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Nitrogen Mustard Compounds

1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid

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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.

Anti-CD20 B9E9 scFv-Streptavidin Fusion Protein

Autologous Hematopoietic Stem Cell Transplantation

Clearing Agent

Indium In 111-DOTA-Biotin

Laboratory Biomarker Analysis

Peripheral Blood Stem Cell Transplantation

Pharmacological Study

Yttrium Y 90-DOTA-Biotin

Ajay Gopal

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.

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.

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

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

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%.

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.

Descriptive statistics on the number and percent toxicities will be calculated.

Descriptive statistics on the responses will be calculated.

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%.

National Cancer Institute (NCI)

Fred Hutchinson Cancer Center

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.

Anti-CD20 B9E9 scFv-Streptavidin Fusion Protein: Given IV

Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSCT

Treatment (PRIT)

Age, Categorical

Age, Continuous

Sex: Female, Male

Non-Hispanic

White

Race/Ethnicity, Customized

United States

Region of Enrollment

Dr. Ajay Gopal

This outcome measure was not done. The starting dose level was level 1 (30 mCi/m2) and in the first stage, up to two patients would be treated at escalating doses in 20 mCi/m2 increments until a DLT was observed. With the 3 participants enrolled, only dose level 5 of 12 was achieved before the study was closed early. The Maximum Tolerated Dose was not determined due to small sample size.

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

Liver

Spleen

Lungs

Kidneys

Bone Marrow

Brain

Dosimetry of Yttrium Y 90 DOTA-biotin

Serious Adverse Events

Other (Not Including Serious) Adverse Events

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.

Anti-CD20 B9E9 scFv-Streptavidin Fusion Protein: Given IV

Incidence of Toxicity, Defined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0

Overall Response Rate

Overall Survival

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.

This outcome measure was not done since 24 patients were needed to provide 80% power to detect statistical significance. The sample size of 3 patients is too small to determine the true 1-year PFS rate.

Progression Free Survival (PFS)

Overall Study

Spots Global Cancer Trial Database for clearing agent