Trial Information

A Phase I Trial of Busulfan, Thiotepa and Melphalan Followed by Autologous or Syngeneic Peripheral Blood Stem Cell Transplantation and Followed by Total Marrow (Skeletal) Irradiation (TMI) in Patients With High-Risk Ewing's Sarcoma, PNET or Rhabdomyosarcoma

OBJECTIVES: I. Estimate the maximum tolerated dose of total bone marrow irradiation (TMI)
that can be administered as planned consolidation utilizing autologous peripheral blood stem
cell support following local radiotherapy (if indicated) and prior busulfan, melphalan, and
thiotepa. II. Examine the efficacy of this dual transplant approach for high-risk patients
with Ewing's sarcoma, peripheral primitive neuroectodermal tumor, or rhabdomyosarcoma in
first complete remission or greater.

OUTLINE: This is a two part, radiation dose escalation study. Peripheral blood stem cells
(PBSC) are collected after 5-6 daily injections of G-CSF. The PBSC are infused in two
halves. One half is given after chemotherapy and the other half after total marrow
irradiation (TMI). Transplant #1 (part one) consists of chemotherapy and PBSC infusion.
Busulfan (BU) is administered orally every 6 hours for 3 days for a total of 12 doses on
days -8, -7 and -6. Melphalan is intravenously infused over 30 minutes for 2 days on days -5
and -4. Thiotepa is intravenously infused over 2 hours on days -3 and -2. PBSC are infused
on day 0, 36-48 hours after completion of chemotherapy. Patients are considered for local
irradiation therapy between transplant #1 and #2 if tissue limiting irradiation doses to
bulk tumor site have not previously been administered. The local irradiation is given
immediately prior to TMI administration. Transplant #2 starts sometime between day 60 and
120 after transplant #1. For transplant #2, cohorts of 4 patients are treated with TMI twice
a day for 5 days at initial dose level on days -5 through -1. TMI is administered over 30-40
minutes. The second half of the PBSC is infused 1-24 hours following the last dose of TMI.
After treatment of at least 4 patients at the initial TMI dose level, dose levels escalate
in the absence of toxicity. If there is no dose limiting toxicity (DLT) in the current group
of 4 patients, the next cohort is treated at the next higher dose level. If 1 of the 4
patients experiences DLT, the next cohort is treated at the same dose. If 1 DLT is seen
among 8 patients treated at a dose, then the next cohort is treated at the next higher dose
level. If 2 patients out of 8 experience DLT, this dose is identified as the maximum
tolerated dose (MTD). If 1 out of 4 or 3 out 8 patients experience DLT at a dose level, the
next lower dose level is identified as the MTD. Each patient in a cohort is observed for a
minimum of 28 days prior to escalation to the higher dose level. Tumor restaging occurs
approximately 9 months after initial transplant, then at 12 months and annually thereafter.

PROJECTED ACCRUAL: An expected 12-16 patients are required to complete this study. Accrual
should last 3-4 years at 4-5 patients per year.