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Chemotherapy, Stem Cell Transplantation and Donor and Patient Vaccination for Treatment of Multiple Myeloma

Primary Purpose

Multiple Myeloma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Myeloma Immunoglobulin Idiotype Vaccine
Bortezomib
Cyclophosphamide
Cyclosporine
Doxorubicin hydrochloride
Etoposide
Fludarabine phosphate
Prednisone
Vincristine Sulfate
Methotrexate
GMCSF (granulocyte macrophage colony stimulating factor)
GCSF (granulocyte colony stimulating factor)
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring Immunoablative, Mobilization, Apheresis, Multiple Myeloma, IgG Multiple Myeloma, IgA Multiple Myeloma

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA: Collection of plasma in recipient: Patients with Immunoglobulin G (IgG) or Immunoglobulin A (IgA) multiple myeloma. Patients have siblings. Human leukocyte antigen (HLA) typing of recipient and donor(s) initiated. Viral antibody screening initiated. INCLUSION CRITERIA: Recipient: Patients with IgG or IgA multiple myeloma. Patients must have achieved at least a partial remission following initial conventional chemotherapy regimen or after autologous stem cell transplantation. Patients who have undergone tandem autologous stem transplants are eligible if they meet all other eligibility criteria. Patients who have achieved at least a partial remission to initial (primary) conventional chemotherapy will be encouraged to proceed to autologous transplantation, but will also be eligible for this protocol. Patients 18-75 years of age. The upper age limit was chosen as it is felt that the toxicities would exceed potential benefit in this older population. Karnofsky performance status greater than or equal to 80%. Life expectancy greater than 6 months. Left ventricular ejection fraction has to be greater than 50% by either multi-gated acquisition scan (MUGA) or 2-D echo. Carbon monoxide diffusing capacity (DLCO) greater than 50% of the expected value when corrected for hemoglobin (Hb)(96). Creatinine less than or equal to 1.5 mg/dl and a creatinine clearance greater than or equal to 50 ml/min. Direct bilirubin less than or equal to 2.0 mg/dl serum glutamic oxaloacetic transaminase (SGOT) less than 4x top normal. M-protein: the concentration in the harvested plasma must be greater than 70% of the total Ig of the corresponding isotype. Patients must be human immunodeficiency virus (HIV)-negative. There is the theoretical possibility that the degree of immune suppression associated with the treatment may result in progression of HIV infection. Patients may be Hepatitis B core antigen positive, but surface antigen negative and without evidence of active infection. Patients must be Hepatitis C negative. Not pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may potentially be harmful to the infant. Consenting first degree relative matched at 6/6 or 5/6 HLA antigens, this may include a mismatch at the D locus. Ability to give informed consent. INCLUSION CRITERIA: Donor: Age 18-75 years. As the potential cerebrovascular and cardiac complications may potentially increase with age, age 75 has been chosen arbitrarily as the upper age limit. However, if it is determined after initial accrual of patients in this upper age range that this procedure is relatively safe, the age range may be extended. No physical contraindications to stem cell donation (i.e. severe atherosclerosis, auto-immune disease, cerebrovascular accident, active malignancy (97). Patients with severe atherosclerosis by history will receive a cardiology consult and be judged eligible on a case by case basis. Donors must be HIV-negative, hepatitis B surface antigen (HBsAg-), and Hepatitis C antibody negative. This is to prevent the possible transmission of these infections to the recipient. Not pregnant or lactating. Donors of childbearing potential must use an effective method of contraception. The effects of cytokine administration on a fetus are unknown and may be potentially harmful. The effects upon breast milk are also unknown and may potentially be harmful to the infant. Normal cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) numbers as defined by Clinical Center standards. Ability to give informed consent.

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Recipient - Chemotherapy Group

Donor - Vaccine Generation Group

Arm Description

Induction chemotherapy with fludarabine, etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and granulocyte colony stimulating factor (GCSF) followed by transplant preparative regimen chemotherapy with fludarabine, cyclophosphamide, mesna, cyclosporine, and methotrexate, followed by stem cell infusion and immunization.

3 subcutaneous injections of myeloma protein within 10 weeks before stem cell collection. The first (week 0) second (week 2), and third injection (week 6) with Id-KLH (Anti-idiotype-keyhole limpet hemocyanin) (0.5 mg subcutaneous day 1) and Granulocyte macrophage-colony stimulating factor (GM-CSF) (250 mcg/m^2 subcutaneous on days 1-4). Stem cell collection is 4 weeks after the third vaccination.

Outcomes

Primary Outcome Measures

Immune Response
Immune cell depletion is defined as immunosuppression of participants T cells prior to transplant measured by cluster of differentiation 4 (CD4) counts (i.e. cells) > 50 cells per ul.Immune T-cell depletion helps to reduce the ability to reject allogeneic cells in participants and is required for engraftment. Engraftment is the body's ability to accept donor cells.
Number of Participants With Adverse Events
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.

Secondary Outcome Measures

Full Information

First Posted
August 23, 2000
Last Updated
September 19, 2017
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00006184
Brief Title
Chemotherapy, Stem Cell Transplantation and Donor and Patient Vaccination for Treatment of Multiple Myeloma
Official Title
Active Immunization of Sibling Stem Cell Transplant Donors Against Purified Myeloma Protein of the Stem Cell Recipient With Multiple Myeloma in the Setting of Non-Myeloablative, HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
September 2017
Overall Recruitment Status
Completed
Study Start Date
February 8, 2001 (Actual)
Primary Completion Date
January 12, 2008 (Actual)
Study Completion Date
January 12, 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Background: The mainstay of therapy for newly diagnosed multiple myeloma patients remains systemic chemotherapy. Although partial remissions of up to 60% are obtained with conventional regimens, multiple myeloma is essentially an incurable disease with a median survival of approximately 30 months. Allogeneic stem cell transplantation (SCT) results in a high percentage of complete remissions, but it can be associated with significant treatment-related mortality, which has been primarily attributed to conventional myeloablative transplant regimens. Recent clinical studies have shown that highly immunosuppressive yet non-myeloablative doses of fludarabine-based chemotherapy can result in alloengraftment. Even with a reduction in treatment related mortality, success with allogeneic SCT is limited by a significant risk of relapse. Donor immunization with myeloma Id in the setting of a non-myeloablative allogeneic SCT may represent a novel strategy for the treatment of multiple myeloma. Objectives: Primary Objectives: To induce cellular and humoral immunity in allogeneic stem cell donors and recipients against the unique idiotype expressed by the recipient's myeloma. To determine whether antigen-specific immunity, induced in the stem cell donor, can be passively transferred to the allogeneic SCT recipient in the setting of a non-myeloablative conditioning regimen. Secondary Objectives: To evaluate the effect of the Fludarabine-(etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide) EPOCH regimen on host T cell depletion and myeloid depletion prior to allogeneic SCT. To determine the efficacy of a novel conventional chemotherapy regimen (Fludarabine-EPOCH) in the setting multiple myeloma. To determine the treatment-related morbidity and mortality of allogeneic stem cell transplantation using a non-myeloablative conditioning regimen in multiple myeloma. To determine if the re-vaccination of allogeneic stem cell donors with the unique idiotype expressed by the recipient's myeloma will enhance cellular and humoral immunity to patient specific-idiotype prior to lymphocyte donation for the treatment of patients with recurrent or progressive disease after transplantation. Eligibility: Patients 18-75 years of age with Immunoglobulin G (IgG) or Immunoglobulin A (IgA) multiple myeloma. Patients must have achieved at least a partial remission following initial conventional chemotherapy regimen or after autologous stem cell transplantation. Consenting first degree relative matched at 6/6 or 5/6 human leukocyte antigen (HLA) antigens. Design: Phase 2 trial using a non-myeloablative conditioning regimen to reduce treatment-related toxicity. Recipient will undergo a plasmapheresis to obtain starting material for the isolation of idiotype protein. Donors would be immunized with an Id vaccine prepared from the patient. Prior to transplantation patients would receive a conventional chemotherapy regimen which contains agents active in myeloma and is T cell depleting. The allogeneic SCT would be performed with a conditioning regimen consisting of cyclophosphamide and fludarabine. The stem cell source would be blood mobilized with filgrastim. Recipients will be immunized with the Id vaccine following transplantation.
Detailed Description
Background: The mainstay of therapy for newly diagnosed multiple myeloma patients remains systemic chemotherapy. Although partial remissions of up to 60% are obtained with conventional regimens, multiple myeloma is essentially an incurable disease with a median survival of approximately 30 months. Allogeneic stem cell transplantation (SCT) results in a high percentage of complete remissions, but it can be associated with significant treatment-related mortality, which has been primarily attributed to conventional myeloablative transplant regimens. Recent clinical studies have shown that highly immunosuppressive yet non-myeloablative doses of fludarabine-based chemotherapy can result in allo-engraftment. Even with a reduction in treatment related mortality, success with allogeneic SCT is limited by a significant risk of relapse. Donor immunization with myeloma Id in the setting of a non-myeloablative allogeneic SCT may represent a novel strategy for the treatment of multiple myeloma. Objectives: Primary Objectives: To induce cellular and humoral immunity in allogeneic stem cell donors and recipients against the unique idiotype expressed by the recipient's myeloma. To determine whether antigen-specific immunity, induced in the stem cell donor, can be passively transferred to the allogeneic SCT recipient in the setting of a non-myeloablative conditioning regimen. Secondary Objectives: To evaluate the effect of the Fludarabine-EPOCH regimen on host T cell depletion and myeloid depletion prior to allogeneic SCT. To determine the efficacy of a novel conventional chemotherapy regimen (Fludarabine-EPOCH) in the setting multiple myeloma. To determine the treatment-related morbidity and mortality of allogeneic stem cell transplantation using a non-myeloablative conditioning regimen in multiple myeloma. To determine if the re-vaccination of allogeneic stem cell donors with the unique idiotype expressed by the recipient's myeloma will enhance cellular and humoral immunity to patient specific-idiotype prior to lymphocyte donation for the treatment of patients with recurrent or progressive disease after transplantation. Eligibility: Patients 18-75 years of age with IgG or IgA multiple myeloma. Patients must have achieved at least a partial remission following initial conventional chemotherapy regimen or after autologous stem cell transplantation. Consenting first degree relative matched at 6/6 or 5/6 HLA antigens. Design: Phase 2 trial using a non-myeloablative conditioning regimen to reduce treatment-related toxicity. Recipient will undergo a plasmapheresis to obtain starting material for the isolation of idiotype protein. Donors would be immunized with an Id vaccine prepared from the patient. Prior to transplantation patients would receive a conventional chemotherapy regimen which contains agents active in myeloma and is T cell depleting. The allogeneic SCT would be performed with a conditioning regimen consisting of cyclophosphamide and fludarabine. The stem cell source would be blood mobilized with filgrastim. Recipients will be immunized with the Id vaccine following transplantation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
Keywords
Immunoablative, Mobilization, Apheresis, Multiple Myeloma, IgG Multiple Myeloma, IgA Multiple Myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Recipient - Chemotherapy Group
Arm Type
Experimental
Arm Description
Induction chemotherapy with fludarabine, etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and granulocyte colony stimulating factor (GCSF) followed by transplant preparative regimen chemotherapy with fludarabine, cyclophosphamide, mesna, cyclosporine, and methotrexate, followed by stem cell infusion and immunization.
Arm Title
Donor - Vaccine Generation Group
Arm Type
Other
Arm Description
3 subcutaneous injections of myeloma protein within 10 weeks before stem cell collection. The first (week 0) second (week 2), and third injection (week 6) with Id-KLH (Anti-idiotype-keyhole limpet hemocyanin) (0.5 mg subcutaneous day 1) and Granulocyte macrophage-colony stimulating factor (GM-CSF) (250 mcg/m^2 subcutaneous on days 1-4). Stem cell collection is 4 weeks after the third vaccination.
Intervention Type
Drug
Intervention Name(s)
Myeloma Immunoglobulin Idiotype Vaccine
Intervention Description
3 subcutaneous (SC) injections of myeloma protein within 10 weeks before stem cell collection the first (week 0), second (week 2), and third injection (week 6) with Id-KLH (0.5 mg SC day 1)
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
Velcade, PS341
Intervention Description
Induction chemotherapy: 1.3 mg/m^2 bolus intravenous injection twice weekly for 2 weeks (days 1, 4, 8, 11) followed by 10 day rest period (day 12-21)
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan, CTX
Intervention Description
Induction chemotherapy: 600 mg/m^2 day 4 Transplant: 1200 mg/m^2 intravenous x 4 days (days -6, -5, -4, -3)
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Other Intervention Name(s)
Sandimmune, Cyclosporin A
Intervention Description
Transplant: 2 mg/kg intravenous every 12 hours continuous intravenous or by mouth (PO) until day + 180
Intervention Type
Drug
Intervention Name(s)
Doxorubicin hydrochloride
Intervention Description
Induction chemotherapy: 10 mg/m^2 day continuous intravenous (CIV) days 1-3
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
Vepesid
Intervention Description
Induction chemotherapy: 50 mg/m^2 day continuous intravenous days 1-3
Intervention Type
Drug
Intervention Name(s)
Fludarabine phosphate
Other Intervention Name(s)
Fludara
Intervention Description
Induction chemotherapy: 25 mg/m^2 day intravenous days 1-3 Transplant: 30 mg/m^2 day x 4 days (days -6, -5, -4, -3 )
Intervention Type
Drug
Intervention Name(s)
Prednisone
Other Intervention Name(s)
Deltasone
Intervention Description
60 mg/m^2 day 1-4
Intervention Type
Drug
Intervention Name(s)
Vincristine Sulfate
Intervention Description
Induction chemotherapy: 0.5 mg/m^2 day continuous intravenous days 1-3
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
MTX, Methotrexate sodium
Intervention Description
Transplant: 5 mg/m^2 intravenous on days +1, +3, +6, +11
Intervention Type
Biological
Intervention Name(s)
GMCSF (granulocyte macrophage colony stimulating factor)
Intervention Description
250 mcg/m^2 subcutaneously every day, days 1-4
Intervention Type
Biological
Intervention Name(s)
GCSF (granulocyte colony stimulating factor)
Other Intervention Name(s)
Filgrastim, Neupogen
Intervention Description
10 mcg/kg per day subcutaneously daily from day 5 until absolute neutrophil count (ANC) > 1000/ul x 2 days
Primary Outcome Measure Information:
Title
Immune Response
Description
Immune cell depletion is defined as immunosuppression of participants T cells prior to transplant measured by cluster of differentiation 4 (CD4) counts (i.e. cells) > 50 cells per ul.Immune T-cell depletion helps to reduce the ability to reject allogeneic cells in participants and is required for engraftment. Engraftment is the body's ability to accept donor cells.
Time Frame
105 days
Title
Number of Participants With Adverse Events
Description
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
Time Frame
9 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: Collection of plasma in recipient: Patients with Immunoglobulin G (IgG) or Immunoglobulin A (IgA) multiple myeloma. Patients have siblings. Human leukocyte antigen (HLA) typing of recipient and donor(s) initiated. Viral antibody screening initiated. INCLUSION CRITERIA: Recipient: Patients with IgG or IgA multiple myeloma. Patients must have achieved at least a partial remission following initial conventional chemotherapy regimen or after autologous stem cell transplantation. Patients who have undergone tandem autologous stem transplants are eligible if they meet all other eligibility criteria. Patients who have achieved at least a partial remission to initial (primary) conventional chemotherapy will be encouraged to proceed to autologous transplantation, but will also be eligible for this protocol. Patients 18-75 years of age. The upper age limit was chosen as it is felt that the toxicities would exceed potential benefit in this older population. Karnofsky performance status greater than or equal to 80%. Life expectancy greater than 6 months. Left ventricular ejection fraction has to be greater than 50% by either multi-gated acquisition scan (MUGA) or 2-D echo. Carbon monoxide diffusing capacity (DLCO) greater than 50% of the expected value when corrected for hemoglobin (Hb)(96). Creatinine less than or equal to 1.5 mg/dl and a creatinine clearance greater than or equal to 50 ml/min. Direct bilirubin less than or equal to 2.0 mg/dl serum glutamic oxaloacetic transaminase (SGOT) less than 4x top normal. M-protein: the concentration in the harvested plasma must be greater than 70% of the total Ig of the corresponding isotype. Patients must be human immunodeficiency virus (HIV)-negative. There is the theoretical possibility that the degree of immune suppression associated with the treatment may result in progression of HIV infection. Patients may be Hepatitis B core antigen positive, but surface antigen negative and without evidence of active infection. Patients must be Hepatitis C negative. Not pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may potentially be harmful to the infant. Consenting first degree relative matched at 6/6 or 5/6 HLA antigens, this may include a mismatch at the D locus. Ability to give informed consent. INCLUSION CRITERIA: Donor: Age 18-75 years. As the potential cerebrovascular and cardiac complications may potentially increase with age, age 75 has been chosen arbitrarily as the upper age limit. However, if it is determined after initial accrual of patients in this upper age range that this procedure is relatively safe, the age range may be extended. No physical contraindications to stem cell donation (i.e. severe atherosclerosis, auto-immune disease, cerebrovascular accident, active malignancy (97). Patients with severe atherosclerosis by history will receive a cardiology consult and be judged eligible on a case by case basis. Donors must be HIV-negative, hepatitis B surface antigen (HBsAg-), and Hepatitis C antibody negative. This is to prevent the possible transmission of these infections to the recipient. Not pregnant or lactating. Donors of childbearing potential must use an effective method of contraception. The effects of cytokine administration on a fetus are unknown and may be potentially harmful. The effects upon breast milk are also unknown and may potentially be harmful to the infant. Normal cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) numbers as defined by Clinical Center standards. Ability to give informed consent.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Claude Sportes, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
47617
Citation
Stevenson GT, Stevenson FK. Antibody to a molecularly-defined antigen confined to a tumour cell surface. Nature. 1975 Apr 24;254(5502):714-6. doi: 10.1038/254714a0. No abstract available.
Results Reference
background
PubMed Identifier
69552
Citation
Stevenson GT, Elliott EV, Stevenson FK. Idiotypic determinants on the surface immunoglobulin of neoplastic lymphocytes: a therapeutic target. Fed Proc. 1977 Aug;36(9):2268-71. No abstract available.
Results Reference
background
PubMed Identifier
6173751
Citation
Miller RA, Maloney DG, Warnke R, Levy R. Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N Engl J Med. 1982 Mar 4;306(9):517-22. doi: 10.1056/NEJM198203043060906. No abstract available.
Results Reference
background
PubMed Identifier
22773122
Citation
Foglietta M, Neelapu SS, Kwak LW, Jiang Y, Nattamai D, Lee ST, Fowler DH, Sportes C, Gress RE, Steinberg SM, Vence LM, Radvanyi L, Dwyer KC, Qazilbash MH, Bryant RN, Bishop MR. Neoantigen and tumor antigen-specific immunity transferred from immunized donors is detectable early after allogeneic transplantation in myeloma patients. Bone Marrow Transplant. 2013 Feb;48(2):269-77. doi: 10.1038/bmt.2012.132. Epub 2012 Jul 9.
Results Reference
result
PubMed Identifier
20661232
Citation
Jamshed S, Fowler DH, Neelapu SS, Dean RM, Steinberg SM, Odom J, Bryant K, Hakim F, Bishop MR. EPOCH-F: a novel salvage regimen for multiple myeloma before reduced-intensity allogeneic hematopoietic SCT. Bone Marrow Transplant. 2011 May;46(5):676-81. doi: 10.1038/bmt.2010.173. Epub 2010 Jul 26.
Results Reference
derived

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Chemotherapy, Stem Cell Transplantation and Donor and Patient Vaccination for Treatment of Multiple Myeloma

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