Multiple Myeloma
Conditions
Keywords
multiple myeloma, transplant, Multiple myeloma patients undergoing transplant
Brief summary
The primary objective of this study is to: • Determine the maximum tolerated dose of thalidomide used in conjunction with dose-intense melphalan, bortezomib and autologous (syngeneic) HSC support in the salvage therapy of patients who failed a prior treatment with dose-intense melphalan The secondary objectives of this study are to: * Determine the toxicities resulting from administration of combinations of thalidomide, bortezomib and melphalan * Determine the complete response (CR) and very good partial response (VgPR) rate in patients undergoing ASCT using thalidomide, bortezomib and melphalan * Evaluate the treatment-free interval after treatment with the combination of thalidomide, bortezomib and melphalan
Detailed description
VELCADE™ (bortezomib) for Injection is a small molecule proteasome inhibitor developed by Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies. VELCADE is currently approved by the United States Food and Drug Administration (US FDA) and it is registered in Europe for the treatment of multiple myeloma patients who have received at least one prior therapy. By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling pathways. The anti-neoplastic effect of bortezomib likely involves several distinct mechanisms, including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition of expression of genes that control cellular adhesion, migration and angiogenesis. Thus, the mechanisms by which bortezomib elicits its antitumor activity may vary among tumor types, and the extent to which each affected pathway is critical to the inhibition of tumor growth could also differ. Bortezomib has a novel pattern of cytotoxicity in National Cancer Institute (NCI) in vitro and in vivo assays (Adams et al., 1999). In addition, bortezomib has cytotoxic activity in a variety of xenograft tumor models, both as a single agent and in combination with chemotherapy and radiation (Steiner et al., 2001; Teicher et al., 1999; Cusack et al., 2001; LeBlanc et al., 2002; Pink et al., 2002). Notably, bortezomib induces apoptosis in cells that over express bcl-2, a genetic trait that confers unregulated growth and resistance to conventional chemotherapeutics (McConkey et al., 1999). Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear factor κB (NF-κB) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct apoptotic effect, and possibly anti-angiogenic and other effects.
Interventions
DRUGThalidomide+Melphalan +Bortezomib+stem cell transplant
Five days prior to transplant, the patient starts thalidomide. Dose range will be from 600mg for 5 days, to 1000mg for 5 days. Thalidomide dose is increased after groups of 3 to 6 patients have been treated. 4 days before the transplant and again on the day before the transplant the patient will be given bortezomib (VELCADE) intravenously at a dose of 1.6 mg/m2 (mg/m2 means that the dose will be calculated based on the patient's height and weight). 2 days before transplant the patient will be given melphalan 200 mg/m2 intravenously. Dexamethasone is given before the VELCADE and the melphalan.
Sponsors
Hackensack Meridian Health
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Each patient must meet all of the following inclusion criteria to be enrolled in the study: * Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care * Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control as described in the S.T.E.P.S program. Participation in the program is required. * Male subject agrees to use an acceptable method for contraception for the duration of the study as described in the S.T.E.P.S program. Participation in the program is required. * Confirmed diagnosis of multiple myeloma, or plasma cell leukemia. * Show progression of disease after a previous dose-intense cycle of melphalan, or less than a complete response after a prior cycle of dose-intense melphalan. Patients may have received more than on prior autologous transplant with high-dose melphalan. * May have received intervening therapies after disease progression after dose-intense melphalan and before enrollment in this protocol. * Recovery from complications of salvage therapy, if administered. * Age: ≥18 yrs but \<76 yrs at the time of melphalan administration. * Gender: There is no gender restriction. * Availability of \>2x106 autologous peripheral blood CD34+ cells/kg or a syngeneic donor meeting eligibility criteria for syngeneic donation. 1. Syngeneic transplantation is preferred.
Exclusion criteria
* Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Thalidomide | Dose escalation will be based on the assessment of tolerability determined after the last patient of each cohort reaches day +21. | Maximum tolerated dose of thalidomide used in conjunction with dose-intense melphalan, bortezomib and autologous (syngeneic) HSC support in the salvage therapy of patients who failed a prior treatment with dose-intense melphalan |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) and Very Good Partial Response (VgPR) Rate | Assessments will be made from Day +28 after transplantation for 3 months and then at 3 month intervals until demonstration of disease progression and initiation of further therapy, an average of 9 months | The complete response (CR) and very good partial response (VgPR) rate in patients undergoing ASCT using thalidomide, bortezomib and melphalan |
| Toxicity Assessment | Patients will be hospitalized or in the outpatient transplant facility until engraftment and resolution of serious adverse events, a median of 16 (range, 11-24) days | Assessment of the toxicities resulting from administration of combinations of thalidomide, bortezomib and melphalan |
| Treatment Free Interval/PFS | PFS was defined as the time from ASCT to disease progression or death from any cause, an average of 9 months | The treatment-free interval after treatment with the combination of thalidomide, bortezomib and melphalan |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORScott D Rowley, MD
John Theurer Cancer Center at Hackensack Univ Medical Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Thalidomide Dose Level 600 mg Phase I - Thalidomide Dose Level 600 mg | 3 |
| Phase I - Thalidomide Dose Level 800 mg Phase I - Thalidomide Dose Level 800 mg | 3 |
| Phase I - Thalidomide Dose Level 1000 mg Phase I - Thalidomide Dose Level 1000 mg | 3 |
| Phase II Phase II Thalidomide Dose Level 1000 mg | 20 |
| Total | 29 |
Baseline characteristics
| Characteristic | Phase I - Thalidomide Dose Level 600 mg | Total | Phase II | Phase I - Thalidomide Dose Level 1000 mg | Phase I - Thalidomide Dose Level 800 mg |
|---|---|---|---|---|---|
| Age, Customized Range | 66 years | 56 years | 55 years | 52 years | 59 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 27 Participants | 19 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 5 Participants | 4 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 21 Participants | 14 Participants | 2 Participants | 3 Participants |
| Region of Enrollment United States | 3 participants | 29 participants | 20 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 15 Participants | 9 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 14 Participants | 11 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 20 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 20 / 20 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 0 / 3 | 3 / 20 |
Outcome results
Primary
Maximum Tolerated Dose of Thalidomide
Maximum tolerated dose of thalidomide used in conjunction with dose-intense melphalan, bortezomib and autologous (syngeneic) HSC support in the salvage therapy of patients who failed a prior treatment with dose-intense melphalan
Time frame: Dose escalation will be based on the assessment of tolerability determined after the last patient of each cohort reaches day +21.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 | Maximum Tolerated Dose of Thalidomide | 1000 mg |
| Phase 2 | Maximum Tolerated Dose of Thalidomide | 1000 mg |
Secondary
Complete Response (CR) and Very Good Partial Response (VgPR) Rate
The complete response (CR) and very good partial response (VgPR) rate in patients undergoing ASCT using thalidomide, bortezomib and melphalan
Time frame: Assessments will be made from Day +28 after transplantation for 3 months and then at 3 month intervals until demonstration of disease progression and initiation of further therapy, an average of 9 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 | Complete Response (CR) and Very Good Partial Response (VgPR) Rate | 0 Participants |
| Phase 2 | Complete Response (CR) and Very Good Partial Response (VgPR) Rate | 3 Participants |
| Phase I - Thalidomide Dose Level 1000 mg | Complete Response (CR) and Very Good Partial Response (VgPR) Rate | 1 Participants |
| Phase 2 | Complete Response (CR) and Very Good Partial Response (VgPR) Rate | 13 Participants |
Secondary
Toxicity Assessment
Assessment of the toxicities resulting from administration of combinations of thalidomide, bortezomib and melphalan
Time frame: Patients will be hospitalized or in the outpatient transplant facility until engraftment and resolution of serious adverse events, a median of 16 (range, 11-24) days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 | Toxicity Assessment | 1 Serious Adverse Events |
| Phase 2 | Toxicity Assessment | 0 Serious Adverse Events |
| Phase I - Thalidomide Dose Level 1000 mg | Toxicity Assessment | 0 Serious Adverse Events |
| Phase 2 | Toxicity Assessment | 3 Serious Adverse Events |
Secondary
Treatment Free Interval/PFS
The treatment-free interval after treatment with the combination of thalidomide, bortezomib and melphalan
Time frame: PFS was defined as the time from ASCT to disease progression or death from any cause, an average of 9 months
Population: Data no longer available, only manuscript information where PFS reported for single Arm/Group of all participants
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Phase 1 | Treatment Free Interval/PFS | 9.3 months | Standard Deviation 0 |