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

Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00607984
• Other study ID #: 3990
• Status: Recruiting
• Phase: N/A
• First received: January 23, 2008
• Last updated: February 5, 2008
• Start date: June 2006

Study information

• Verified date: January 2008
• Source: Rabin Medical Center
• Contact: Jerry Stein, MD
• Phone: +97239253604
• Email: jstein[@]clalit.org.il
• Is FDA regulated: No
• Health authority: Israel: Ministry of Health
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. primary completion date: December 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 21 Years

Eligibility

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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Central Nervous System Neoplasms
• Central Nervous System Tumors
• Neoplasms
• Nervous System Neoplasms
• Tumors

Intervention

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

Locations

Country	Name	City	State
Israel	Schneider Children's Medical Center of Israel	Petach Tikva

Sponsors (1)

Lead Sponsor	Collaborator
Rabin Medical Center

Country where clinical trial is conducted

Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	survival		10 yeaer follow up	Yes
Secondary	toxicity		180 days	Yes