MT2004-30: Tomotherapy for Solid Tumors

OBJECTIVES:

Primary

- To determine the maximum tolerated dose of tomographic total marrow irradiation (TMI)
when given prior to an alkylator-intensive conditioning regimen in patients with
high-risk or relapsed solid tumors.

Secondary

- To determine the feasibility of performing positron emission tomography (PET) scans and
spot radiation to PET-positive lesions after transplantation.

- To determine the change in bone mineral density and turnover in patients treated with an
alkylator-intensive conditioning regimen and TMI.

OUTLINE:

- Mobilization chemotherapy and peripheral blood progenitor cell (PBPC) collection:
Patients receive ifosfamide intravenously (IV) and etoposide IV on days -100 through
-30.

Beginning 24 hours after completion of chemotherapy, patients receive filgrastim (G-CSF)
subcutaneously (SC) or IV until blood counts recover. Patients then receive an increased dose
of G-CSF SC or IV once daily for 3 consecutive days. Beginning on day -97, patients undergo
up to 4 collections of PBPCs. Patients who do not yield an adequate number of cells undergo
bone marrow harvest.

- Bone marrow harvest: Patients undergo bone marrow aspirate and biopsy 2 weeks after the
last dose of G-CSF. If the aspirate or biopsy is morphologically free of tumor cells and
demonstrates > 20% cellularity, then patients receive sargramostim (GM-CSF) daily for 5
days followed by bone marrow harvest.

- Total marrow irradiation (TMI) with tomotherapy: Patients undergo escalating doses of
TMI* to all bony sites using helical tomotherapy image-guided intensity-modulated
radiotherapy on days -11 to -9.

NOTE: *Patients with primary CNS tumors do not receive TMI but are eligible to receive
chemotherapy and hematopoietic progenitor cell rescue in accordance with the protocol.

- Conditioning regimen: Patients receive busulfan IV over 2 hours four times daily on days
-8 to -6, high-dose melphalan IV over 30 minutes on days -5 to -4, and thiotepa IV over
2 hours on days -3 to -2.

- Autologous CD34+ hematopoietic progenitor cell transplantation: Patients undergo
reinfusion of autologous G-CSF-mobilized peripheral blood or bone marrow progenitor
cells on day 0. Patients also receive G-CSF support beginning on day 0 and continuing
until blood counts recover for 2 consecutive days.

- Post-transplantation radiotherapy: Patients may receive additional radiotherapy to areas
of known metastatic disease, PET-positive lesions, primary disease (if not previously
irradiated to maximum tolerated dose), and lungs beginning on day 60 post
transplantation. Patients with prior lung metastasis may receive up to 10 fractions of
whole-lung irradiation.

Patients may also receive additional radiotherapy to primary disease if maximum tolerated
dose has not yet been reached.

Patients undergo bone mineral density studies at baseline and at days 60, 120, and 180 post
transplantation. Patients also undergo blood sample collection periodically during study for
pharmacokinetic analysis of busulfan.

Patients undergo PET scans at baseline and on day 60.

After completion of study therapy, patients are followed at days 180 and 365 and then
periodically thereafter.

Inclusion Criteria:

- Diagnosis Patients must have had histologic verification of malignancy at original
diagnosis. Diseases included are:

- Ewing's Family Tumors (ES/PNET/DSRCT): metastatic at the time of diagnosis and/or
relapsed after therapy

- Renal tumors: relapsed (all histology-Wilm's tumor) or at diagnosis (clear cell
sarcoma and Rhabdoid tumor),

- Hepatoblastoma: metastatic at the time of diagnosis and/or relapsed after therapy

- Rhabdomyosarcoma: metastatic at the time of diagnosis and/or relapsed after
therapy

- Soft tissue sarcomas: chemotherapy responsive metastatic disease or chemotherapy
responsive relapsed disease

- Primary Malignant Brain Neoplasms at diagnosis and/or relapse

- Retinoblastoma: disseminated at diagnosis and/or relapsed

- Other High Risk Metastatic or Relapsed Solid Tumors: To be approved by two or
more physicians on the study committee

- Disease Status: Patients must have either: 1) no evidence of disease or 2) stable,
non-progressive disease (defined as non-progressive abnormalities on physical exam or
computated tomography (CT) and/or magnetic resonance imaging [MRI]) within 4 weeks of
study entry.

- Age: Patients must be 0-70 years of age at the time of study entry.

- Performance Level: Karnofsky > or = 50% for patients > 10 years of age and Lansky > or
= 50% for patients < or = 10 years of age. Note: Neurologic deficits in patients with
central nervous system (CNS) tumors must be stable for a minimum of 1 week prior to
study entry.

- Organ Function:

- Hematologic: prior to receiving total marrow irradiation (TMI) patients should
have a hemoglobin of >10 gm/dl and a platelet count > 20,000/μl. Patients may
receive transfusions as necessary.

- Renal: glomerular flow rate (GFR) ≥ 50 ml/min/1.73m^2 or serum creatinine ≤ 2.5 x
upper limit of normal (ULN) for age

- Hepatic: aspartate aminotransferase/alanine aminotransferase (AST or ALT) ≤ 5 x
ULN and bilirubin ≤ 5 x ULN

- Cardiac: ejection fraction > 45% or no clinical evidence of heart failure

- Pulmonary: oxygen saturation > 92% at rest (on room air)

Exclusion Criteria:

- Disease Status: patients with progressive, non-therapy responsive disease will not be
eligible.

- Infection: patients who have active, uncontrolled infections or those who are HIV+.

- Pregnancy or Breast-Feeding: pregnant or breast-feeding women will not be entered on
this study.

- Prior Radiation Therapy: patients must be eligible to receive TMI via tomographic
radiation therapy (as determined by radiation oncology staff). If not eligible (due to
extensive prior radiation or other circumstances), patients can be treated on study
but will not receive radiation and will be analyzed on a separate arm.