Tandem Auto Transplantation in Myeloma Patients With <12 Months of Prior Treatment

Multiple Myeloma Clinical Trial

Official title:

Tandem Autotransplantation for Multiple Myeloma in Participants With Less Than 12 Months of Preceding Therapy, Incorporating Velcade (Bortezomib) With the Transplant Chemotherapy and During Maintenance

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01548573
• Other study ID #: 201202818
• Secondary ID: 7R01CA115399
• Status: Terminated
• Phase: Phase 2
• First received: February 29, 2012
• Last updated: November 26, 2013
• Start date: May 2012
• Est. completion date: March 2014

Study information

• Verified date: November 2013
• Source: University of Iowa
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This study is designed to decrease toxicity associated with prior tandem transplant protocols by reducing the intensity of induction, consolidation and maintenance therapy, while increasing event-free survival by adding bortezomib (Velcade®), thalidomide, gemcitabine and carmustine to the transplant regimens to down-regulate the rescue of myeloma cells by the micro-environment and to prevent DNA repair post high-dose alkylating agent therapy. By reducing drug resistance, it is hoped that 3-year event-free survival will be increased significantly when compared to Total Therapy II. Additionally, participants will have the option of providing biospecimens for a sub-study evaluating gene expression profiling at specific timepoints to better understand drug-resistance in myeloma, and to determine whether there are genes or gene products in the resistant population that can be targeted by novel therapies.

Description:

This study is targeted towards patients who have been diagnosed with Multiple Myeloma, POEMS(Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), or myeloma plus amyloidosis and have had no more than 12 months of prior treatment. Furthermore, participants cannot have had a prior autologous or allogeneic transplant. The study schema consists of one round of induction chemotherapy, two transplants, one round of consolidation chemotherapy, and two years of maintenance treatment. This study design differs from its historical predecessors in the following manner:

• In contrast to Total Therapy II and III, which only allow enrollment of patients with one cycle or one month of treatment prior to enrollment, the proposed study allows enrollment of participants with up to 12 months of prior treatment.

• Induction therapy has been reduced to a single cycle.

• Bortezomib and thalidomide have been added to the transplant regimen.

• Carmustine is added to the second transplant.

• Gemcitabine is added to the second transplant regimen.

• Consolidation treatment has been reduced to a single cycle.

• The first year of maintenance consists of 12 28-day cycles of bortezomib,dexamethasone, and either thalidomide, lenalidomide, or cyclophoshamide. The second year of maintenance therapy consists of lenalidomide and dexamethasone.

• The novel agents thalidomide and bortezomib are not introduced upfront, but only with transplantation, consolidation, and maintenance.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 20
• Est. completion date: March 2014
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Participants must have had a diagnosis of symptomatic MM, MM + amyloidosis, or POEMS (osteosclerotic myeloma: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) requiring treatment. Participants with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy. Note that study participants do not need to have active disease at the time of study entry, as participants may have received up to 12 months of prior chemotherapy, which might have induced a response.

2. Protein criteria must be present (quantifiable M-component of IgG, IgA, IgD, or IgE and/or urinary kappa or lambda light chain, Bence-Jones protein, or Free Kappa Light Chain or Free Lambda Light Chain) in order to evaluate response. Non-secretory participants are eligible provided the participant has > 20% plasmacytosis OR multiple (>3) focal plasmacytomas or focal lesions on MRI.

3. Participants must have received no more than 12 months of prior chemotherapy for this disease. Participants may have received prior radiotherapy provided approval has been obtained from the PI.

4. Participants must not have had a prior transplant.

5. Participants must be 18-80 years of age at the time of study entry.

6. Ejection fraction by ECHO or MUGA of = 40% performed.

7. Participants must have adequate pulmonary function studies, > 50% of predicted on mechanical aspects (FEV1, FVC) and diffusion capacity (DLCO) > 50% of predicted (adjusted for hemoglobin). If the participant is unable to complete pulmonary function tests due to disease related pain or condition, a participant may still be enrolled provided that the PI or enrolling investigator documents that the participant is a transplant candidate.

8. Participants must have a creatinine < 3 mg/dl and a calculated creatinine clearance >30mL/min. The Cockroft-Gault equation may be used to obtain calculated creatinine clearance.

9. Participants must have a performance status of 0-2 based on ECOG criteria. Participants with a poor performance status (3-4)based solely on bone pain will be eligible, provided there is documentation to verify this.

10. Participants must sign the most current IRB-approved study ICF (Informed Consent Form).

Exclusion Criteria:

1. Prior autologous or allogeneic transplant.

2. Platelet count < 30 x 109/L, unless myeloma-related. If MM-related, the enrolling investigator must document this.

3. > grade 3 neuropathy.

4. Known hypersensitivity to bortezomib, boron, or mannitol.

5. Uncontrolled diabetes.

6. Recent (< 6 months) myocardial infarction, unstable angina, difficult to control congestive heart failure, uncontrolled hypertension, or difficult to control cardiac arrhythmias.

7. Participants must not have light chain deposition disease-related renal failure or creatinine >3 mg/dl.

8. Participants must not have a concurrent malignancy unless it can be adequately treated by surgical, non-chemotherapeutic intervention. Participants may have a history of prior malignancy, provided that he/she has not had any treatment within 365 days of study entry AND that life expectancy exceeds 5 years at the time of study entry.

9. Participants must not have life-threatening co-morbidities.

10. Women of child-bearing potential must have a documented negative pregnancy test documented within one week of study entry. Women and men of reproductive potential may not participate unless they have agreed, by signing the study ICF, to use effective contraceptive method(s) as outlined in that form.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• DPACE (Dexamethasone, Cisplatin, Adriamycin, Cyclophosphamide, Etoposide)
Dexamethasone 20 mg oral on days 1-4 and 8-11; Cisplatin 10 mg/m2/day on days 1-4 Continuous Infusion (CI); Adriamycin 10 mg/m2/day on days 1-4 CI; Cyclophosphamide 400 mg/m2/day or 600 mg/m2 (if high-risk MM) on days 1-4 CI; Etoposide 40 mg/m2/day on days 1-4 CI.

Procedure:
• Transplant 1 (Velcade, Thalidomide, Dexamethasone, Melphalan)
Dexamethasone 20 mg oral on days -4 to -1 and +2 to +5;Velcade 1mg/m2 IV Bolus on days -4, -1, +2, and +5; Thalidomide 100mg/day oral on days -4 to +5; Melphalan 100 mg/m2 on days -4 and -1 (Patients > 70 years of age or with a creatinine > 2.0 mg/dl will receive a reduced dose of Melphalan of 70 mg/m2 on days -4 and -1); Peripheral blood stem cell infusion will be given intravenously on day 0, at least 18 hours after the second dose of melphalan.
• Transplant 2 (Velcade, Gemcitabine, Carmustine, Dexamethasone, Melphalan)
Dexamethasone 20 mg oral on days -4 to -1, and on day +2 to day +5; Carmustine 300mg/m2 on day -4; Melphalan 140 mg/m2 on day -1 (Patients > 70 years of age or with a creatinine > 2.0 mg/dl may receive Melphalan 100 mg/m2 at the discretion of the treating physician);Velcade 1mg/m2 will be given on days -4, -1, +2, +5; Gemcitabine 1000 mg/m2 on days -4 and -1;Peripheral blood stem cell infusion will be given intravenously on day 0, at least 18 hours after melphalan.

Drug:
• Consolidation VDT-PACE (Velcade, Dexamethasone, Thalidomide, Cisplatin, Adriamycin, Cyclophosphamide, Etoposide)
Dexamethasone 20 mg oral on days 1-4 and days 8-11; Thalidomide 100mg oral on days 1-11; Velcade 1mg/m2 IV Bolus on days 1, 4, 8, 11; Cisplatin 10 mg/m2 on days 1-4 continuous infusion (CI); Adriamycin® 10mg/m2 on days 1-4 CI; Cyclophosphamide 400 mg/m2 on days 1-4 CI; Etoposide 40 mg/m2 on days 1-4 CI.
• Maintenance Year 1 (Velcade, Thalidomide, Dexamethasone OR Velcade, Revlimid, Dexamethasone OR Velcade, Cyclophosphamide, Dexamethasone in 28 day cycles x 12)
Velcade 1.0mg/m2 IV Bolus on days 1, 4, 15, 18; Thalidomide 100mg oral daily (Thalidomide may be replaced by Revlimid 10-25mg x21 days or Cytoxan 500mg on days 1 and 15); Dexamethasone 20mg oral on days 1-4 and 15-18
• Maintenance Year 2 (Revlimid and Dexamethasone in 28 day cycles x 12)
Revlimid 10-15mg x 21 days; Dexamethasone 20mg on days 1, 8, 15, 22

Locations

Country	Name	City	State
United States	University of Iowa Holden Comprehensive Cancer Center	Iowa City	Iowa

Sponsors (2)

Lead Sponsor	Collaborator
University of Iowa	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-Free Survival (EFS)	To determine whether, in comparison to Total Therapy II, the median Event-Free Survival (EFS) can be increased from 4.8 years to 7.2 years, which represents an increase in median EFS of approximately 50%, based on an intent-to-treat analysis.	8 years	No
Primary	Identification of Drug Resistant Genes	To determine whether repeated bone marrow samples analyzed for gene expression profiling (GEP) can identify genes related to drug resistance in myeloma. The drug resistant genes or the gene products might then be targeted specifically to eradicate myeloma cells surviving tandem transplantation.	5 years	No
Secondary	Number of grade 3 non-hematologic and grade 4 hematologic serious adverse events associated with the addition of bortezomib, thalidomide, and dexamethasone into autologous transplant regimens.	To determine whether bortezomib, thalidomide and dexamethasone with transplant 1 and velcade/gemcitabine with transplant 2 can be safely incorporated into well-tested pre-transplant regimens of high-dose melphalan and carmustine/melphalan in doses equivalent to the BEAM(BCNU, etoposide, arabinoside, melphalan)regimen. Treatment-related toxicities will be compared to those reported in the literature using similar intensive approaches.	2 years	Yes
Secondary	Overall survival	To determine the median overall survival based on an intent-to-treat analysis, which should exceed 10 years, based on the projected 10-year survival of Total Therapy III, keeping in mind that participants are included in this protocol with up to 12 months of prior therapy.	10 years	No

External Links

•   University of Iowa Myeloma Program website