or disease Intervention/treatment Phase
Central Nervous System Tumors Tumors Drug: thiotepa melphalan Not Applicable

Detailed Description:

Despite progress in the treatment of children and adolescents suffering from solid tumors and tumors of the CNS, patients with metastatic disease (or with disease with other high risk features) continue to suffer from relapse when treated with standard chemotherapy protocols. In these patients, high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) has been proposed as consolidation therapy in this high-risk population.

The paradigm for successfully utilization of autologous stem cell transplantation is childhood neuroblastoma. A large, well performed, randomized study in children with high risk neuroblastoma showed that application of autologous stem cell transplant can lead to improved disease free and overall survival, effects that were further augmented by the administration of biological agents with specific activity against this tumor. Smaller non-controlled studies and case series have shown that ASCT is feasible in children with solid tumors or with tumors of the central nervous system. Despite the many reports in the literature, there is little agreement among investigators as to the ideal combination of chemotherapeutic agents that should be included in the high dose chemotherapy regimen administered prior to ASCT for these patients. The choice of agents in these protocols is dictated by the use of drugs whose dose limiting toxicity is hematopoietic, a concern that is obviated by the subsequent infusion of autologous stem cells. As such, the majority of HDC protocols exploit the steep dose response curve of alkylating agents, where administration of high doses had usually been limited by fear of inducing permanent myeloablation.

A major limitation of many HDC protocols is that many of the alkylating agents that are used have already been utilized in front line protocols. A further problem in the design of HDC protocols that is unique to patients suffering from CNS tumors, is that the administered agents must traverse the blood brain barrier (BBB) in order to reach the site of the tumor.

A major breakthrough in the the application of HDC in children nwith CNS tumors occurred with the use of Thiotepa, a highly myeloablative bifunctional alkylating agent that partitions equally across the BBB. Thiotepa is now a mainstay of all HDC protocols for children with CNS tumors.

Hara et al. pioneered a novel combination of Thiotepa with Melpahlan, also an alkylating agent, in the treatment of children with a variety of solid tumors. They catalogued the toxicity of this protocol, and suggested a dose level of each drug in the combination that led to toxicity levels of grade ≤3. Of note, in the Hara series, some patients also received high dose Busulfan.

We piloted the Hara protocol in our center on 14 patients and found that the dose levels suggested in their study were not tolerated well by children in our center. We decided to modify the Hara protocol by reducing the doses of both Thiotepa and Melphalan to reduce the incidence of severe gastrointestinal toxicity that our patients experienced. In addition, after two patients succumbed to fulminant gram positive infections on the original protocol, we instituted the empiric administration of Vancomycin for primary treatment of febrile neutropenia in these patients, pending the results of blood cultures. We also decided to restrict admission to the protocol to patients with minimal amounts of residual disease as measured by MRI / CT scan or biochemical markers prior to transplant.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: High Dose Thiotepa and Melphalan With Autologous Hematopoietic Stem Cell Transplant in Children and Adolescents With Solid Tumors
Study Start Date : June 2006
Estimated Primary Completion Date : December 2010

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: single Drug: thiotepa melphalan
thiotepa 900 mg per meter squared total, on days -11,-10,-4,-3 melphalan 140 mg per meter squared total on days -11,-10,-4,-3 autologous stem cell transplant in day 0

Primary Outcome Measures :
  1. survival [ Time Frame: 10 yeaer follow up ]

Secondary Outcome Measures :
  1. toxicity [ Time Frame: 180 days ]

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age 1-21 years
  • CNS tumors, hepatic tumors and other solid tumors that are chemosensitive
  • Minimal disease as determined by either radiological studies or biochemical markers (as determined by treating physician).
  • Consent of patient or surrogate.

Exclusion Criteria:

  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • No known HIV or AIDS infection
  • No active bacterial, fungal, or viral infection
  • No medical condition that would preclude study treatment
  • Positive pregnancy test or failure to use contraceptives.
  • Creatinine >1.5 times limit of normal for age
  • SGOT or SGPT more than 3 times normal.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00607984

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Contact: Jerry Stein, MD +97239253604
Contact: Isaac Yaniv, MD +97239253704

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Schneider Children's Medical Center of Israel Recruiting
Petach Tikva, Israel, 49202
Contact: Jerry Stein, MD    +97239253604   
Contact: Isaac Yaniv, MD    +97239253704   
Sponsors and Collaborators
Rabin Medical Center
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Principal Investigator: Jerry Stein, MD Schneider Children's Medical Center, Israel
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Responsible Party: Jerry Stein MD, Schneider Children's Medical Center of Israel Identifier: NCT00607984    
Other Study ID Numbers: 3990
First Posted: February 6, 2008    Key Record Dates
Last Update Posted: February 6, 2008
Last Verified: January 2008
Keywords provided by Rabin Medical Center:
brain tumor
tumors of central nervous system and other solid tumors
Additional relevant MeSH terms:
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Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs