90 Y-BC8-DOTA Monoclonal Antibody, Fludarabine Phosphate, and Total-Body Irradiation Followed By Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Multiple Myeloma
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Purpose
This phase I trial is studying the side effects and best dose of yttrium Y 90 anti-CD45 monoclonal antibody BC8 when given together with fludarabine phosphate and total-body irradiation followed by donor peripheral blood stem cell transplant in treating patients with multiple myeloma. Radiolabeled monoclonal antibodies, such as yttrium Y 90 anti-CD45 monoclonal antibody BC8, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving chemotherapy drugs, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving yttrium Y 90 anti-CD45 monoclonal antibody BC8, fludarabine phosphate, and total-body irradiation before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening and may be an effective treatment for multiple myeloma
| Condition | Intervention | Phase |
|---|---|---|
|
Refractory Multiple Myeloma Stage I Multiple Myeloma Stage II Multiple Myeloma Stage III Multiple Myeloma |
Drug: fludarabine phosphate Radiation: total-body irradiation Procedure: peripheral blood stem cell transplantation Drug: cyclosporine Drug: mycophenolate mofetil Procedure: allogeneic hematopoietic stem cell transplantation Radiation: yttrium Y 90 anti-CD45 monoclonal antibody BC8 |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Phase I Study of 90Y-BC8-DOTA Monoclonal Antibody, Fludarabine and TBI Followed by HLA-Matched, Allogeneic Peripheral Blood Stem Cell Transplant for the Treatment of Multiple Myeloma |
- Assessment of the tissue localization of 111In-BC8-DOTA Ab to establish reproducibly favorable biodistributions [ Time Frame: Up to 72 hours post infusion ] [ Designated as safety issue: No ]
- MTD of radiation delivered via 90 Y-BC8-DOTA when combined with FLU and 2 Gy TBI as a preparative regimen followed by HLA-matched, related or unrelated HCT for patients with multiple myeloma [ Time Frame: Up to 180 days ] [ Designated as safety issue: Yes ]MTD is defined as the dose that is associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as a Grade III/IV regimen-related toxicity (Bearman scale) occurring within 30 days post-transplant. Dose modification will be conducted according to Storer's two-stage design. A two-parameter logistic model will be fit to the data, thereby generating a dose-response curve based on the observed toxicity rate at the various dose levels. Based on this fitted model, the MTD is estimated to be the dose that is associated with a toxicity rate of 25%.
- Potential efficacy of this approach, within the limits of a phase I study, by examining disease response, duration of remission, DFS, and OS [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]Will look at overall and disease-free survival among all patients treated as well as among patients treated at the estimated MTD, recognizing the limitations of assessing efficacy in a phase I trial.
| Estimated Enrollment: | 20 |
| Study Start Date: | January 2012 |
| Estimated Primary Completion Date: | December 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Treatment (monoclonal antibody, chemo, TBI, transplant)
Patients receive 90Y-BC8 Ab IV on day -12 and fludarabine phosphate IV on days -4 to -2. Patients undergo TBI and allogeneic peripheral blood stem cell transplant on day 0. Patients also receive graft-vs-host disease prophylaxis comprising cyclosporine PO BID on days -3 to 56 with taper to day 180 or on days -3 to 100 with taper to 180; and mycophenolate mofetil IV or PO BID on days 0-27, or 0-40 with taper to 96.
|
Drug: fludarabine phosphate
Given IV
Other Names:
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic peripheral blood stem cell transplantation
Other Names:
Drug: cyclosporine
Given PO
Other Names:
Drug: mycophenolate mofetil
Given IV or PO
Other Names:
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic peripheral blood stem cell transplantation
Radiation: yttrium Y 90 anti-CD45 monoclonal antibody BC8
Given IV
Other Names:
|
Detailed Description:
PRIMARY OBJECTIVES:
I. To assess the tissue localization of 111In-BC8-DOTA antibody therapy (Ab) and establish reproducibly favorable biodistributions.
II. To estimate the maximum tolerated dose (MTD) of radiation delivered via 90Y-BC8-DOTA Ab when combined with fludarabine phosphate (FLU) and 2 Gy total-body irradiation (TBI) as a preparative regimen followed by HLA-matched, related or unrelated hematopoietic cell transplant (HCT) for patients with multiple myeloma.
SECONDARY OBJECTIVES:
I. To assess the potential efficacy of this approach, within the limits of a phase I study, by examining disease response, duration of remission, disease free survival (DFS), and overall survival (OS).
OUTLINE: This is a dose-escalation study of yttrium Y 90 anti-CD45 monoclonal antibody BC8 (90Y-BC8 Ab).
Patients receive 90Y-BC8 Ab intravenously (IV) on day -12 and fludarabine phosphate IV on days -4 to -2. Patients undergo TBI and allogeneic peripheral blood stem cell transplant on day 0. Patients also receive graft-vs-host disease prophylaxis comprising cyclosporine orally (PO) twice daily (BID) on days -3 to 56 with taper to day 180 or on days -3 to 100 with taper to 180; and mycophenolate mofetil IV or PO BID on days 0-27, or 0-40 with taper to 96.
After completion of study treatment patients are followed up every 6 months for 2 years and then annually thereafter.
Eligibility| Ages Eligible for Study: | 18 Years to 65 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Patients must have history of symptomatic myeloma requiring treatment (defined as significant anemia [hemoglobin (HgB) less than 10 gm/dl], renal dysfunction [creatinine greater than 2.0] not attributable to other causes, lytic bone disease on imaging, or hypercalcemia) and meet one of the following requirements:
- Have at least 1 high risk feature at diagnosis (including deletion 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16) or deletion 17 by fluorescence in situ hybridization [FISH], beta 2 microglobulin greater than 3.5, lactate dehydrogenase [LDH] greater than 1.5 x upper limit of normal [ULN]) (prior to chemotherapy); OR
- Have progressive disease on primary therapy with or without prior autologous stem cell transplant; OR
- Have persistent or progressive disease following autologous transplant; it is acceptable for these patients to have a second transplant for disease reduction
- Bone marrow cellularity of at least 50 percent of normal by core biopsy (25% cellularity = 50% of normal)
- Eastern Cooperative Oncology Group (ECOG) less than or equal to 2
- Measured creatinine clearance greater than 50 ml/min or estimated creatinine clearance greater than 50 ml/min
- For females of childbearing potential, must have a negative pregnancy test
Patients must have an human leukocyte antigen (HLA)-identical sibling donor or an HLA-matched unrelated donor who meets standard Seattle Cancer Care Alliance (SCCA) and or National Marrow Donor Program (NMDP) criteria for peripheral blood stem cell (PBSC) donation, as follows:
- Sibling donor: A patient and sibling donor should be matched for HLA-A, B, C, DRB1 and DQB1 by an intermediate resolution deoxyribonucleic acid (DNA)-based method
- Unrelated donor: An unrelated donor and recipient should be typed by a high resolution DNA-based method, and ideally matched for HLA-A, B, C, DRB1 and DQB1 alleles, or if there is only a single locus disparity mismatched for an HLA-DQB1 antigen or allele; an unrelated donor may also be mismatched for any single 1) one HLA-A, B or C antigen or allele, or 2) HLA-DRB1 allele (with or without matching for HLA-DQB1)
- Ability to provide informed consent
- DONOR: Patients must have an HLA matched donor as well as standard SCCA and or NMDP criteria for PBSC donation; donors must consent and be eligible to undergo GCSF mobilization and PBSC harvest; marrow is not allowed as a source of stem cells on this study
Exclusion Criteria:
Patients with the following organ dysfunction:
- Left ventricular ejection fraction less than 35 percent
- Corrected diffusion capacity of carbon monoxide (DLCO) less than 35 percent or receiving supplemental continuous oxygen
- Liver abnormalities: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction as evidences by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis, or symptomatic biliary disease
- Pregnant or breast-feeding females
- Circulating antibody against mouse immunoglobulin (HAMA)
- Prior allogeneic transplant
- Plasmacytomas greater than 1cm in marrow areas measured by magnetic resonance imaging (MRI) or extramedullary plasmacytomas (radiated lesions are exempt from this criteria); patients may receive cytoreductive therapy, including allogeneic stem cell transplant (ASCT) (if high risk) or second ASCT (if failed a prior ASCT) to achieve disease control
- Prior radiation to maximally tolerated levels to any critical normal organ, or greater than 20 Gy prior radiation to large areas of the bone marrow (e.g., external radiation therapy to whole pelvis)
- Patients who are known to be seropositive for human immunodeficiency virus (HIV)
- Fertile men and women unwilling to use contraceptives during and for 12 months post-transplant
Contacts and Locations| United States, Washington | |
| Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | Recruiting |
| Seattle, Washington, United States, 98109 | |
| Contact: William I. Bensinger 206-667-4933 | |
| Principal Investigator: William I. Bensinger | |
| Principal Investigator: | William Bensinger | Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium |
More Information
No publications provided
| ClinicalTrials.gov Identifier: | NCT01503242 History of Changes |
| Other Study ID Numbers: | 2450.00, NCI-2010-02041, R21CA155911 |
| Study First Received: | December 30, 2011 |
| Last Updated: | May 13, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Multiple Myeloma Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases Antibodies |
Immunoglobulins Antibodies, Monoclonal Cyclosporins Cyclosporine Mycophenolate mofetil Fludarabine monophosphate Mycophenolic Acid Vidarabine Fludarabine Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Immunosuppressive Agents |
ClinicalTrials.gov processed this record on May 21, 2013