Total Skeletal Irradiation in Multiple Myeloma Before Second Autologous Hematopoietic Stem Cell Transplantation
The purpose of this study is to improve the efficacy of the HDC regimen by adding a novel, "targeted" means administering a variation of total body irradiation (TBI) radiation i.e., total skeletal irradiation (TSI) administered by helical tomotherapy (HT) before, and in addition to the current standard of HDC, at a dose of 200 mg/m2 (HDMel200). The underlying postulate of this endeavor is that TSI-HT will provide additional cytoreduction to HDMel alone, without producing additional (serious) toxicity. We will utilize a classical Phase I study design (i.e., dose escalation) in myeloma patients undergoing AHSCT2 to define a maximum tolerated dose (MTD) and dose limiting toxicity (DLT). Finally, although comparisons to other therapies are not typical (and/or feasible) for a Phase I study, we will compare, whenever possible, both the toxicity and the antimyeloma activity of the AHSCT2 to AHSCT1.
This protocol will standardize, as much as possible the use of AHSCT2 both as a "tandem" and "salvage" procedure. Since sufficient AHSC (CD34+ cells) are routinely collected in adequate numbers for multiple AHSCTs, but recently used infrequently, it is important to work towards defining the optimal utilization of this resource.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Evaluation of a Method Designed to Improve Outcome of High-Dose Chemotherapy (HDC) and Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for Selected Patients With Myeloma: A Phase I Study Using Total Marrow Irradiation (TMI) Administered Via Helical Tomotherapy (HT)Plus High-Dose Melphalan and Amifostine Before AHSCT2|
- Define the maximum tolerated dose of a derived high dose therapy regimen [ Time Frame: Day 100 post transplant ] [ Designated as safety issue: Yes ]MTD of high dose therapy consisting of escalating doses of Total Skeletal Irradiation administered via Helical Tomotherapy, followed by standard high dose chemotherapy of high dose Melphalan (200mg/m2) with amifostine cytoprotection before AHSCT.
- Determine the dose-limiting toxicity (DLT) of TSI-HT therapy [ Time Frame: Day 100 post transplant ] [ Designated as safety issue: Yes ]This objective will also include detailed short and long term assessment of hematopoiesis even if it is not the dose limiting toxicity.
- Compare toxicities to those produced by the AHSCT1 regimen [ Time Frame: Day 100 post transplant ] [ Designated as safety issue: Yes ]Determine if quantity and severity of toxicities of TSI regimen are less than toxicities experienced in AHSCT1.
- Compare antitumor results obtained by TSI-HT before AHSCT [ Time Frame: End of study (June 2013 - anticipated) ] [ Designated as safety issue: No ]Compare using standard outcome parameters (ie; response rate, relapse rate, disease-free survival or progression-free survival and overall survival) to high dose chemotherapy/AHSCT1
|Study Start Date:||June 2010|
|Estimated Primary Completion Date:||June 2015 (Final data collection date for primary outcome measure)|
|Experimental: Total Skeletal Irradiation||
Radiation: Total Skeletal Irradiation
Escalating doses of TSI starting at 200cGy (escalating up to 400cGy unless maximum tolerated dose is determined in lower dose level) in cohort 1 over 5 days followed by high dose melphalan and cytoprotection followed by autologous hematopoietic stem cell transplant
While HDC/AHSCT is active most patients eventually relapse; obviously, those with lesser responses progress as well. Many investigators regard HDC/AHSCT as a "mature" modality a useful if fixed element in an evolving treatment paradigm that focuses on the introduction of new (non-HDC/AHSCT) agents with unique mechanisms of action. However, data from several related sources (including both the syngeneic and second ["tandem" or salvage] AHSCT experience), suggests that the efficacy of HDC/AHSCT could be improved by obtaining better cytoreduction of the HDC component, thus prolonging survival and possibly even producing an increase in cures. However, to do so will require additional attention to the sources of relapse following HDC/AHSCT, mainly the residual myeloma in the patient, but perhaps also the inadvertent reinfusion of clonogenic myeloma cells in the AHSCT. For reasons discussed herein, this study will focus on the former.
We believe that the agents with more potent activity vs. the (multiple) myeloma cancer stem cell (MM-CSC) and/or their microenvironment are ultimately needed to increase the cure rate in myeloma. Unfortunately, preliminary data suggest current modalities used in myeloma therapy are only variably effective vs. these targets, and that newer agents with such activity are only now becoming available for clinical trials.
The use of these newer agents are most likely to augment, not supplant, current modalities, lending even more urgency to optimizing existing elements to try to improve the efficacy of HDC/AHSCT and especially to determine if activity vs. MM-CSC and/or the microenvironment of these current modalities can be augmented. Radiation seems especially attractive to re-evaluate, given new, "targeted" methods of administration such as those described herein. Impetus for this effort comes from the known radiosensitivity of clonogenic myeloma cells (a population that at least may contain MM-CSC), and especially given the ability of local radiotherapy to provide local disease control in myeloma, and especially given the ability of local radiotherapy to cure some patients with solitary plasmacytoma "proving" activity of radiotherapy vs. MM-CSC in this closely-related diagnosis.
It is important to note that improvement in current modalities may offer better clinical outcomes even if major effects vs. the MM-CSC and microenvironment interaction are not produced. We do not currently have the ability to measure such effects; this will not be part of this trial.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01182233
|United States, New York|
|University of Rochester Medical Center||Recruiting|
|Rochester, New York, United States, 14642|
|Contact: Robin Boerman 585-273-1507 Robin_Boerman@urmc.rochester.edu|
|Contact: Sarah Duffy, MS, CCRP 585-275-3817 email@example.com|
|Principal Investigator: Becker Michael, MD|
|Principal Investigator:||Gordon Phillips, MD||University of Rochester|