Safety And Efficacy Of Lenalidomide As Maintenance Therapy In Patients With Newly Diagnosed Multiple Myeloma Following A Tandem Autologous-Allogeneic Transplant

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2010 by Fondazione Neoplasie Sangue Onlus
Sponsor:
Information provided by:
Fondazione Neoplasie Sangue Onlus
ClinicalTrials.gov Identifier:
NCT01264315
First received: December 20, 2010
Last updated: NA
Last verified: December 2010
History: No changes posted
  Purpose

Rationale: We recently reported a study where overall and event free survivals in newly diagnosed myeloma patients receiving an autologous transplant followed by an allograft from an HLA-identical sibling were superior as compared to those undergoing a double autologous transplant. A larger multicenter study by the Gruppo Italiano Trapianti di Midollo (GITMO), co-ordinated by our group and recently closed, employing a tandem auto-allo approach in newly diagnosed patients confirmed the achievement of prolonged event free and overall survival. Importantly, the achievement of at least very good partial remission at the time of allografting conferred a significant advantage in both event-free-survival (HR 0,23, CI 0,11-0,48; p=0,0001) and overall survival (HR 0,26; CI 0,09-0,79; p=0,02). Moreover, recent advances in the understanding of the pathogenesis of multiple myeloma have identified specific signalling pathways that have become targets for biologically-based drugs such as thalidomide, bortezomib and lenalidomide and employed in several trials, including after allograft. The aim of the current proposal is to combine the post-transplant efficacy of graft-vs.-myeloma with the anti-myeloma effect of lenalidomide in newly diagnosed myeloma patients with an HLA-identical sibling treated with a tandem autograft-allograft approach. Maintenance/consolidation of the response may be a key factor to further improve rate of clinical and molecular (as a prelude to cure) remissions and prolong overall and event free survivals after allografting. We would like to investigate the safety and efficacy of lenalidomide as consolidation/maintenance therapy in patient undergoing tandem autologous-allogeneic transplant.

Objectives of study: To evaluate 1) toxicity and tolerability of lenalidomide after allografting; 2)To evaluate efficacy of lenalidomide in inducing complete remission, defined as negative immunofixation, 12 months after allografting; 3) overall-survival; 4) event-free survival; 5) molecular remission rate. Furthermore we plan to compare molecular remission rate in patients treated with lenalidomide after tandem auto-allo transplant and after double autologous transplant and to monitor minimal residual disease in patients achieving clinical CR with lenalidomide.

Patient Selection: Patients with newly diagnosed multiple myeloma with an HLA identical sibling suitable for PBSC donation will be included. Complete cytogenetic analysis at diagnosis will be required. The patient must have the capacity to give informed consent. Age >18 and < 65. Negative pregnancy test and willing to use contraceptive techniques during and for 12 months following treatment is required. Only very unfitted patients will be excluded.

Treatment plan: Lenalidomide will be started at 6 months post-allotransplant at the dose of 10 mg/day continuously in all patients (unless in molecular CR), if the following conditions are present:

  • absolute neutrophil count > 1 x 109/L without the use of growth factors;
  • platelet count > 75 x 109/L without transfusion support;
  • calculated or measured creatinine clearance: ≥ 20 mL/minute;
  • total bilirubin < 2 x the upper limit of normal,
  • AST and ALT < 2.5 x upper limit of normal
  • less than 1 mg/kg/day of prednisone, and no more than 2 immunosuppressive drugs other than steroid to control GVHD (if more immunosuppression is required to control GVHD, the maintenance therapy with lenalidomide will be held until this criteria will be satisfied) Treatment will be continued without interruption, unless not tolerated, until unacceptable adverse events are experienced or progressive disease occurs. Moreover, lenalidomide will be discontinued in patients who achieve and maintain molecular remission for 2 consecutive controls at least 6 weeks apart.

Safety section - dose modification plan: During the study patients will be monitored for the occurrence of side effects. Toxicity events will be graded according to the NCI toxicity criteria. In case of severe toxicity, the lenalidomide dose will be reduced or withheld as outlined in the protocols.

Statistical section: - Total patient sample size: 53. This is a phase 2 study designed according to a Simon's two-stage Minimax Design. An early stopping rule will be established to interrupt the study in case of futility (a non satisfactory response rate). In stage I 27 patients will be enrolled; if < 14 complete remissions will be observed, the trial will be stopped. In stage II 26 more patients will be enrolled. If ≥ 32 responses will be observed, it will be concluded that the lenalidomide maintenance is active in increasing the complete remission rate after auto-allograft.

Analysis plan: Toxicity monitoring will be incorporated into the study design by requiring that the trial be terminated after an initial stage if the number of observed toxicities (treatment related deaths) is excessive.


Condition Intervention Phase
Multiple Myeloma
Drug: Lenalidomide
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Safety And Efficacy Of Lenalidomide As Maintenance Therapy In Patients With Newly Diagnosed Multiple Myeloma Following A Tandem Autologous-Allogeneic Transplant

Resource links provided by NLM:


Further study details as provided by Fondazione Neoplasie Sangue Onlus:

Primary Outcome Measures:
  • Lenalidomide toxicity and tolerability after allografting [ Time Frame: 6 years ] [ Designated as safety issue: Yes ]
    To evaluate toxicity and tolerability of lenalidomide after allografting.

  • Lenalidomide efficacy [ Time Frame: 1 years ] [ Designated as safety issue: Yes ]
    To evaluate efficacy of lenalidomide in inducing complete remission, defined as negative immunofixation, 12 months after allografting.


Secondary Outcome Measures:
  • Overall survival [ Time Frame: 6 years ] [ Designated as safety issue: Yes ]
  • Progression free survival [ Time Frame: 6 years ] [ Designated as safety issue: Yes ]
  • Event free survival [ Time Frame: 6 years ] [ Designated as safety issue: Yes ]
  • Molecular remission rate [ Time Frame: 6 years ] [ Designated as safety issue: Yes ]
    To evaluate molecular remission rate, and to compare molecular remission rate in patients treated with lenalidomide after tandem auto-allo transplant and after double autologous transplant (study protocol RV-MM-PI-209): molecular remission is defined as the disappearance of the disease- and patient-specific molecular marker by polymerase chain reaction (PCR)-based assay, in both bone marrow and blood on two consecutive tests at least six weeks apart.

  • Minimal residual disease [ Time Frame: 6 years ] [ Designated as safety issue: Yes ]
    To monitor minimal residual disease in patients achieving clinical CR with lenalidomide.


Estimated Enrollment: 53
Study Start Date: September 2008
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Lenalidomide

    Lenalidomide will be started at 6 months post-allotransplant at 10 mg/day continuously in all patients:

    • absolute neutrophil count >1x109/L without growth factors
    • platelet count >75x109/L without transfusion support
    • calculated/measured creatinine clearance: ≥20mL/minute
    • total bilirubin <2 x the upper limit of normal
    • AST (SGOT) and ALT (SGPT) <2.5 x upper limit of normal
    • <1mg/kg/day of prednisone, and no more than 2 immunosuppressive drugs other than steroid to control GVHD

    Treatment will be continued without interruption, unless not tolerated, until unacceptable adverse events or progressive disease occur. In case of disease progression occurring before the start of lenalidomide, the patient will be withdrawn from study and treated according to the center preference. Lenalidomide will be discontinued in patients achieving and maintaining molecular remission for 2 consecutive controls at least 6 weeks apart.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Newly diagnosed multiple myeloma patients with an HLA identical sibling suitable for PBSC donation and treated in induction with thalidomide or bortezomib or lenalidomide conteining regimes.
  2. Complete cytogenetic analysis at diagnosis, including FISH analysis for chromosome deletions 13 and 17, and translocations (4;14) (11;14) and (14;16).
  3. The patient must have the capacity to give informed consent.
  4. Age >18 and < 65
  5. If female, the patient is either postmenopausal since at least 24 consecutive months or surgically sterilized or she agrees to practice sexual abstinence or to use two reliable methods for contraception (e.g. a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide) for the duration of study
  6. If male, the patient agrees to practice sexual abstinence or to use a latex condom during any sexual contact with women of childbearing potential for the duration of study
  7. Negative pregnancy test

Exclusion Criteria:

  1. Karnofsky score less than 60 (see appendix C), unless due solely to myeloma
  2. Left ventricular ejection fraction less than 40%, or symptomatic coronary artery disease or other cardiac failure requiring therapy
  3. Bilirubin greater than 2 X the upper limit of normal, or SGPT and SGOT > 4 X the upper limit of normal
  4. DLCO < 40% (corrected) or receiving continuous supplemental oxygen.
  5. Creatinine clearance < 40 cc/min at the time of initial autografting evaluation.
  6. Patients with poorly controlled hypertension
  7. Patients with active non-hematologic malignancies (except non-melanoma skin cancers).
  8. Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a >20% risk of disease recurrence
  9. Seropositive for HIV
  10. Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment.
  11. To evaluate toxicity and tolerability of lenalidomide after allografting
  12. To evaluate efficacy of lenalidomide in inducing complete remission 12 months after allografting
  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: NCT01264315

Contacts
Contact: Lorenzo Perinetto +390116635814 gismm2001@yahoo.com
Contact: Benedetto Bruno, MD +390116334354 benedetto.bruno@unito.it

Locations
Italy
A.O.U. San Giovanni Battista Recruiting
Torino, Italy, 10126
Contact: Benedetto Bruno, MD    +390116334354    benedetto.bruno@unito.it   
Principal Investigator: Benedetto Bruno, MD         
Sponsors and Collaborators
Fondazione Neoplasie Sangue Onlus
Investigators
Principal Investigator: Benedetto Bruno, MD Division of Hematology - University of Torino - A.O.U. San Giovanni Battista - Torino - Italy
  More Information

No publications provided

Responsible Party: Rag. Lorenzo Perinetto, Fondazione Neoplasie Sangue Onlus
ClinicalTrials.gov Identifier: NCT01264315     History of Changes
Other Study ID Numbers: RV-MM-GITMO-413, 2008-004529-41
Study First Received: December 20, 2010
Last Updated: December 20, 2010
Health Authority: Italy: Ministry of Health

Keywords provided by Fondazione Neoplasie Sangue Onlus:
Lenalidomide
Tandem Autologous-Allogeneic Transplant

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
Lenalidomide
Thalidomide
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antineoplastic Agents
Growth Inhibitors
Growth Substances
Immunologic Factors
Immunosuppressive Agents
Leprostatic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014