Anti-CD20 Radioimmunotherapy Before Chemotherapy and Stem Cell Transplant in Treating Patients With High-Risk B-Cell Malignancies

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of anti-cluster of differentiation (CD)20 radioimmunotherapy (RIT), and to see how well it works when given before chemotherapy and stem cell transplant in treating patients with B-cell malignancies that have not responded to treatment or have come back after responding to treatment. CD20 is a protein found on the cells of a type of cancer cell called B-cells. Anti-CD20 RIT attaches radioactive material to a drug that is designed to target CD20, which brings radioactive material to the cancer cells to kill the cells. This may kill more tumor cells while causing fewer side effects to healthy tissue. Adding anti-CD20 to standard chemotherapy and stem cell transplant may be more effective in treating patients with B-cell malignancies.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) of 90Y activity that can be delivered via pretargeted radioimmunotherapy (PRIT) using B9E9-fusion protein (B9E9-FP), clearing agent (CA), and radiolabeled tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin when followed by carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy and autologous stem cell transplantation. SECONDARY OBJECTIVES: I. To assess the overall and progression-free survival of the above regimen in such patients. II. To evaluate the response rates of the above therapy. III. To evaluate the toxicity and tolerability of the above therapy. IV. To evaluate the feasibility of delivering sequential high-dose PRIT and chemotherapy. TERTIARY OBJECTIVES: I. Assess biodistribution and pharmacokinetics of B9E9-FP and radiolabeled DOTA-Biotin. II. Assess ability of the clearing agent (CA) to remove excess B9E9-FP from the serum. III. Evaluate the impact, if any, of circulating rituximab on biodistributions. OUTLINE: This is a phase I, dose-escalation study of yttrium Y 90 DOTA-biotin followed by a phase II study. B9E9-FP INFUSION: Patients receive B9E9-fusion protein intravenously (IV) over a minimum of 2 hours on day -17. CLEARING AGENT INFUSION: Patients receive clearing agent IV over a minimum of 30 minutes on day -15. RADIOBIOTIN INFUSION: Patients receive indium In 111-DOTA-biotin IV and yttrium Y 90 DOTA-biotin IV over 2-5 minutes on day -14. BEAM CHEMOTHERAPY: Patients receive BEAM chemotherapy comprising carmustine IV over 3 hours on day -7; etoposide IV over 2 hours twice daily (BID) and cytarabine IV over 4 hours BID on days -6 to -3; and melphalan IV over 30 minutes on day -2. STEM CELL INFUSION: Patients undergo autologous peripheral blood stem cell transplant (PBSCT) on day 0 per standard of care. After completion of study treatment, patients are followed up at 1, 3, 6, and 12 months, and then annually thereafter.

Official Title
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Evaluation of Pretargeted Anti-CD20 Radioimmunotherapy Combined With BEAM Chemotherapy and Autologous Stem Cell Transplantation for High-Risk B-Cell Malignancies

Conditions
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Burkitt Lymphoma, CD20-Positive Neoplastic Cells Present, Diffuse Large B-Cell Lymphoma, Indolent Non-Hodgkin Lymphoma, Mantle Cell Lymphoma, Recurrent B-Cell Non-Hodgkin Lymphoma, Refractory Mature B-Cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: Anti-CD20 B9E9 scFv-Streptavidin Fusion Protein
* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Drug: Carmustine
* Drug: Clearing Agent
* Drug: Cytarabine
* Drug: Etoposide
* Radiation: Indium In 111-DOTA-Biotin
* Other: Laboratory Biomarker Analysis
* Drug: Melphalan
* Procedure: Peripheral Blood Stem Cell Transplantation
* Other: Pharmacological Study
* Radiation: Yttrium Y 90-DOTA-Biotin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a histologically confirmed diagnosis of lymphoma expressing the CD20 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) as well as other select high-risk lymphomas (e.g., Burkitt?s, double hit diffuse large B-cell lymphoma [DLBCL], transformed indolent B-cell non-Hodgkin lymphoma [B-NHL], etc.) in accordance with current transplant standard of care for these patients Creatinine (Cr) < 2.0 Bilirubin < 1.5 mg/dL, with the exception of patients thought to have Gilbert?s syndrome, who may have a total bilirubin above 1.5 mg/dL All patients eligible for therapeutic study must have (>= 2 x 10^6 CD34/kg) autologous hematopoietic stem cells harvested and cryopreserved Patients must have an expected survival of > 60 days and must be free of major infection Patients of childbearing potential must agree to abstinence or the use of effective contraception DONOR SELECTION: Not applicable; this protocol employs autologous transplantation, utilizing the patient?s own hematopoietic stem cells obtained from either the peripheral blood or bone marrow Exclusion Criteria: Systemic anti-lymphoma therapy given in the previous 30 days before the scheduled 90Y therapy dose Inability to understand or give an informed consent Prior radiation > 20 Gy to any critical normal organ (e.g., lung, liver, spinal cord, both kidneys) within 1 year of the treatment date Active central nervous system lymphoma Other serious medical conditions considered to represent contraindications to bone marrow transplant (BMT) (e.g., abnormally decreased cardiac ejection fraction, diffusion capacity of the lung for carbon monoxide [DLCO] < 50% predicted, patient on supplemental oxygen, acquired immune deficiency syndrome [AIDS], etc.) Pregnancy or breast feeding Prior bone marrow or stem cell transplant Southwest Oncology Group (SWOG) performance status >= 2.0 Known sensitivity to kanamycin and other aminoglycosides; patients with known hypersensitivity to kanamycin or any other aminoglycoside antibiotic will be excluded

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (PRIT)<br>B9E9-FP INFUSION: Patients receive B9E9-fusion protein IV over a minimum of 2 hours on day -17. CLEARING AGENT INFUSION: Patients receive clearing agent IV over a minimum of 30 minutes on day -15. RADIOBIOTIN INFUSION: Patients receive indium In 111-DOTA-biotin IV and yttrium Y 90 DOTA-biotin IV over 2-5 minutes on day -14. BEAM CHEMOTHERAPY: Patients receive BEAM chemotherapy comprising carmustine IV over 3 hours on day -7; etoposide IV over 2 hours BID and cytarabine IV over 4 hours BID on days -6 to -3; and melphalan IV over 30 minutes on day -2. STEM CELL INFUSION: Patients undergo autologous PBSCT on day 0 per standard of care. | Biological: Anti-CD20 B9E9 scFv-Streptavidin Fusion Protein<br>* Given IV<br>* Other names: scFv B9E9-streptavidin Fusion Protein;Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous PBSCT<br>* Other names: Autologous Stem Cell Transplantation;Drug: Carmustine<br>* Given IV<br>* Other names: WR-139021;Drug: Clearing Agent<br>* Given IV<br>Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Radiation: Indium In 111-DOTA-Biotin<br>* Given IV<br>* Other names: In 111-DOTA-Biotin;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo autologous PBSCT<br>* Other names: Peripheral Stem Cell Transplantation;Other: Pharmacological Study<br>* Correlative studies<br>Radiation: Yttrium Y 90-DOTA-Biotin<br>* Given IV<br>* Other names: yttrium Y 90 DOTA-biotin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Yttrium Y 90 DOTA-biotin Defined as the Dose That is Associated With a True Dose Limiting Toxicity (DLT) Rate of 25%, Where a DLT is Defined as a Therapy-related Grade III or IV Bearman (Transplant) Toxicity | Following the completed observation of the final patient, a two-parameter logistic model will be fit to the data, thereby generating a dose-toxicity curve based on the observed DLT rate at the various dose levels visited. Based on this fitted model, the MTD is estimated to be the dose that is associated with a DLT rate of 25%. | Up to 30 days after transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dosimetry of Yttrium Y 90 DOTA-biotin | Assessed using OLINDA dosimetry software. The estimated dose to normal organs and tumor sites will be described based on the tumor to normal organ ratios derived from dosimetry estimates coupled with the absorbed dose to normal organs based on the administered activity of yttrium Y 90 DOTA-biotin. | Up to 7 days after infusion | 
| Incidence of Toxicity, Defined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Descriptive statistics on the number and percent toxicities will be calculated. | Up to 30 days after transplant | 
| Overall Response Rate | Descriptive statistics on the responses will be calculated. | Up to 4 years | 
| Overall Survival | Overall survival will be estimated. | Up to 4 years | 
| Progression Free Survival (PFS) | If the true 1-year PFS rate using the proposed approach is 54%, then 24 patients will provide 80% power to detect a statistically significant increased rate of PFS from the fixed rate of 30%, based on a one-sample chi-square test with one-sided significance level of 5%. | 1 year from autologous stem cell transplant |