Iodine I 131 Tositumomab, Etoposide and Cyclophosphamide Followed by Autologous Stem Cell Transplant in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

Phase 2

Completed

• Conditions: Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Waldenström Macroglobulinemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Lymphoblastic Lymphoma
• Interventions: Drug: cyclophosphamide; Drug: etoposide; Radiation: iodine I 131 tositumomab; Procedure: quality-of-life assessment; Procedure: peripheral blood stem cell transplantation

• Registration Number: NCT00073918
• Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary

This phase II trial is studying how well giving iodine I 131 tositumomab together with etoposide and cyclophosphamide followed by autologous stem cell transplant works in treating patients with relapsed or refractory non-Hodgkin's lymphoma. Radiolabeled monoclonal antibodies, such as iodine I 131 tositumomab, can find cancer cells and deliver radioactive cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as etoposide and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Combining a radiolabeled monoclonal antibody with combination chemotherapy before autologous stem cell transplant may kill more cancer cells

Detailed Description

PRIMARY OBJECTIVES:

I. To assess the progression-free survival of patients receiving 131 I labeled tositumomab antibody, etoposide (VP-16) and cyclophosphamide (CY) followed by autologous transplantation.

II. To examine the potential efficacy of 131 I labeled tositumomab antibody, etoposide (VP-16) and cyclophosphamide (CY) followed by autologous transplantation.

SECONDARY OBJECTIVES:

I. To assess the overall survival of patients receiving 131 I labeled tositumomab antibody, etoposide (VP-16) and cyclophosphamide (CY) followed by autologous transplantation.

II. To evaluate the toxicity and tolerability of the above therapy.

OUTLINE:

RADIOIMMUNOTHERAPY: Patients receive a test dose of iodine I 131 tositumomab intravenously (IV) on day -24 to determine biodistribution. Patients then receive therapeutic iodine I 131 tositumomab IV over approximately 40-60 minutes on day -14 and are entered into radiation isolation until day -4.

CHEMOTHERAPY: Patients receive etoposide IV on day -4 and cyclophosphamide IV on day -2.

AUTOLOGOUS STEM CELL TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell transplant on day 0.

After completion of study treatment, patients are followed at 1, 3, 6, and 12 months and then annually thereafter.

Study Timeline

• Study Start: 1999-02
• Study First Submitted: 2003-12-10
• Study First Submitted QC: 2003-12-10
• Study First Posted: 2003-12-11
• Primary Completion: 2011-10-02
• Study Completion: 2011-10-02
• Results First Submitted: 2016-12-02
• Results First Submitted QC: 2016-12-02
• Results First Posted: 2017-01-27
• Status Verified: 2017-07
• Last Update Submitted: 2017-07-21
• Last Update Posted: 2017-08-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 111

Inclusion Criteria

• Patients must have a histologically confirmed diagnosis of lymphoma expressing the cluster of differentiation (CD)20 antigen and generally must have failed at least one prior standard systemic therapy; the exception will be mantle cell lymphoma (MCL) patients, who may be enrolled while in first complete remission (CR) in accordance with current transplant standard of care for these patients
• Note: Patients with clinically non-transformed follicular lymphomas do not require repeat biopsies for immunophenotyping since these tumors are uniformly reactive with the tositumomab antibody
• Patients must have tumor burdens < 500cc by computed tomography (CT) or magnetic resonance (MRI) volumetric measurements and must not have splenomegaly at the time of enrollment; splenomegaly will be defined as a spleen volume > 2 standard deviations of the mean spleen volume to body weight ratio (mean = 3.84 cc/kg, SD = 1.53 cc/kg); thus, patients with > 6.9cc/kg will be defined as having splenomegaly; patients with splenomegaly that is thought to be due to G CSF/GM-CSF effect and not due to lymphomatous involvement of the spleen can been deemed eligible with the approval of an investigator
• Patients must have normal renal function (creatinine [Cr] < 2.0)
• Patients must have normal hepatic function (bilirubin < 1.5mg/dL), with the exception of patients thought to have Gilbert's syndrome, who may have a total bilirubin above 1.5mg/dL
• All patients eligible for therapeutic study must have autologous hematopoietic stem cells (2 x 10^6 CD34+ cells/kg) harvested and cryopreserved
• Patients must have an expected survival of > 60 days and must be free of major infection

Exclusion Criteria

• Circulating anti-mouse antibody (HAMA)
• Systemic anti-lymphoma therapy given within 30 days prior to anticipated treatment date
• Inability to understand or give an informed consent
• Prior radiation > 20 Gy to any critical normal organ (e.g., lung, liver, spinal cord, or over 25% of red marrow)
• Central nervous system lymphoma
• Other serious medical conditions considered to represent contraindications to autologous stem cell transplant (ASCT) (e.g., active coronary artery disease, pulmonary dysfunction [forced expiratory volume in 1 second (FEV1) < 70% expected, Vital Capacity < 70% expected, diffusing capacity of the lung for carbon monoxide (DLCO) < 50%, patient on supplemental oxygen], AIDS, etc.)
• Pregnancy
• Prior bone marrow or stem cell transplant
• Presence of circulating lymphoma cells by morphology or flow cytometry (>= 0.1%) at or near the time of peripheral blood stem cell (PBSC) collection if unpurged PBSC are to be used
• Southwest Oncology Group (SWOG) performance status >= 2.0
• Unable to perform self-care during radiation isolation
• Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma/well differentiated lymphocytic lymphoma (ineligible because these tumors express very low surface densities of CD20)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (radio labeled monoclonal antibody, chemotherapy)	iodine I 131 tositumomab	RADIOIMMUNOTHERAPY: Patients receive a test dose of iodine I 131 tositumomab IV on day -24 to determine biodistribution. Patients then receive therapeutic iodine I 131 tositumomab IV over approximately 40-60 minutes on day -14 and are entered into radiation isolation until day -4. CHEMOTHERAPY: Patients receive etoposide IV on day -4 and cyclophosphamide IV on day -2. AUTOLOGOUS STEM CELL TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell transplantation on day 0.
Treatment (radio labeled monoclonal antibody, chemotherapy)	peripheral blood stem cell transplantation	RADIOIMMUNOTHERAPY: Patients receive a test dose of iodine I 131 tositumomab IV on day -24 to determine biodistribution. Patients then receive therapeutic iodine I 131 tositumomab IV over approximately 40-60 minutes on day -14 and are entered into radiation isolation until day -4. CHEMOTHERAPY: Patients receive etoposide IV on day -4 and cyclophosphamide IV on day -2. AUTOLOGOUS STEM CELL TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell transplantation on day 0.
Treatment (radio labeled monoclonal antibody, chemotherapy)	quality-of-life assessment	RADIOIMMUNOTHERAPY: Patients receive a test dose of iodine I 131 tositumomab IV on day -24 to determine biodistribution. Patients then receive therapeutic iodine I 131 tositumomab IV over approximately 40-60 minutes on day -14 and are entered into radiation isolation until day -4. CHEMOTHERAPY: Patients receive etoposide IV on day -4 and cyclophosphamide IV on day -2. AUTOLOGOUS STEM CELL TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell transplantation on day 0.
Treatment (radio labeled monoclonal antibody, chemotherapy)	cyclophosphamide	RADIOIMMUNOTHERAPY: Patients receive a test dose of iodine I 131 tositumomab IV on day -24 to determine biodistribution. Patients then receive therapeutic iodine I 131 tositumomab IV over approximately 40-60 minutes on day -14 and are entered into radiation isolation until day -4. CHEMOTHERAPY: Patients receive etoposide IV on day -4 and cyclophosphamide IV on day -2. AUTOLOGOUS STEM CELL TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell transplantation on day 0.
Treatment (radio labeled monoclonal antibody, chemotherapy)	etoposide	RADIOIMMUNOTHERAPY: Patients receive a test dose of iodine I 131 tositumomab IV on day -24 to determine biodistribution. Patients then receive therapeutic iodine I 131 tositumomab IV over approximately 40-60 minutes on day -14 and are entered into radiation isolation until day -4. CHEMOTHERAPY: Patients receive etoposide IV on day -4 and cyclophosphamide IV on day -2. AUTOLOGOUS STEM CELL TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell transplantation on day 0.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival	At year 3	Kaplan-Meier estimate of progression-free survival at 3 years will be used as the primary determinant of potential efficacy.

Secondary Outcome Measures

Name	Time	Method
5 Year Overall Survival	Up to 15 years	Survival will be estimated using the method of Kaplan and Meier. Associated confidence intervals will be provided as part of the analysis.
Response Rate	From date of transplant through date of relapse/progression or death, assessed up to 15 years	Response rates will be estimated as the percentage of patients
Toxicity as Assessed by Common Terminology Criteria (CTC) v 2.0	From date of first exposure to study drug, through date of relapse/progression or other significant medical event confounding further assessment, assessed up to 15 years	Grade 3-4 Bearman non-hematologic toxicity will be carefully monitored throughout this study. The protocol will be terminated due to safety concerns if there exists sufficient evidence suggesting that the true rate of grade 3-4 nonhematologic toxicity exceeds 25%. All patients, regardless of histology, will be evaluated together for purposes of toxicity. Sufficient evidence will be taken to be a lower limit to the appropriate 90% one-sided confidence interval in excess of 25%

Trial Locations

Locations (1)

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States