Antithymocyte Globulin and Sirolimus in Treating Patients With Relapsed Multiple Myeloma

University of Rochester

Status and phase

Completed

Phase 1

Conditions

Multiple Myeloma and Plasma Cell Neoplasm

Drug/Agent Toxicity by Tissue/Organ

Treatments

Drug: sirolimus

Biological: anti-thymocyte globulin

Study type

Interventional

Funder types

Other

Identifiers

NCT00317798

URCC-U11405

GENZ-URCC-U11405

CDR0000480087

Details and patient eligibility

About

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.

Full 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.

Enrollment

18 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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