Rituximab, Yttrium Y 90 Ibritumomab Tiuxetan, Melphalan, and Autologous Peripheral Stem Cell Transplant in Treating Patients With Previously Treated Multiple Myeloma

Sponsor

Mayo Clinic (Other)

Overall Status

Completed

CT.gov ID

NCT00477815

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

155.2

Actual Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. A peripheral stem cell transplant using stem cells from the patient may be able to replace blood-forming cells that were destroyed by chemotherapy. Giving monoclonal antibody therapy together with chemotherapy and autologous peripheral stem cell transplant may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of yttrium Y 90 ibritumomab tiuxetan when given together with rituximab, melphalan, and autologous peripheral stem cell transplant in treating patients with previously treated multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Biological: rituximab Drug: melphalan Biological: Stem Cell Biological: Sargramostim (GM-CSF) Radiation: 90Y-Zevalin Biological: 111In Zevalin	Phase 1

Detailed Description

OBJECTIVES:

Primary

Determine the safety of rituximab, yttrium Y 90 ibritumomab tiuxetan, high-dose melphalan, and autologous peripheral blood stem cell transplantation in patients with previously treated multiple myeloma.
Determine the effect of rituximab and yttrium Y 90 ibritumomab tiuxetan on the clonotypic B-cells at baseline and at B-cell recovery in these patients.

Secondary

Determine the response rate and progression factors (time to progression, progression-free survival, and duration of response) in patients treated with this regimen.
Determine the effect of rituximab and yttrium Y 90 ibritumomab tiuxetan on the clonal plasma cells in the blood and marrow prior to high-dose melphalan.

OUTLINE: This is a dose-escalation study of yttrium Y 90 ibritumomab tiuxetan.

Patients receive rituximab IV followed by a dosimetry dose of indium In 111 ibritumomab tiuxetan IV over 10 minutes on day -22. Patients with acceptable biodistribution receive rituximab IV followed by yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day -14, high-dose melphalan IV over 1 hour on days -2 and -1, and undergo autologous peripheral blood stem cell transplantation on day 0. Patients also receive sargramostim (GM-CSF) subcutaneously beginning on day 0 and continuing until blood counts recover.

Cohorts of 3-6 patients receive escalating doses of yttrium Y 90 ibritumomab tiuxetan 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.

Bone marrow, blood, and urine samples are collected at baseline and then periodically during study for biomarker correlative studies.

After completion of study treatment, patients are followed every 3 months for 5 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Trial of Zevalin Radioimmunotherapy With High-Dose Melphalan and Stem Cell Transplant for Multiple Myeloma

Actual Study Start Date :

May 31, 2005

Actual Primary Completion Date :

Jul 28, 2011

Actual Study Completion Date :

May 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab + Zevalin Determine the dose level that is both tolerable and achieves the greatest B cell recovery in patients with multiple myeloma.	Biological: rituximab 375 mg/m2 given as an IV infusion once weekly for four doses (days 1, 8, 15, and 22) Other Names: Rituxan, Chimeric Pan-B, C2B8, mouse-human chimeric antibody to CD20 antigen Drug: melphalan 100/m2 in 1000 ml 0.9% NaCI IV infusion over 1 hour daily x 2 days. Biological: Stem Cell greater than or equal to 2 x 106 CD34+/kg by IV Biological: Sargramostim (GM-CSF) 500 mcg by Subcutaneous QD Radiation: 90Y-Zevalin Dose escalation scheme. The dose of Zevalin will be based on the calculated radiation to the liver. Other Names: Y2B8, 90Y-ibritumomab tiuxetan, IDEC Y2B8 Biological: 111In Zevalin 5.0 mCi by IV

Arm

Intervention/Treatment

Experimental: Rituximab + Zevalin

Determine the dose level that is both tolerable and achieves the greatest B cell recovery in patients with multiple myeloma.

Biological: rituximab

375 mg/m2 given as an IV infusion once weekly for four doses (days 1, 8, 15, and 22)

Other Names:

Rituxan, Chimeric Pan-B, C2B8, mouse-human chimeric antibody to CD20 antigen

Drug: melphalan

100/m2 in 1000 ml 0.9% NaCI IV infusion over 1 hour daily x 2 days.

Biological: Stem Cell

greater than or equal to 2 x 106 CD34+/kg by IV

Biological: Sargramostim (GM-CSF)

500 mcg by Subcutaneous QD

Radiation: 90Y-Zevalin

Dose escalation scheme. The dose of Zevalin will be based on the calculated radiation to the liver.

Other Names:

Y2B8, 90Y-ibritumomab tiuxetan, IDEC Y2B8

Biological: 111In Zevalin

5.0 mCi by IV

Outcome Measures

Primary Outcome Measures

Toxicity as measured by CTCAE v 3.0 [19 Months]
Clonotypic B cells [19 months]

Secondary Outcome Measures

Response (complete response, very good partial response, partial response) [19 months]
Time to progression and duration of response [5 years]
Impact of rituximab and yttrium Y 90 ibritumomab tiuxetan on the clonal plasma cells in the blood and marrow prior to high-dose melphalan [1 week]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of multiple myeloma
Previously treated disease
Candidate for high-dose chemotherapy with melphalan and autologous stem cell transplantation
No definite evidence of myelodysplasia on pretreatment bone marrow by morphology or by chromosome analysis (e.g., monosomy 7)
Chromosome abnormalities from the myeloma clone allowed

PATIENT CHARACTERISTICS:

ECOG performance status 0-2
ANC ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Bilirubin ≤ 2.0 mg/dL
Alkaline phosphatase ≤ 3 times upper limit of normal (ULN)
AST ≤ 3 times ULN
Creatinine ≤ 2 times ULN
LVEF ≥ 45%
Corrected pulmonary diffusion capacity ≥ 50%
No uncontrolled infection
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No other active malignancy (with the exception of nonmelanoma skin cancer) that requires myelosuppressive chemotherapy or radiation therapy
No HIV positivity

PRIOR CONCURRENT THERAPY:

More than 3 weeks since prior myelosuppressive chemotherapy, except cyclophosphamide pulsing for stem cell collection)
No other concurrent immunotherapy, radiotherapy, chemotherapy or antimyeloma therapy
Concurrent chronic corticosteroids at doses of prednisone ≤ 20 mg per day (or equivalent) allowed
Concurrent adjuvant hormonal therapy (e.g., tamoxifen citrate or leuprolide acetate) allowed