MT2004-30: Tomotherapy for Solid Tumors

Phase 1

Terminated

• Conditions: Sarcoma; Brain and Central Nervous System Tumors; Kidney Cancer; Liver Cancer; Retinoblastoma
• Interventions: Biological: filgrastim; Drug: busulfan; Drug: etoposide; Drug: ifosfamide; Drug: melphalan; Drug: thiotepa; Procedure: stem cell transplantation; Radiation: tomotherapy; Radiation: total marrow irradiation; Drug: Mesna; Radiation: Whole lung radiation

• Registration Number: NCT00623077
• Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary

RATIONALE: A peripheral blood stem cell transplant or bone marrow transplant using stem cells from the patient may be able to replace immune cells that were destroyed by chemotherapy and image-guided intensity-modulated radiation therapy used to kill tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of bone marrow radiation therapy followed by an autologous stem cell transplant in treating patients with high-risk or relapsed solid tumors.

Detailed Description

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.

Study Timeline

• Study Start: 2005-08
• Study First Submitted: 2008-02-22
• Study First Submitted QC: 2008-02-22
• Study First Posted: 2008-02-25
• Primary Completion: 2012-07
• Study Completion: 2016-10
• Status Verified: 2017-12
• Last Update Submitted: 2017-12-03
• Last Update Posted: 2017-12-05

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 23

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Total Marrow Irradiation (MTI) with Tomotherapy	etoposide	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.
Total Marrow Irradiation (MTI) with Tomotherapy	filgrastim	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.
Total Marrow Irradiation (MTI) with Tomotherapy	busulfan	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.
Total Marrow Irradiation (MTI) with Tomotherapy	thiotepa	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.
Total Marrow Irradiation (MTI) with Tomotherapy	stem cell transplantation	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.
Total Marrow Irradiation (MTI) with Tomotherapy	tomotherapy	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.
Total Marrow Irradiation (MTI) with Tomotherapy	total marrow irradiation	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.
Total Marrow Irradiation (MTI) with Tomotherapy	Whole lung radiation	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.
Total Marrow Irradiation (MTI) with Tomotherapy	melphalan	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.
Total Marrow Irradiation (MTI) with Tomotherapy	ifosfamide	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.
Total Marrow Irradiation (MTI) with Tomotherapy	Mesna	TMI given prior to alkylator intensive conditioning regimen (Busulfan 9.6 mg/kg intravenously (IV) (\>4 yrs of age) or 13.2 mg/kg IV (\< 4 years of age), Melphalan 100 mg/m\^2, Thiotepa 500 mg/m\^2 for high risk solid tumor patients, Whole lung radiation 1500cGy in 10 fractions by Day 60, stem cell transplantation on day 0. Ifosfamide, etoposide, and mesna are given Days 0-4 followed by filgrastim for 3 doses. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose of tomotherapy up to 12 Gy	Day 42	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%.

Secondary Outcome Measures

Name	Time	Method
Percent of patients who had PET scans and "spot radiation" to PET-positive lesions after transplantation	Day 60 Post Transplant	PET-CT scan is done prior to and after transplant. Radiation is given before and after transplant.
Change in bone mineral density	Baseline, 6 and 12 Months Post Transplantation	the change in bone density and turnover in patients exposed to alkylator intensive conditioning regimen followed by tomographic total marrow irradiation (TMI).
Rate of Treatment Related Mortality in Non-TMI Treated Patients	Day 100 Post Transplant	Determined in patients who were not treated with total marrow irradiation; all deaths without previous relapse or progression are usually considered as related to transplantation.
Rate of Primary Neutrophil Engraftment	Day 42	Neutrophil engraftment is defined as the first day of three consecutive days where the neutrophil count (absolute neutrophil count) is 500 cells/mm3 (0.5 x 109/L) or greater.
Overall Survival	From date of enrollment to date of death or censored at the date of last documented contact	Determined in patients not receiving total marrow irradiation. The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. Also called survival rate.
Disease-Free Survival	1 Year	In patients not receiving total marrow irradiation, the length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.

Trial Locations

Locations (1)

Masonic Cancer Center at University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States