Total Skeletal Irradiation in Multiple Myeloma Before Second Autologous Hematopoietic Stem Cell Transplantation
| Status: | Recruiting |
|---|---|
| Conditions: | Blood Cancer, Hematology |
| Therapuetic Areas: | Hematology, Oncology |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 11/8/2014 |
| Start Date: | June 2010 |
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
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.
"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.
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.
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.
Inclusion Criteria:
- Age
- Documented myeloma confirmed at protocol entry
- Adequate presence of >/=2.0x10e6/kg cryopreserved CD34+ cells
- Adequate organ function
- Prior therapy is allowed as long as the organ function parameters are maintained
and/or excessive radiation exposure is not produced
- Chemosensitivity
Exclusion Criteria:
- Uncontrolled infection
- Pregnant or lactating females
- Patients in >/= very good partial response after initial primary non-transplant
therapy and/or AHSCT1
- Patients unwilling to practice adequate forms of contraception if clinically
indicated
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