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

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

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.

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.

Intervention(s) in this Clinical Trial

• Biological: filgrastim
  • Beginning 24 hours after chemotherapy end: 10 microgram/kg/day subcutaneously (SQ) or intravenously (IV) until absolute neutrophile count (ANC) > 1,000/mm^2. Starting that day, increase dose to 15 microgram/kg/day SQ or IV given as a single injection for 3 doses.
• Drug: busulfan
  • Part of pre-transplant conditioning chemotherapy: Administered as 1.1 mg/kg if <12 kg intravenously (IV) or 0.8 mg/kg if >12 kg IV every 6 hours on Days -8 through -6.
• Drug: etoposide
  • Part of Mobilization chemotherapy and Peripheral blood progenitor cell collections (day -100 to -30): Given as 100 mg/m^2/day intravenous (IV) over 1 hour for 5 days.
• Drug: ifosfamide
  • Part of Mobilization chemotherapy and Peripheral blood progenitor cell collections (day -100 to -30): Given as 1.8 g/m^2/day intravenous (IV) over 1 hour on for 5 days.
• Drug: melphalan
  • Part of pre-transplant conditioning chemotherapy: Administered as 50 mg/m^2 intravenous (IV) over 30 min on Days -5 through -4.
• Drug: thiotepa
  • Part of pre-transplant conditioning chemotherapy: Administered as 250 mg/m^2 intravenously (IV) over 2 hrs on Days -3 through -2.
• Procedure: stem cell transplantation
  • Regardless of whether the patient will be receiving peripheral cells or bone marrow, infusion will be intravenous on day 0, immediately after thawing.
• Procedure: positron emission tomography
  • At the initial visit a PET/CT scan should be obtained so that post-transplant radiation to PET positive areas can be planned.
• Radiation: tomotherapy
  • We plan to deliver the total marrow irradiation (TMI) to the upper half of the body using Tomotherapy TMI as explained in this protocol. However the lower part of the body will be treated with Anterior/Posterior linac based radiation treatment. Tomotherapy will then be delivered at a dose rate so as to keep the total treatment time to no more than 30 minutes. We anticipate that the dose rate will be around 400 cGy /minute (instantaneous dose rate).
• Radiation: total marrow irradiation
  • TMI will be delivered to all bony sites as part of the conditioning. Additional "spot" therapy to PET positive lesions, primary disease (if not previously irradiated to maximum tolerated dose), and lungs will be performed on Day +60. Cohorts of 3 patients will be treated at a total dose of 600 cGy, 900 cGy or 1200 cGy on Days -11 through -9.
• Drug: Mesna
  • Part of Mobilization chemotherapy and Peripheral blood progenitor cell collections (day -100 to -30): Given as 1.8 g/m^2/day divided in every 6 hrs dosing for 5 days.
• Radiation: Whole lung radiation
  • At Day 60, patients with prior lung metastasis should receive whole lung irradiation (1500cGy in 10 fractions).

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Tomotherapy
  • TMI given prior to alkylator intensive conditioning regimen for high risk solid tumor patients. Cohorts of patients (n=3) will be treated with increasing doses of TMI (600, 1000, 1200 cGy) directed toward the bones.

Primary Measures

• Maximum tolerated dose of tomotherapy up to 12 Gy
  • Time Frame: Day 42
    Safety Issue?: Yes

Secondary Measures

• Feasibility of performing PET scans and "spot radiation" to PET-positive lesions after transplantation
  • Time Frame: Before and After Transplant
    Safety Issue?: No
• Change in bone mineral density
  • Time Frame: Baseline, 6 and 12 Months Post Transplantation
    Safety Issue?: Yes

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 Note: Patients with primary central nervous system (CNS) tumors do not experience metastasis outside of the neuroaxis and thus, would not benefit from therapy directed toward bones.
• Therefore, this group of patients will not receive total marrow irradiation (TMI), but will be eligible for chemotherapy and HPC rescue parts of the protocol.
• 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 TMI patients should have a hemoglobin of >10 gm/dl and a platelet count > 20,000/μl. Patients may receive transfusions as necessary.
• Renal: GFR ≥ 50 ml/min/1.73m^2 or serum creatinine ≤ 2.5 x upper limit of normal (ULN) for age
• Hepatic: 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Masonic Cancer Center, University of Minnesota Other

Overall Clinical Trial Officials and Contacts

Michael R. Verneris, MD Principal Investigator Masonic Cancer Center, University of Minnesota  

Overall Contact: Timothy Krepski 612-273-2800 tkrepsk1@fairview.org

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00623077

Study ID Number: 2005LS023

ClinicalTrials.gov Identifier: NCT00623077

Health Authority: United States: Food and Drug Administration

Clinical trial summary from the National Cancer Institute's PDQ® database