Antithymocyte Globulin and Sirolimus in Treating Patients With Relapsed Multiple Myeloma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
JJ Ifthikharuddin, University of Rochester
ClinicalTrials.gov Identifier:
NCT00317798
First received: April 24, 2006
Last updated: August 29, 2011
Last verified: August 2011
  Purpose

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.


Condition Intervention Phase
Drug/Agent Toxicity by Tissue/Organ
Multiple Myeloma and Plasma Cell Neoplasm
Biological: anti-thymocyte globulin
Drug: sirolimus
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot, Phase-I Trial of Rabbit Anti-Thymocyte Globulin (rATG, Thymoglobulin™) in Combination With Rapamycin in Relapsed Multiple Myeloma (MM)

Resource links provided by NLM:


Further study details as provided by University of Rochester:

Primary Outcome Measures:
  • Dose-limiting toxicity and maximum tolerated dose [ Time Frame: Duration of the study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Relapse rates as measured by standard response criteria [ Time Frame: Duration of the study ] [ Designated as safety issue: No ]
  • Laboratory correlative studies [ Time Frame: During treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 18
Study Start Date: April 2006
Study Completion Date: April 2011
Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Intervention Details:
    Biological: anti-thymocyte globulin
    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
    Drug: sirolimus
    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
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00317798

Locations
United States, New York
James P. Wilmot Cancer Center at University of Rochester Medical Center
Rochester, New York, United States, 14642
Sponsors and Collaborators
University of Rochester
Investigators
Principal Investigator: J. J. Ifthikharuddin, MD James P. Wilmot Cancer Center
Principal Investigator: Martin S. Zand, MD, PhD James P. Wilmot Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: JJ Ifthikharuddin, Principal Investigator, University of Rochester
ClinicalTrials.gov Identifier: NCT00317798     History of Changes
Other Study ID Numbers: CDR0000480087, URCC-U11405, GENZ-URCC-U11405
Study First Received: April 24, 2006
Last Updated: August 29, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Rochester:
drug/agent toxicity by tissue/organ
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
refractory multiple myeloma

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Plasmacytoma
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
Antilymphocyte Serum
Sirolimus
Everolimus
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents

ClinicalTrials.gov processed this record on September 30, 2014