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Antithymocyte Globulin and Sirolimus in Treating Patients With Relapsed Multiple Myeloma

Primary Purpose

Drug/Agent Toxicity by Tissue/Organ, Multiple Myeloma and Plasma Cell Neoplasm

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
anti-thymocyte globulin
sirolimus
Sponsored by
University of Rochester
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Drug/Agent Toxicity by Tissue/Organ focused on measuring drug/agent toxicity by tissue/organ, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma

Eligibility Criteria

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

DISEASE CHARACTERISTICS: Previously diagnosed multiple myeloma (MM) based on standard criteria Soft tissue (not bone only) plasmacytomas allowed Measurable disease, meeting both of the following criteria: Monoclonal population of plasma cell in the bone marrow Quantifiable serum and/or urine monoclonal protein (i.e., generally, but not exclusively, IgG > 1 g/dL, IgA > 0.5 g/dL, or urine light-chain excretion ≥ 200 mg/24 hours) Steroid-refractory disease, defined as less than a minimum response to prior high-dose glucocorticoid therapy Minimal response requires all of the following criteria: 25-49% reduction in the level of serum monoclonal paraprotein maintained for ≥ 6 weeks 50-89% reduction in 24-hour urinary light-chain excretion, but still > 200 mg/24 hours, maintained for ≥ 6 weeks 25-49% reduction in the size of soft tissue plasmacytomas (clinically or by CT scan or MRI) No increase in size or number of lytic bone lesions High-dose glucocorticoid therapy defined as 480 mg dexamethasone (or equivalent) alone or as part of a vincristine, doxorubicin, and dexamethasone regimen Must have undergone autologous transplantation OR received ≥ 2 conventional lines of therapy Currently requiring therapy for progressive disease, as indicated by any of the following criteria: 25% increase in paraprotein Development of new or progression of pre-existing lytic bone lesions or soft tissue plasmacytomas Hypercalcemia not attributable to any other cause Relapse from complete remission No nonsecretory MM PATIENT CHARACTERISTICS: Zubrod performance status 0-2 3-4 allowed if, in the opinion of the investigator, secondary to MM-related bone pain Life expectancy ≥ 3 months Creatinine ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN Bilirubin ≤ 1.5 times ULN Calcium < 14 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception HIV negative Hepatitis B surface antigen and hepatitis C antibody negative No known history of allergy to rabbit proteins No history of cardiac amyloidosis No poorly controlled hypertension, diabetes mellitus, coronary artery disease, or other serious medical or psychiatric illness No myocardial infarction within the past 6 weeks No New York Heart Association class III or IV heart failure No uncontrolled angina No severe uncontrolled ventricular arrhythmias No evidence of acute ischemia or active conduction system abnormality by electrocardiogram No active systemic infection requiring treatment unless adequately controlled with appropriate antimicrobial therapy (e.g., treated central line infection) No acute viral illness No pathologic fractures or symptomatic hyperviscosity No other prior malignancy except adequately treated basal cell or squamous cell skin cancer, cervical cancer in situ, or any other cancer with a disease-free status for ≥ 3 years PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 8 weeks since prior immunotherapy or antibody therapy At least 4 weeks since prior major surgery (except for kyphoplasty) At least 3 weeks since prior conventional chemotherapy or radiotherapy for MM At least 3 weeks since prior bortezomib, thalidomide, or clarithromycin for MM No prior anti-thymocyte globulin No concurrent radiotherapy No other concurrent antineoplastic therapy with known activity against MM, including clarithromycin No other concurrent investigational agents

Sites / Locations

  • James P. Wilmot Cancer Center at University of Rochester Medical Center

Outcomes

Primary Outcome Measures

Dose-limiting toxicity and maximum tolerated dose

Secondary Outcome Measures

Relapse rates as measured by standard response criteria
Laboratory correlative studies

Full Information

First Posted
April 24, 2006
Last Updated
August 29, 2011
Sponsor
University of Rochester
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1. Study Identification

Unique Protocol Identification Number
NCT00317798
Brief Title
Antithymocyte Globulin and Sirolimus in Treating Patients With Relapsed Multiple Myeloma
Official Title
A Pilot, Phase-I Trial of Rabbit Anti-Thymocyte Globulin (rATG, Thymoglobulin™) in Combination With Rapamycin in Relapsed Multiple Myeloma (MM)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2011
Overall Recruitment Status
Completed
Study Start Date
April 2006 (undefined)
Primary Completion Date
April 2011 (Actual)
Study Completion Date
April 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Rochester

4. Oversight

5. Study Description

Brief Summary
RATIONALE: Biological therapies, such as antithymocyte globulin may stimulate the immune system in different ways and stop cancer cells from growing. Sirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It may also prevent or reduce the side effects of antithymocyte globulin. Giving antithymocyte globulin together with sirolimus may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best dose of antithymocyte globulin when given together with sirolimus in treating patients with relapsed multiple myeloma.
Detailed Description
OBJECTIVES: Primary Determine the safety and tolerability, in terms of clinical and laboratory toxicity, of anti-thymocyte globulin (ATG) combined with sirolimus in patients with relapsed multiple myeloma. Determine the dose-limiting toxicity of this regimen in these patients. Determine the maximum tolerated dose of ATG when administered with sirolimus in these patients. Secondary Determine the clinical activity of this regimen, in terms of measurability of improvement in clinical benefits, in these patients. Assess patients for sensitivity of CD 138^-positive myeloma cells to ATG prior to treatment. Determine the pharmacokinetics, in terms of ATG levels in blood and bone marrow, in these patients. Assess the binding capability of ATG to bone marrow resident myeloma cells. Determine if an ATG-resistant clone emerges after treatment. OUTLINE: This is an open-label, pilot, dose-escalation study of anti-thymocyte globulin (ATG). Patients receive ATG IV over 6-12 hours for 4, 6, or 8 days and oral sirolimus once daily on days 1-30 in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of ATG until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. Bone marrow aspirates and blood samples are collected at baseline and periodically during study treatment for drug sensitivity and pharmacokinetic studies. After completion of study treatment, patients are followed every 3 weeks for up to 2 months and then monthly thereafter. PROJECTED ACCRUAL: A total of 18 patients will be accrued for this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Drug/Agent Toxicity by Tissue/Organ, Multiple Myeloma and Plasma Cell Neoplasm
Keywords
drug/agent toxicity by tissue/organ, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Intervention Type
Biological
Intervention Name(s)
anti-thymocyte globulin
Intervention Description
Escalating doses of rATG,intravenously, starting at 6 mg/kg to a maximum of 14.5 mg/kg. Rapamycin is given orally, starting at a dose of 1 mg daily beginning on day 1 and terminating on day 30. The dose of rapamycin was adjusted to maintain a constant blood level of 4-6 ng/ml in all subjects
Intervention Type
Drug
Intervention Name(s)
sirolimus
Intervention Description
escalating doses of rATG, intravenously, starting at 6 mg/kg to a maximum of 14.5 mg/kg. Rapamycin is given orally, starting at a dose of 1 mg daily beginning on day 1 and terminating on day 30. The dose of rapamycin was adjusted to maintain a constant blood level of 4-6 ng/ml in all subjects
Primary Outcome Measure Information:
Title
Dose-limiting toxicity and maximum tolerated dose
Time Frame
Duration of the study
Secondary Outcome Measure Information:
Title
Relapse rates as measured by standard response criteria
Time Frame
Duration of the study
Title
Laboratory correlative studies
Time Frame
During treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Previously diagnosed multiple myeloma (MM) based on standard criteria Soft tissue (not bone only) plasmacytomas allowed Measurable disease, meeting both of the following criteria: Monoclonal population of plasma cell in the bone marrow Quantifiable serum and/or urine monoclonal protein (i.e., generally, but not exclusively, IgG > 1 g/dL, IgA > 0.5 g/dL, or urine light-chain excretion ≥ 200 mg/24 hours) Steroid-refractory disease, defined as less than a minimum response to prior high-dose glucocorticoid therapy Minimal response requires all of the following criteria: 25-49% reduction in the level of serum monoclonal paraprotein maintained for ≥ 6 weeks 50-89% reduction in 24-hour urinary light-chain excretion, but still > 200 mg/24 hours, maintained for ≥ 6 weeks 25-49% reduction in the size of soft tissue plasmacytomas (clinically or by CT scan or MRI) No increase in size or number of lytic bone lesions High-dose glucocorticoid therapy defined as 480 mg dexamethasone (or equivalent) alone or as part of a vincristine, doxorubicin, and dexamethasone regimen Must have undergone autologous transplantation OR received ≥ 2 conventional lines of therapy Currently requiring therapy for progressive disease, as indicated by any of the following criteria: 25% increase in paraprotein Development of new or progression of pre-existing lytic bone lesions or soft tissue plasmacytomas Hypercalcemia not attributable to any other cause Relapse from complete remission No nonsecretory MM PATIENT CHARACTERISTICS: Zubrod performance status 0-2 3-4 allowed if, in the opinion of the investigator, secondary to MM-related bone pain Life expectancy ≥ 3 months Creatinine ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN Bilirubin ≤ 1.5 times ULN Calcium < 14 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception HIV negative Hepatitis B surface antigen and hepatitis C antibody negative No known history of allergy to rabbit proteins No history of cardiac amyloidosis No poorly controlled hypertension, diabetes mellitus, coronary artery disease, or other serious medical or psychiatric illness No myocardial infarction within the past 6 weeks No New York Heart Association class III or IV heart failure No uncontrolled angina No severe uncontrolled ventricular arrhythmias No evidence of acute ischemia or active conduction system abnormality by electrocardiogram No active systemic infection requiring treatment unless adequately controlled with appropriate antimicrobial therapy (e.g., treated central line infection) No acute viral illness No pathologic fractures or symptomatic hyperviscosity No other prior malignancy except adequately treated basal cell or squamous cell skin cancer, cervical cancer in situ, or any other cancer with a disease-free status for ≥ 3 years PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 8 weeks since prior immunotherapy or antibody therapy At least 4 weeks since prior major surgery (except for kyphoplasty) At least 3 weeks since prior conventional chemotherapy or radiotherapy for MM At least 3 weeks since prior bortezomib, thalidomide, or clarithromycin for MM No prior anti-thymocyte globulin No concurrent radiotherapy No other concurrent antineoplastic therapy with known activity against MM, including clarithromycin No other concurrent investigational agents
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
J. J. Ifthikharuddin, MD
Organizational Affiliation
James P. Wilmot Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Martin S. Zand, MD, PhD
Organizational Affiliation
James P. Wilmot Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
James P. Wilmot Cancer Center at University of Rochester Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States

12. IPD Sharing Statement

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Antithymocyte Globulin and Sirolimus in Treating Patients With Relapsed Multiple Myeloma

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