Ignite Creation Date:
2024-05-05 @ 11:10 PM
Last Modification Date:
2024-10-26 @ 10:29 AM
Study NCT ID:
NCT01264315
Status:
COMPLETED
Last Update Posted:
2023-05-26
First Post:
2010-12-20
Brief Title:
Safety And Efficacy Of Lenalidomide As Maintenance Therapy In Patients With Newly Diagnosed Multiple Myeloma Following A Tandem Autologous-Allogeneic Transplant
Sponsor:
Fondazione EMN Italy Onlus
Organization:
Fondazione EMN Italy Onlus
Study Overview
Official Title:
Safety And Efficacy Of Lenalidomide As Maintenance Therapy In Patients With Newly Diagnosed Multiple Myeloma Following A Tandem Autologous-Allogeneic Transplant
Status:
COMPLETED
Status Verified Date:
2023-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 023 CI 011-048 p00001 and overall survival HR 026 CI 009-079 p002 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 Maintenanceconsolidation 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 consolidationmaintenance therapy in patient undergoing tandem autologous-allogeneic transplant
Objectives of study To evaluate 1 toxicity and tolerability of lenalidomide after allografting 2To 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 mgday continuously in all patients unless in molecular CR if the following conditions are present
absolute neutrophil count 1 x 109L without the use of growth factors
platelet count 75 x 109L without transfusion support
calculated or measured creatinine clearance 20 mLminute
total bilirubin 2 x the upper limit of normal
AST and ALT 25 x upper limit of normal
less than 1 mgkgday 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 Simons 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
Objectives of study To evaluate 1 toxicity and tolerability of lenalidomide after allografting 2To 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 mgday continuously in all patients unless in molecular CR if the following conditions are present
absolute neutrophil count 1 x 109L without the use of growth factors
platelet count 75 x 109L without transfusion support
calculated or measured creatinine clearance 20 mLminute
total bilirubin 2 x the upper limit of normal
AST and ALT 25 x upper limit of normal
less than 1 mgkgday 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 Simons 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
Detailed Description:
A Pre-transplant phase Induction Therapy
Patients will start induction treatment with lenalidomide and dexamethasone RD for 4 cycles every 28 days as was detailed also in the GIMEMA protocol RV-MM-PI-209
Lenalidomide will be given orally at the dose of 25 mgday for 21 days followed by a 7 day rest period day 22 to 28
Dexamethasone will be given orally at the dose of 40 mg on days 1 8 15 and 22 every 28 days
If a patient relapses during RD before the end of the 4th cycle the induction treatment may be held and stem cell collection may be attempted with cyclophosphamide according to physician willing
For dose reduction during induction therapy see Appendix O Antithrombotic prophylaxis as per protocol RV-MM-PI-209 For patients not previously enrolled in protocol RV-MM-PI-209 we recommend prophylaxes with aspirin for patients without additional thrombotic risk factors and low molecular weight heparin LMWH 100 Ukg for the others
Otherwise induction schemas are accepted provided thalidomide lenalidomide or bortezomib alone or in combination are included
B Peripheral Blood Stem Cell PBSC Mobilization and collection
After 1-2 months from the completion of the last induction course patients will undergo PBSC mobilization with cyclophosphamide 4 gm2 and G-CSF 10 ugkgday starting at day 5 until completion of PBSC collection to collect an adequate number of PBSC 4 to 10 x 106kg CD 34 cells Patients who fail to collect the minimum of 4 x 106kg CD 34 cells will receive a second course of cyclophosphamide for a second mobilization attempt Patients who fails to collect a minimum of 4 x 106kg CD 34 will be withdrawn from the study
C High-Dose Melphalan Autologous PBSC Transplant
High dose melphalan will be given 4 to 8 weeks after high dose cyclophosphamide
1 Melphalan will be administered at a cumulative dose of 200 mgm2 This will be given in one dose infused on day -2 Dose will be calculated according to the participating institutional standard practice for using body weight High dose Melphalan is administered via a central catheter as per single center procedure
2 Peripheral Blood Stem Cell or Bone Marrow Infusion Infuse 2 x 106 CD 34 cells kg hydration requirements and pre-medication per guidelines of the institution
3 G-CSF Administer G-CSF 5 ugkgday subcutaneously or intravenously from day 3 until ANC 1000 for 3 days
D Allogeneic transplant phase Non-myeloablative PBSC Allografting
Pre-conditioning Upon recovery from high-dose melphalan between 40-120 days post autografting preferably within 60 days patients will proceed to nonmyeloablative allograft If indicated radiation to high risk skeletal lesions may be given pre-transplant If interval exceeds 120 days present to PCC for discussion and approval
Recovery from high-dose melphalan will be defined by patients achieving the following clinical criteria after receiving high dose melphalan
1 mucositis and gastrointestinal symptoms resolved off hyperalimentation and intravenous hydration
2 have completed steroids for autologous GVHD
3 LFT renal function values within the inclusion criteria for initial autograft
4 off IV antibiotics and amphotericin for documented infections
5 patients should be CMV antigenemia negative
6 if patients have experienced CMV infection post-autograft they must have completed therapy with Ganciclovir or Foscarnet and have been off this therapy for two weeks and remain CMV antigenemia negative
7 should have completed administration of any radiotherapy
8 any patient who does not fulfill these criteria can be discussed with the principle investigator for recommendations as to the timing of the allograft
Patients will start induction treatment with lenalidomide and dexamethasone RD for 4 cycles every 28 days as was detailed also in the GIMEMA protocol RV-MM-PI-209
Lenalidomide will be given orally at the dose of 25 mgday for 21 days followed by a 7 day rest period day 22 to 28
Dexamethasone will be given orally at the dose of 40 mg on days 1 8 15 and 22 every 28 days
If a patient relapses during RD before the end of the 4th cycle the induction treatment may be held and stem cell collection may be attempted with cyclophosphamide according to physician willing
For dose reduction during induction therapy see Appendix O Antithrombotic prophylaxis as per protocol RV-MM-PI-209 For patients not previously enrolled in protocol RV-MM-PI-209 we recommend prophylaxes with aspirin for patients without additional thrombotic risk factors and low molecular weight heparin LMWH 100 Ukg for the others
Otherwise induction schemas are accepted provided thalidomide lenalidomide or bortezomib alone or in combination are included
B Peripheral Blood Stem Cell PBSC Mobilization and collection
After 1-2 months from the completion of the last induction course patients will undergo PBSC mobilization with cyclophosphamide 4 gm2 and G-CSF 10 ugkgday starting at day 5 until completion of PBSC collection to collect an adequate number of PBSC 4 to 10 x 106kg CD 34 cells Patients who fail to collect the minimum of 4 x 106kg CD 34 cells will receive a second course of cyclophosphamide for a second mobilization attempt Patients who fails to collect a minimum of 4 x 106kg CD 34 will be withdrawn from the study
C High-Dose Melphalan Autologous PBSC Transplant
High dose melphalan will be given 4 to 8 weeks after high dose cyclophosphamide
1 Melphalan will be administered at a cumulative dose of 200 mgm2 This will be given in one dose infused on day -2 Dose will be calculated according to the participating institutional standard practice for using body weight High dose Melphalan is administered via a central catheter as per single center procedure
2 Peripheral Blood Stem Cell or Bone Marrow Infusion Infuse 2 x 106 CD 34 cells kg hydration requirements and pre-medication per guidelines of the institution
3 G-CSF Administer G-CSF 5 ugkgday subcutaneously or intravenously from day 3 until ANC 1000 for 3 days
D Allogeneic transplant phase Non-myeloablative PBSC Allografting
Pre-conditioning Upon recovery from high-dose melphalan between 40-120 days post autografting preferably within 60 days patients will proceed to nonmyeloablative allograft If indicated radiation to high risk skeletal lesions may be given pre-transplant If interval exceeds 120 days present to PCC for discussion and approval
Recovery from high-dose melphalan will be defined by patients achieving the following clinical criteria after receiving high dose melphalan
1 mucositis and gastrointestinal symptoms resolved off hyperalimentation and intravenous hydration
2 have completed steroids for autologous GVHD
3 LFT renal function values within the inclusion criteria for initial autograft
4 off IV antibiotics and amphotericin for documented infections
5 patients should be CMV antigenemia negative
6 if patients have experienced CMV infection post-autograft they must have completed therapy with Ganciclovir or Foscarnet and have been off this therapy for two weeks and remain CMV antigenemia negative
7 should have completed administration of any radiotherapy
8 any patient who does not fulfill these criteria can be discussed with the principle investigator for recommendations as to the timing of the allograft
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2008-004529-41 | EUDRACT_NUMBER | None | None |