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Dose Escalation of Total Marrow Irradiation Added to an Alkylator-Intense Conditioning Regimen for Patients With High Risk or Relapsed Solid Tumors

Phase 1
70 Years
Not Enrolling
Brain and Central Nervous System Tumors, Kidney Cancer, Liver Cancer, Retinoblastoma, Sarcoma

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Trial Information

Dose Escalation of Total Marrow Irradiation Added to an Alkylator-Intense Conditioning Regimen for Patients With High Risk or Relapsed Solid Tumors



- 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.


- 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.


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

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

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

- 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

- 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.

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated dose of tomotherapy up to 12 Gy

Outcome Description:

is a state-of-the- art means of delivering highly conformal radiation to tumors of targeted volume with high therapeutic gain. Tomotherapy offers unique advantages over total body irridiation and is expected to improve clinical outcome. The MTD is defined as the highest dose studied for which the incidence of dose limiting toxicity is less than 33%.

Outcome Time Frame:

Day 42

Safety Issue:


Principal Investigator

Michael R. Verneris, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota


United States: Food and Drug Administration

Study ID:




Start Date:

August 2005

Completion Date:

June 2014

Related Keywords:

  • Brain and Central Nervous System Tumors
  • Kidney Cancer
  • Liver Cancer
  • Retinoblastoma
  • Sarcoma
  • metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor
  • recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor
  • childhood hepatoblastoma
  • recurrent childhood liver cancer
  • stage IV childhood liver cancer
  • adult primary liver cancer
  • previously treated childhood rhabdomyosarcoma
  • recurrent childhood rhabdomyosarcoma
  • previously untreated childhood rhabdomyosarcoma
  • metastatic childhood soft tissue sarcoma
  • recurrent childhood soft tissue sarcoma
  • recurrent adult soft tissue sarcoma
  • stage IV adult soft tissue sarcoma
  • recurrent Wilms tumor and other childhood kidney tumors
  • stage IV Wilms tumor
  • stage V Wilms tumor
  • rhabdoid tumor of the kidney
  • stage IV renal cell cancer
  • childhood mixed glioma
  • recurrent childhood cerebellar astrocytoma
  • recurrent childhood cerebral astrocytoma
  • recurrent childhood ependymoma
  • recurrent childhood medulloblastoma
  • recurrent childhood pineoblastoma
  • recurrent childhood supratentorial primitive neuroectodermal tumor
  • recurrent childhood visual pathway glioma
  • untreated childhood brain stem glioma
  • untreated childhood cerebellar astrocytoma
  • childhood infratentorial ependymoma
  • childhood supratentorial ependymoma
  • childhood high-grade cerebellar astrocytoma
  • childhood high-grade cerebral astrocytoma
  • childhood low-grade cerebellar astrocytoma
  • childhood low-grade cerebral astrocytoma
  • newly diagnosed childhood ependymoma
  • childhood atypical teratoid/rhabdoid tumor
  • recurrent retinoblastoma
  • extraocular retinoblastoma
  • intraocular retinoblastoma
  • childhood renal cell carcinoma
  • clear cell renal cell carcinoma
  • recurrent renal cell cancer
  • recurrent childhood visual pathway and hypothalamic glioma
  • unspecified adult solid tumor, protocol specific
  • unspecified childhood solid tumor, protocol specific
  • Carcinoma, Renal Cell
  • Kidney Neoplasms
  • Liver Neoplasms
  • Nervous System Neoplasms
  • Retinoblastoma
  • Central Nervous System Neoplasms
  • Neuroectodermal Tumors, Primitive
  • Neuroectodermal Tumors, Primitive, Peripheral
  • Sarcoma



Masonic Cancer Center at University of MinnesotaMinneapolis, Minnesota  55455