Ignite Creation Date:
2024-05-05 @ 11:47 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00135200
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-03-15
First Post:
2005-08-24
Brief Title:
Clinical Trial of Consolidation Treatment With Iodine I 131 Tositumomab for Multiple Myeloma
Sponsor:
University of Michigan Rogel Cancer Center
Organization:
University of Michigan Rogel Cancer Center
Study Overview
Official Title:
A Phase II Clinical Trial of Consolidation Treatment With Iodine I 131 Tositumomab for Multiple Myeloma
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-03
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:
This study is for patients with newly diagnosed or relapsed multiple myeloma The main purpose of this study is to see how their disease responds to consolidation treatment treatment aimed at further decreasing cancer cells with a radioactive antibody protein called iodine I 131 tositumomab known by the tradename Bexxar and also to look at the side effects which occur with this type of treatment The investigators will also be looking at how long disease responds to treatment if it responds at all and how long patients who have had this treatment survive
Bexxar is a monoclonal antibody protein to which radioactive iodine 131 is attached The monoclonal antibody in Bexxar tositumomab targets a protein called CD20 found on the surface of a variety of B-cells including lymphoma cells and some myeloma cells The antibody is given as an infusion and finds its way to these cells The radioactive iodine attached to the antibody delivers radiation directly to these cells which works to harm or kill the cancer cells Approximately 20-25 of patients with multiple myeloma have this protein on the surface of their tumor cells In addition this protein was found on the surface of myeloma stem cells While myeloma stem cells represent a minority of all myeloma cells less than 5 these cells are resistant to chemotherapy and are believed to be responsible for a recurrence of the disease after chemotherapy In this study Bexxar will be used after patients complete a course of chemotherapy and have residual myeloma cells left in their body The Investigators are hoping that the treatment with Bexxar will decrease and possibly eliminate residual myeloma cells resistant to chemotherapy
Bexxar is a monoclonal antibody protein to which radioactive iodine 131 is attached The monoclonal antibody in Bexxar tositumomab targets a protein called CD20 found on the surface of a variety of B-cells including lymphoma cells and some myeloma cells The antibody is given as an infusion and finds its way to these cells The radioactive iodine attached to the antibody delivers radiation directly to these cells which works to harm or kill the cancer cells Approximately 20-25 of patients with multiple myeloma have this protein on the surface of their tumor cells In addition this protein was found on the surface of myeloma stem cells While myeloma stem cells represent a minority of all myeloma cells less than 5 these cells are resistant to chemotherapy and are believed to be responsible for a recurrence of the disease after chemotherapy In this study Bexxar will be used after patients complete a course of chemotherapy and have residual myeloma cells left in their body The Investigators are hoping that the treatment with Bexxar will decrease and possibly eliminate residual myeloma cells resistant to chemotherapy
Detailed Description:
Multiple myeloma is ranked second in hematological malignancies in the United States Munshi et al 2001 Because no curable option exists patients with early stage disease are typically observed without treatment until the disease progresses or symptoms appear
The majority of patients will respond to initial chemotherapy however all treated patients repeatedly relapse with shorter remissions following each subsequent course of chemotherapy Rajkumar et al 2002a Regimens most commonly used for initial therapy include melphalan and prednisone MP which induce remission in approximately 50 of patients Alexanian et al 1969 VAD-vincristine adriamycin and dexamethasone with response rates in the 50 range Salmon et al 1994 Barlogie et al 1984 Alexanian et al 1986 dexamethasone pulses and more recently introduced combinations of thalidomide with dexamethasone Rajkumar et al 2002b Weber et al 2003 All these regimens have comparable response rates With the exception of the recent report which showed a superior response rate to the combination of thalidomide with dexamethasone versus dexamethasone pulses Rajkumar et al 2004 multiple other comparative studies did not show superiority of any of these regimens for overall survival Complete responses to any of these regimens are observed infrequently 5 Patients who complete initial therapy usually proceed to high dose chemotherapy with autologous stem cell transplant support Alternatively patients may be placed on maintenance regimen or can be observed Except for one study with alternate day high dose of Prednisone Berenson et al 2002 no convincing evidence exists that maintenance impacts the natural history of the disease Kyle 2002 The Myeloma Trialists Collaborative Group 2001
High dose chemotherapy has been used as consolidation in multiple myeloma by a number of investigators Barlogie et al 1986 Cunningham et al 1994 Harousseau et al 1995 A randomized trial conducted by French Myeloma Intergroup IFM 90 provided evidence that treatment with high dose chemotherapy and autologous stem cell transplant ASCT after initial therapy results in significantly longer event-free survival median 28 vs 18 months and overall survival 57 vs 42 months if compared to conventional chemotherapy Attal et al 1996 The benefit of auto transplantation was seen in patients of all ages Siegel et al 1999 More recently similar results were reported from a large randomized study in Great Britain Childs et al 2003 Based on these studies in patients eligible for transplant consolidation of initial therapy with high dose therapy followed by ASCT is considered a standard of care NCCN Guidelines 2004 However ASCT is not curative even in patients who achieve complete response CR which is observed in 20-30 of patients who completed ASCT Contamination of autologous stem cell collection with malignant myeloma cells may play some role In support of this notion syngeneic bone marrow transplants showed better and more durable outcomes than those seen with ASCT Gahrton et al 1999 Another reason for failure of autologous stem cell transplant is ineffective eradication of myeloma clone with high dose chemotherapy In an effort to provide more effective elimination of malignant clones some investigators developed intensified treatment regimens Improved results have been reported using Total Therapy which involves a sequence of treatments including tandem ASCT Barlogie et al 1999 Barlogie at al 2004 The notion that intensification of therapy improves outcomes has been validated in a recent randomized study which showed that consolidation of initial therapy with tandem autologous stem cell transplant was superior than consolidation with single autologous stem cell transplant as measured by an improved duration of responses and overall survival Attal at al 2003 In contrast to ASCT allogeneic stem cell transplantation can provide stem cell products free of malignant cells as well as the benefit of graft-versus-myeloma effect
However very high 1-year mortality 30-60 was reported in early allogeneic bone marrow transplant studies with disease free survival in only 15-30 of patients and no superior survival if compared to ASCT Bensinger et al 1996 Bjorkstrand et al 1996 Barlogie et al 1995 More recent studies including allogeneic transplants with nonmyeloablative conditioning regimens provide more encouraging results Reynolds et al 2001 Badros et al 2002 Recently a combined treatment with ASCT followed by a non-myeloablative allogeneic stem cell transplant showed very promising outcomes and improved although still significant toxicity with CR rates in 55-60 range Kroger et al 2002 Maloney et al 2003 It is too early to determine whether improved responses using this approach will result in an increased survival
Emerging data suggest that achieving CR or near CR nCR will result in more durable remission and longer survival Recent analysis of long term outcomes of patients treated on randomized French study IMG90 clearly indicates that the longest survivors are those patients who achieve at least very good partial response or complete response Harousseau 2003 At 7 years 60 of patients were alive in a group which achieved CR or near CR In contrast in a group of patients who achieved PR but less than CR or near CR only 30 were alive and among patients who had less than PR none were alive Similar results have bee recently reported for patients who underwent allogeneic stem cell transplant Corradini et al 2003 It is not clear whether CR in response to initial therapy and prior to transplant may have similar impact on overall outcomes Regardless of specific transplant approach survival curves do not plateau and all patients are expected to relapse regardless of method of intensification therapy possibly due to persistence of residual population of chemotherapy-resistant clonogenic myeloma cells
For patients who have relapsed or are refractory to therapy there is no agreed upon standard treatment Anderson et al 2002 Kyle 2002 Treatment options include salvage chemotherapy autologous stem cell transplant if not previously done or as a second transplant or allogeneic stem cell transplant full or low intensity Kyle 2002 Salvage chemotherapy is most widely used in clinical practice Among a variety of salvage regimens both monotherapy and combination therapy have been applied Monotherapy with Dexamethasone or other steroids administered as pulse therapy produced responses in the 35-40 range Alexanian et al 1983 Gertz et al 1995 Thalidomide used as a single agent showed a 32 response rate in this patient population Singhal et al 1999 More recently VELCADE as a single agent induced at least minimal responses ie 25 reduction in monoclonal protein in 35 of patients and at least a stabilization of the disease in 59 of patients with relapsedrefractory multiple myeloma using strict SWOG criteria Richardson et al 2003 Combination therapies historically show higher response rates VAD has been demonstrated as an effective regimen in patients refractory to alkylating agents with response rates of 60 Lokhorst et al 1989 A similar regimen called DVd with Doxil Vincristine and dexamethasone showed comparable efficacy and acceptable toxicity Hussein et al 2002 Rifkin et al 2004 Newer combinations including combinations of VELCADE thalidomide and Revlimid analog of thalidomide are promising and appear to be able to induce higher response rates and complete remissions as per unpublished yet reports from different meetings Agarwal et al 2003 Orlowski et al 2003 Richardson et al 2003 Richardson et al 2004
Clonogenic Multiple Myeloma Cells
Myeloma is characterized by an accumulation of malignant plasma cells in bone marrow Numerous observations indicated that malignant plasma cells have low proliferative capacity and it is believed that the vast majority of the malignant cell population in myeloma is represented by terminally differentiated plasma cells similar to their normal counterparts Barlogie et al 1989 It is unclear whether these terminally differentiated malignant plasma cells are capable of self-renewal During the past decade several studies indicated that multiple myeloma similarly to other malignancies may consist of heterogenous population of malignant cells Bakkus et al 1994 Billadeau et al 1996
Clonotypic studies identified a population of circulating B-cells in blood samples of patients with myeloma Bergsagel et al 1995 Chen and Epstein 1996 sharing the same clonotypic CDR3 region as is detected in the bone marrow malignant plasma cells Pilarski et al 1996 Szczepek et al 1998 Further studies provided additional insights into the evolution of the myeloma clone supporting a notion of heterogeneity of the population of clonal cells in myeloma Taylor et al 2002 The B-cell component of the myeloma clone appeared to be clonogenic in xenografted mice Pilarski et al 2000 Reiman et al 2001 Moreover clonotypic cells with B-cell phenotype express CD19CD20 antigens and may represent a reservoir of disease that persists after therapy including high dose chemotherapy Kiel et al 1999 Rottenburger et al 1999 Pilarski et al 2002
The majority of myeloma cells express CD138 a highly specific surface antigen of terminally differentiated plasma cells which is absent on highly proliferative normal plasmablast and earlier stages of B-cells Jego et al 2001 Based on these observations it was hypothesized that clonogenic myeloma cells should lack CD138 expression Using CD138 and CD138- subsets of cells isolated from myeloma cell lines and from primary myeloma patient samples Matsui et al 2004 showed that only a minority of all myeloma cells have CD138- phenotype 5 However only CD138- have clonogenic potential as demonstrated in colony formation assays in methylcellulose and after transplantation to NODSCID mice Moreover these cells express B-cell antigens including CD19 and CD20 and their growth could be inhibited by in vitro treatment with rituximab an antibody directed against CD20 antigen Matsui et al 2004
Rationale for anti-CD20 Therapy in Myeloma
Recent observations that clonogenic cells in myeloma express CD20 Kiel et al 1999 Rottenburger et al 1999 and that their growth could be inhibited in vitro by rituximab an anti-CD20 antibody Matsui et al 2004 provides a rationale for using CD20-directed therapy in patients with myeloma Moreover CD19CD20 clonotypic cells appear to be more refractory than CD19-CD20- cells to commonly used chemotherapy regimens in myeloma including high dose therapy with stem cell transplant Kiel et al 1999 Rottenburger et al 1999 Therefore CD20 directed treatment of myeloma would complement chemotherapy by targeting chemoresistant clonogenic myeloma cells
Previous studies showed that therapy with Rituximab unlabeled anti-CD20 antibody could be active in multiple myeloma Hussein et al 1999 Treon et al 2002
In this study we propose to apply therapy with Bexxar a radiolabeled anti-CD20 antibody Bexxar Therapeutic Regimen is composed of the murine anti-CD20 monoclonal antibody Tositumomab and Iodine I 131 Tositumomab Iodine I 131 Tositumomab is a radio-iodinated derivative of Tositumomab that has been covalently linked to Iodine-131
We hypothesized that radiolabeled anti-CD20 antibody will be more efficacious than unlabeled antibody ie rituximab in eradication of highly radiosensitive myeloma cells similarly to what was observed in non-Hodgkins lymphoma Horning et al 2000 Davis et al 2001 Flinn et al 2001 Witzig et al 2002 It is presumed that higher efficacy of radiolabeled anti-CD20 antibody if compared to unlabeled antibody may be due to crossfire effect as the radiation is delivered not only to target cells but also to neighboring cells both expressing and not-expressing CD20 Vose et al 1999 In the proposed design we will apply Bexxar after completion of a course of initial chemotherapy for newly diagnosed patients or a course of salvage chemotherapy provided that patients achieve at least partial response to prior therapy ie 50 reduction of tumor mass and reach a plateau of their response to prior therapy By using patients in a period of stable disease we will have a better chance to observe the effects of radioimmunotherapy against CD20 cells which represent a minority of all malignant cells In addition we will evaluate the impact of Bexxar therapy on clonogenic myeloma cells using clonogenic assays as described in Methods
We anticipate that majority of newly diagnosed patients will be eligible and will subsequently proceed to autologous stem cell transplant as part of standard therapy of myeloma NCCN Guidelines 2004 if as hypothesized bexxar treatment does have the potential to eliminate clonogenic myeloma stem cells stem cells collected post-bexxar treatment should be depleted of re-populating myeloma cells Therefore this combination of chemotherapy and targeted therapy against clonogenic cells may have a potential of eliminating myeloma clones Although stem cell collections and autologous stem cell transplants have been used without apparent difficulties in the past in patients treated with anti-CD20 radio-conjugates Ratanatharatorn et al 2001 Kaminski et al 2001 Ansell et al 2002 we plan to collect backup stem cells prior to treatment with Bexxar to allow to proceed with the standard stem cell transplant in the unlikely cases of failure of collection of stem cells post-Bexxar Anti-CD20 radioimmunotherapy was previously used in combination with chemotherapy without additional toxicity Emmanoulides et al 2001 Gregory et al 2001 Press et al 2003
Radioimmunotherapy of B-Cell Malignancies
Radiolabeled monoclonal antibodies are efficacious in treating B-cell malignancies for the following reasons B-lymphocytes lymphoma and myeloma cells are inherently sensitive to radiotherapy Parker et al 1980 the local emission of ionizing radiation by radiolabeled antibodies may kill cells with or without the target antigen in close proximity to the bound antibody and penetrating radiation may obviate the problem of limited access in bulky or poorly vascularized tumors
Early investigations of therapeutic radiolabeled antibodies for B-cell lymphoma were performed with iodinated antibodies Press et al 1989 Kaminski et al 1993 Wahl et al 1994 Press et al 1995 Currently two treatment regimens have been approved for treatment of relapsedrefractory and transformed follicular lymphoma The Bexxar Treatment Regimen includes murine anti-CD20 antibody Tositumomab iodinated with Iodine I 131 The Main anti-tumor effect comes from high energy beta particles emitted by I 131 In addition I 131 is emitting also low energy gamma radiation allowing for gamma camera measurements and calculation of individualized dose of radioactive tracer for a given patient during therapeutic phase see below In Zevalin a murine anti-CD20 antibody ibritumomab is covalently linked to 90Yttrium 90Y which is a pure beta emitter Lack of gamma radiation from 90Y does not allow for dosimetric assessments and a fixed dose of Zevalin is used for all patients based on their weight This can possibly result in either under- or overdosing of some patients
In addition to treatment of follicular lymphoma ongoing studies explore a possibility of treatment with either Bexxar or Zevalin of other B-cell malignancies In particular anti-CD20 radioimmunotherapy appears very promising as part of treatment of mantle cell lymphoma large cell lymphoma and Waldenstroms macroglobulinemia
Iodine I 131 Tositumomab
Background
Tositumomab is a murine IgG2a lambda monoclonal antibody directed against the CD20 antigen which is found on the surface of normal and malignant B lymphocytes Tositumomab is produced in an antibiotic-free culture of mammalian cells and is composed of two murine gamma 2a heavy chains of 451 amino acids each and two lambda light chains of 220 amino acids each The approximate molecular weight of Tositumomab is 150 kD In vitro studies have demonstrated that upon binding to the CD20 antigen Tositumomab is capable of inducing apoptosis In addition Tositumomab induces antibody-dependent cellular cytotoxicity ADCC and complement-dependent cellular cytotoxicity CDC Iodine I 131 Tositumomab is a radio-iodinated derivative of Tositumomab that has been covalently linked to Iodine-131 Unbound radio-Iodine and other reactants have been removed by chromatographic purification steps This agent produces its cytotoxic effect through the antitumor effects of ionizing radiation as well as the more direct antitumor effects of the antibody The goal of treatment with Iodine I 131 Tositumomab is selective delivery of radiotherapy to radiosensitive malignant cells thus minimizing toxicity to the normal organs
Bexxar Clinical Experience
The dosing regimen and maximally tolerated dose of Bexxar were established in a phase III single-center study conducted at the University of Michigan Kaminski et al 2000 The RIT-II-001 trial included 47 patients and was designed to validate the dosing methodology developed at Michigan Vose et al 2000 The RIT-II-002 trial randomized 78 patients to receive either the tositumomab and I 131-tositumomab regimen or the unlabeled tositumomab to determine the value added of the radionuclide component Davis et al 2001 Patients treated on the radiolabeled antibody arm showed a higher overall response rate OR 55 vs 19 and complete response rate CR 33 vs 8 The RIT-II-004 study enrolled 60 patients with chemotherapy-refractory disease no response or response lasting less than 6 months to the last chemotherapy received to assess the efficacy of the Bexxar therapeutic regimen in this patient population Kaminski et al 2001 The number of patients who achieved longer duration of response to Bexxar was about 5 times higher than the number of patients who had a longer duration to chemotherapy p 0001 In addition patients treated with Bexxar achieved a higher overall response OR rate 47 vs 12 and complete response CR rate 20 vs 2 than patients treated with chemotherapy In summary all 4 initial studies including the Phase III trial showed high response rates and duration of responses in patients with relapsed or refractory low grade or follicular lymphoma including transformed follicular lymphoma previously-treated with chemotherapy Most remarkably patients who achieved complete responses experienced often particularly long duration of responses lasting for years In recognition of remarkable activity the FDA approved an expanded indication for the Bexxar Therapeutic Regimen on January 3 2005
The majority of patients will respond to initial chemotherapy however all treated patients repeatedly relapse with shorter remissions following each subsequent course of chemotherapy Rajkumar et al 2002a Regimens most commonly used for initial therapy include melphalan and prednisone MP which induce remission in approximately 50 of patients Alexanian et al 1969 VAD-vincristine adriamycin and dexamethasone with response rates in the 50 range Salmon et al 1994 Barlogie et al 1984 Alexanian et al 1986 dexamethasone pulses and more recently introduced combinations of thalidomide with dexamethasone Rajkumar et al 2002b Weber et al 2003 All these regimens have comparable response rates With the exception of the recent report which showed a superior response rate to the combination of thalidomide with dexamethasone versus dexamethasone pulses Rajkumar et al 2004 multiple other comparative studies did not show superiority of any of these regimens for overall survival Complete responses to any of these regimens are observed infrequently 5 Patients who complete initial therapy usually proceed to high dose chemotherapy with autologous stem cell transplant support Alternatively patients may be placed on maintenance regimen or can be observed Except for one study with alternate day high dose of Prednisone Berenson et al 2002 no convincing evidence exists that maintenance impacts the natural history of the disease Kyle 2002 The Myeloma Trialists Collaborative Group 2001
High dose chemotherapy has been used as consolidation in multiple myeloma by a number of investigators Barlogie et al 1986 Cunningham et al 1994 Harousseau et al 1995 A randomized trial conducted by French Myeloma Intergroup IFM 90 provided evidence that treatment with high dose chemotherapy and autologous stem cell transplant ASCT after initial therapy results in significantly longer event-free survival median 28 vs 18 months and overall survival 57 vs 42 months if compared to conventional chemotherapy Attal et al 1996 The benefit of auto transplantation was seen in patients of all ages Siegel et al 1999 More recently similar results were reported from a large randomized study in Great Britain Childs et al 2003 Based on these studies in patients eligible for transplant consolidation of initial therapy with high dose therapy followed by ASCT is considered a standard of care NCCN Guidelines 2004 However ASCT is not curative even in patients who achieve complete response CR which is observed in 20-30 of patients who completed ASCT Contamination of autologous stem cell collection with malignant myeloma cells may play some role In support of this notion syngeneic bone marrow transplants showed better and more durable outcomes than those seen with ASCT Gahrton et al 1999 Another reason for failure of autologous stem cell transplant is ineffective eradication of myeloma clone with high dose chemotherapy In an effort to provide more effective elimination of malignant clones some investigators developed intensified treatment regimens Improved results have been reported using Total Therapy which involves a sequence of treatments including tandem ASCT Barlogie et al 1999 Barlogie at al 2004 The notion that intensification of therapy improves outcomes has been validated in a recent randomized study which showed that consolidation of initial therapy with tandem autologous stem cell transplant was superior than consolidation with single autologous stem cell transplant as measured by an improved duration of responses and overall survival Attal at al 2003 In contrast to ASCT allogeneic stem cell transplantation can provide stem cell products free of malignant cells as well as the benefit of graft-versus-myeloma effect
However very high 1-year mortality 30-60 was reported in early allogeneic bone marrow transplant studies with disease free survival in only 15-30 of patients and no superior survival if compared to ASCT Bensinger et al 1996 Bjorkstrand et al 1996 Barlogie et al 1995 More recent studies including allogeneic transplants with nonmyeloablative conditioning regimens provide more encouraging results Reynolds et al 2001 Badros et al 2002 Recently a combined treatment with ASCT followed by a non-myeloablative allogeneic stem cell transplant showed very promising outcomes and improved although still significant toxicity with CR rates in 55-60 range Kroger et al 2002 Maloney et al 2003 It is too early to determine whether improved responses using this approach will result in an increased survival
Emerging data suggest that achieving CR or near CR nCR will result in more durable remission and longer survival Recent analysis of long term outcomes of patients treated on randomized French study IMG90 clearly indicates that the longest survivors are those patients who achieve at least very good partial response or complete response Harousseau 2003 At 7 years 60 of patients were alive in a group which achieved CR or near CR In contrast in a group of patients who achieved PR but less than CR or near CR only 30 were alive and among patients who had less than PR none were alive Similar results have bee recently reported for patients who underwent allogeneic stem cell transplant Corradini et al 2003 It is not clear whether CR in response to initial therapy and prior to transplant may have similar impact on overall outcomes Regardless of specific transplant approach survival curves do not plateau and all patients are expected to relapse regardless of method of intensification therapy possibly due to persistence of residual population of chemotherapy-resistant clonogenic myeloma cells
For patients who have relapsed or are refractory to therapy there is no agreed upon standard treatment Anderson et al 2002 Kyle 2002 Treatment options include salvage chemotherapy autologous stem cell transplant if not previously done or as a second transplant or allogeneic stem cell transplant full or low intensity Kyle 2002 Salvage chemotherapy is most widely used in clinical practice Among a variety of salvage regimens both monotherapy and combination therapy have been applied Monotherapy with Dexamethasone or other steroids administered as pulse therapy produced responses in the 35-40 range Alexanian et al 1983 Gertz et al 1995 Thalidomide used as a single agent showed a 32 response rate in this patient population Singhal et al 1999 More recently VELCADE as a single agent induced at least minimal responses ie 25 reduction in monoclonal protein in 35 of patients and at least a stabilization of the disease in 59 of patients with relapsedrefractory multiple myeloma using strict SWOG criteria Richardson et al 2003 Combination therapies historically show higher response rates VAD has been demonstrated as an effective regimen in patients refractory to alkylating agents with response rates of 60 Lokhorst et al 1989 A similar regimen called DVd with Doxil Vincristine and dexamethasone showed comparable efficacy and acceptable toxicity Hussein et al 2002 Rifkin et al 2004 Newer combinations including combinations of VELCADE thalidomide and Revlimid analog of thalidomide are promising and appear to be able to induce higher response rates and complete remissions as per unpublished yet reports from different meetings Agarwal et al 2003 Orlowski et al 2003 Richardson et al 2003 Richardson et al 2004
Clonogenic Multiple Myeloma Cells
Myeloma is characterized by an accumulation of malignant plasma cells in bone marrow Numerous observations indicated that malignant plasma cells have low proliferative capacity and it is believed that the vast majority of the malignant cell population in myeloma is represented by terminally differentiated plasma cells similar to their normal counterparts Barlogie et al 1989 It is unclear whether these terminally differentiated malignant plasma cells are capable of self-renewal During the past decade several studies indicated that multiple myeloma similarly to other malignancies may consist of heterogenous population of malignant cells Bakkus et al 1994 Billadeau et al 1996
Clonotypic studies identified a population of circulating B-cells in blood samples of patients with myeloma Bergsagel et al 1995 Chen and Epstein 1996 sharing the same clonotypic CDR3 region as is detected in the bone marrow malignant plasma cells Pilarski et al 1996 Szczepek et al 1998 Further studies provided additional insights into the evolution of the myeloma clone supporting a notion of heterogeneity of the population of clonal cells in myeloma Taylor et al 2002 The B-cell component of the myeloma clone appeared to be clonogenic in xenografted mice Pilarski et al 2000 Reiman et al 2001 Moreover clonotypic cells with B-cell phenotype express CD19CD20 antigens and may represent a reservoir of disease that persists after therapy including high dose chemotherapy Kiel et al 1999 Rottenburger et al 1999 Pilarski et al 2002
The majority of myeloma cells express CD138 a highly specific surface antigen of terminally differentiated plasma cells which is absent on highly proliferative normal plasmablast and earlier stages of B-cells Jego et al 2001 Based on these observations it was hypothesized that clonogenic myeloma cells should lack CD138 expression Using CD138 and CD138- subsets of cells isolated from myeloma cell lines and from primary myeloma patient samples Matsui et al 2004 showed that only a minority of all myeloma cells have CD138- phenotype 5 However only CD138- have clonogenic potential as demonstrated in colony formation assays in methylcellulose and after transplantation to NODSCID mice Moreover these cells express B-cell antigens including CD19 and CD20 and their growth could be inhibited by in vitro treatment with rituximab an antibody directed against CD20 antigen Matsui et al 2004
Rationale for anti-CD20 Therapy in Myeloma
Recent observations that clonogenic cells in myeloma express CD20 Kiel et al 1999 Rottenburger et al 1999 and that their growth could be inhibited in vitro by rituximab an anti-CD20 antibody Matsui et al 2004 provides a rationale for using CD20-directed therapy in patients with myeloma Moreover CD19CD20 clonotypic cells appear to be more refractory than CD19-CD20- cells to commonly used chemotherapy regimens in myeloma including high dose therapy with stem cell transplant Kiel et al 1999 Rottenburger et al 1999 Therefore CD20 directed treatment of myeloma would complement chemotherapy by targeting chemoresistant clonogenic myeloma cells
Previous studies showed that therapy with Rituximab unlabeled anti-CD20 antibody could be active in multiple myeloma Hussein et al 1999 Treon et al 2002
In this study we propose to apply therapy with Bexxar a radiolabeled anti-CD20 antibody Bexxar Therapeutic Regimen is composed of the murine anti-CD20 monoclonal antibody Tositumomab and Iodine I 131 Tositumomab Iodine I 131 Tositumomab is a radio-iodinated derivative of Tositumomab that has been covalently linked to Iodine-131
We hypothesized that radiolabeled anti-CD20 antibody will be more efficacious than unlabeled antibody ie rituximab in eradication of highly radiosensitive myeloma cells similarly to what was observed in non-Hodgkins lymphoma Horning et al 2000 Davis et al 2001 Flinn et al 2001 Witzig et al 2002 It is presumed that higher efficacy of radiolabeled anti-CD20 antibody if compared to unlabeled antibody may be due to crossfire effect as the radiation is delivered not only to target cells but also to neighboring cells both expressing and not-expressing CD20 Vose et al 1999 In the proposed design we will apply Bexxar after completion of a course of initial chemotherapy for newly diagnosed patients or a course of salvage chemotherapy provided that patients achieve at least partial response to prior therapy ie 50 reduction of tumor mass and reach a plateau of their response to prior therapy By using patients in a period of stable disease we will have a better chance to observe the effects of radioimmunotherapy against CD20 cells which represent a minority of all malignant cells In addition we will evaluate the impact of Bexxar therapy on clonogenic myeloma cells using clonogenic assays as described in Methods
We anticipate that majority of newly diagnosed patients will be eligible and will subsequently proceed to autologous stem cell transplant as part of standard therapy of myeloma NCCN Guidelines 2004 if as hypothesized bexxar treatment does have the potential to eliminate clonogenic myeloma stem cells stem cells collected post-bexxar treatment should be depleted of re-populating myeloma cells Therefore this combination of chemotherapy and targeted therapy against clonogenic cells may have a potential of eliminating myeloma clones Although stem cell collections and autologous stem cell transplants have been used without apparent difficulties in the past in patients treated with anti-CD20 radio-conjugates Ratanatharatorn et al 2001 Kaminski et al 2001 Ansell et al 2002 we plan to collect backup stem cells prior to treatment with Bexxar to allow to proceed with the standard stem cell transplant in the unlikely cases of failure of collection of stem cells post-Bexxar Anti-CD20 radioimmunotherapy was previously used in combination with chemotherapy without additional toxicity Emmanoulides et al 2001 Gregory et al 2001 Press et al 2003
Radioimmunotherapy of B-Cell Malignancies
Radiolabeled monoclonal antibodies are efficacious in treating B-cell malignancies for the following reasons B-lymphocytes lymphoma and myeloma cells are inherently sensitive to radiotherapy Parker et al 1980 the local emission of ionizing radiation by radiolabeled antibodies may kill cells with or without the target antigen in close proximity to the bound antibody and penetrating radiation may obviate the problem of limited access in bulky or poorly vascularized tumors
Early investigations of therapeutic radiolabeled antibodies for B-cell lymphoma were performed with iodinated antibodies Press et al 1989 Kaminski et al 1993 Wahl et al 1994 Press et al 1995 Currently two treatment regimens have been approved for treatment of relapsedrefractory and transformed follicular lymphoma The Bexxar Treatment Regimen includes murine anti-CD20 antibody Tositumomab iodinated with Iodine I 131 The Main anti-tumor effect comes from high energy beta particles emitted by I 131 In addition I 131 is emitting also low energy gamma radiation allowing for gamma camera measurements and calculation of individualized dose of radioactive tracer for a given patient during therapeutic phase see below In Zevalin a murine anti-CD20 antibody ibritumomab is covalently linked to 90Yttrium 90Y which is a pure beta emitter Lack of gamma radiation from 90Y does not allow for dosimetric assessments and a fixed dose of Zevalin is used for all patients based on their weight This can possibly result in either under- or overdosing of some patients
In addition to treatment of follicular lymphoma ongoing studies explore a possibility of treatment with either Bexxar or Zevalin of other B-cell malignancies In particular anti-CD20 radioimmunotherapy appears very promising as part of treatment of mantle cell lymphoma large cell lymphoma and Waldenstroms macroglobulinemia
Iodine I 131 Tositumomab
Background
Tositumomab is a murine IgG2a lambda monoclonal antibody directed against the CD20 antigen which is found on the surface of normal and malignant B lymphocytes Tositumomab is produced in an antibiotic-free culture of mammalian cells and is composed of two murine gamma 2a heavy chains of 451 amino acids each and two lambda light chains of 220 amino acids each The approximate molecular weight of Tositumomab is 150 kD In vitro studies have demonstrated that upon binding to the CD20 antigen Tositumomab is capable of inducing apoptosis In addition Tositumomab induces antibody-dependent cellular cytotoxicity ADCC and complement-dependent cellular cytotoxicity CDC Iodine I 131 Tositumomab is a radio-iodinated derivative of Tositumomab that has been covalently linked to Iodine-131 Unbound radio-Iodine and other reactants have been removed by chromatographic purification steps This agent produces its cytotoxic effect through the antitumor effects of ionizing radiation as well as the more direct antitumor effects of the antibody The goal of treatment with Iodine I 131 Tositumomab is selective delivery of radiotherapy to radiosensitive malignant cells thus minimizing toxicity to the normal organs
Bexxar Clinical Experience
The dosing regimen and maximally tolerated dose of Bexxar were established in a phase III single-center study conducted at the University of Michigan Kaminski et al 2000 The RIT-II-001 trial included 47 patients and was designed to validate the dosing methodology developed at Michigan Vose et al 2000 The RIT-II-002 trial randomized 78 patients to receive either the tositumomab and I 131-tositumomab regimen or the unlabeled tositumomab to determine the value added of the radionuclide component Davis et al 2001 Patients treated on the radiolabeled antibody arm showed a higher overall response rate OR 55 vs 19 and complete response rate CR 33 vs 8 The RIT-II-004 study enrolled 60 patients with chemotherapy-refractory disease no response or response lasting less than 6 months to the last chemotherapy received to assess the efficacy of the Bexxar therapeutic regimen in this patient population Kaminski et al 2001 The number of patients who achieved longer duration of response to Bexxar was about 5 times higher than the number of patients who had a longer duration to chemotherapy p 0001 In addition patients treated with Bexxar achieved a higher overall response OR rate 47 vs 12 and complete response CR rate 20 vs 2 than patients treated with chemotherapy In summary all 4 initial studies including the Phase III trial showed high response rates and duration of responses in patients with relapsed or refractory low grade or follicular lymphoma including transformed follicular lymphoma previously-treated with chemotherapy Most remarkably patients who achieved complete responses experienced often particularly long duration of responses lasting for years In recognition of remarkable activity the FDA approved an expanded indication for the Bexxar Therapeutic Regimen on January 3 2005
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 |
|---|---|---|---|
| IRB 2005-0403 and HUM 43767 | OTHER | University of Michigan Medical IRB | None |