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

This study has been terminated.
(Met study stopping rules)
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Guido Tricot, University of Iowa
ClinicalTrials.gov Identifier:
NCT01548573
First received: February 29, 2012
Last updated: May 19, 2017
Last verified: May 2017
  Purpose
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.

Condition Intervention Phase
Multiple Myeloma Drug: Dexamethasone Procedure: Tandem autologous stem cell transplant Drug: Cisplatin Drug: Doxorubicin Drug: Cyclophosphamide Drug: Etoposide Drug: Bortezomib Drug: Thalidomide Drug: Melphalan Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Guido Tricot, University of Iowa:

Primary Outcome Measures:
  • Event-Free Survival (EFS) [ Time Frame: 8 years ]
    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.

  • Identification of Drug Resistant Genes [ Time Frame: 5 years ]
    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.


Secondary Outcome Measures:
  • 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. [ Time Frame: 2 years ]
    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.

  • Overall Survival [ Time Frame: 10 years ]
    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.


Enrollment: 19
Actual Study Start Date: May 2012
Study Completion Date: August 2014
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tandem autologous stem cell transplant

Induction: DPACE(dexamethasone,cisplatin,doxorubicin,cyclophosphamide,etoposide) chemotherapy plus stem cell collection. Additional stem cell collection and/or chemotherapy may be required.

After collection, participants will receive dexamethasone x 4 days every 14 days.

Transplant 1: The transplant preparative regimen will be bortezomib/thalidomide/dexamethasone/melphalan.

Once recovered, participants start thalidomide daily and dexamethasone x 4 days every 21 days.

Consolidation (if administered): VDT-PACE(bortezomib,dexamethasone,thalidomide,cisplatin,doxorubicin,cyclophosphamide, etoposide) Transplant 2: 8 weeks to 6 months after the first transplant, participants will have the second transplant Maintenance: Year 1- VTD (bortezomib, thalidomide, dexamethasone) cycles. Year 2 - VCD (bortezomib, cyclophosphamide, dexamethasone)cycles.

Drug: Dexamethasone
Given PO
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Procedure: Tandem autologous stem cell transplant Drug: Cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Drug: Doxorubicin
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: Cyclophosphamide
Given IV or PO
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: Etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
  • Vepesid
Drug: Bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Drug: Thalidomide
Given PO
Other Names:
  • Kevadon
  • Synovir
  • THAL
  • Thalomid
Drug: Melphalan
Given IV
Other Names:
  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin

Detailed 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.
  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01548573

Locations
United States, Iowa
University of Iowa Holden Comprehensive Cancer Center
Iowa City, Iowa, United States, 52242
Sponsors and Collaborators
University of Iowa
National Cancer Institute (NCI)
Investigators
Principal Investigator: Guido J Tricot, MD, PhD University of Iowa
  More Information

Responsible Party: Guido Tricot, Director, Holden Cancer Center Bone Marrow Transplant and Myeloma Program, University of Iowa
ClinicalTrials.gov Identifier: NCT01548573     History of Changes
Other Study ID Numbers: 201202818
7R01CA115399 ( US NIH Grant/Contract Award Number )
Study First Received: February 29, 2012
Results First Received: April 4, 2017
Last Updated: May 19, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Guido Tricot, University of Iowa:
multiple myeloma
POEMS (Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes)
amyloidosis
bone marrow transplant
autologous

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Liposomal doxorubicin
Etoposide phosphate
Cisplatin
Dexamethasone
Doxorubicin
Cyclophosphamide
Bortezomib
Etoposide
Melphalan
Thalidomide
Dexamethasone acetate
Dexamethasone 21-phosphate
BB 1101
Antineoplastic Agents
Anti-Inflammatory Agents
Antiemetics

ClinicalTrials.gov processed this record on June 23, 2017