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Trial record 67 of 107 for:    "Vascular Hemostatic Disease" | "Doxorubicin"

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

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ClinicalTrials.gov Identifier: NCT00006184
Recruitment Status : Completed
First Posted : August 24, 2000
Results First Posted : January 24, 2013
Last Update Posted : October 20, 2017
Sponsor:
Information provided by (Responsible Party):
Ronald Gress, M.D., National Institutes of Health Clinical Center (CC)

Tracking Information
First Submitted Date  ICMJE August 23, 2000
First Posted Date  ICMJE August 24, 2000
Results First Submitted Date  ICMJE December 13, 2012
Results First Posted Date  ICMJE January 24, 2013
Last Update Posted Date October 20, 2017
Actual Study Start Date  ICMJE February 8, 2001
Actual Primary Completion Date January 12, 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 13, 2012)
  • Immune Response [ Time Frame: 105 days ]
    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 [ Time Frame: 9 years ]
    Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00006184 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Chemotherapy, Stem Cell Transplantation and Donor and Patient Vaccination for Treatment of Multiple Myeloma
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE
  • Drug: Myeloma Immunoglobulin Idiotype Vaccine
    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)
  • Drug: Bortezomib
    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)
    Other Names:
    • Velcade
    • PS341
  • Drug: Cyclophosphamide
    Induction chemotherapy: 600 mg/m^2 day 4 Transplant: 1200 mg/m^2 intravenous x 4 days (days -6, -5, -4, -3)
    Other Names:
    • Cytoxan
    • CTX
  • Drug: Cyclosporine
    Transplant: 2 mg/kg intravenous every 12 hours continuous intravenous or by mouth (PO) until day + 180
    Other Names:
    • Sandimmune
    • Cyclosporin A
  • Drug: Doxorubicin hydrochloride
    Induction chemotherapy: 10 mg/m^2 day continuous intravenous (CIV) days 1-3
  • Drug: Etoposide
    Induction chemotherapy: 50 mg/m^2 day continuous intravenous days 1-3
    Other Name: Vepesid
  • Drug: Fludarabine phosphate
    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 )
    Other Name: Fludara
  • Drug: Prednisone
    60 mg/m^2 day 1-4
    Other Name: Deltasone
  • Drug: Vincristine Sulfate
    Induction chemotherapy: 0.5 mg/m^2 day continuous intravenous days 1-3
  • Drug: Methotrexate
    Transplant: 5 mg/m^2 intravenous on days +1, +3, +6, +11
    Other Names:
    • MTX
    • Methotrexate sodium
  • Biological: GMCSF (granulocyte macrophage colony stimulating factor)
    250 mcg/m^2 subcutaneously every day, days 1-4
  • Biological: GCSF (granulocyte colony stimulating factor)
    10 mcg/kg per day subcutaneously daily from day 5 until absolute neutrophil count (ANC) > 1000/ul x 2 days
    Other Names:
    • Filgrastim
    • Neupogen
Study Arms  ICMJE
  • Experimental: Recipient - Chemotherapy Group
    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.
    Interventions:
    • Drug: Bortezomib
    • Drug: Cyclophosphamide
    • Drug: Cyclosporine
    • Drug: Doxorubicin hydrochloride
    • Drug: Etoposide
    • Drug: Fludarabine phosphate
    • Drug: Prednisone
    • Drug: Vincristine Sulfate
    • Drug: Methotrexate
    • Biological: GCSF (granulocyte colony stimulating factor)
  • Donor - Vaccine Generation Group
    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.
    Interventions:
    • Drug: Myeloma Immunoglobulin Idiotype Vaccine
    • Drug: Bortezomib
    • Biological: GMCSF (granulocyte macrophage colony stimulating factor)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 13, 2012)
20
Original Enrollment  ICMJE
 (submitted: June 23, 2005)
69
Actual Study Completion Date  ICMJE January 12, 2008
Actual Primary Completion Date January 12, 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00006184
Other Study ID Numbers  ICMJE 000201
00-C-0201
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ronald Gress, M.D., National Institutes of Health Clinical Center (CC)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Claude Sportes, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP