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

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.

Study Overview

• Status: Terminated
• Conditions: Diffuse Large B-Cell Lymphoma; Burkitt Lymphoma; Mantle Cell Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; Indolent Non-Hodgkin Lymphoma; CD20-Positive Neoplastic Cells Present; Refractory Mature B-Cell Non-Hodgkin Lymphoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Etoposide; Other: Pharmacological Study; Drug: Cytarabine; Drug: Melphalan; Drug: Carmustine; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Biological: Anti-CD20 B9E9 scFv-Streptavidin Fusion Protein; Drug: Clearing Agent; Radiation: Indium In 111-DOTA-Biotin; Radiation: Yttrium Y 90-DOTA-Biotin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (PRIT); 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.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Etoposide; Given IV; Other Names: Demethyl Epipodophyllotoxin Ethylidine Glucoside; EPEG; Lastet; Toposar; Vepesid; VP 16-213; VP-16; VP-16-213; Other: Pharmacological Study; Correlative studies; Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosar-U; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Drug: Melphalan; Given IV; Other Names: CB-3025; L-PAM; L-Sarcolysin; Alanine Nitrogen Mustard; L-Phenylalanine Mustard; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; Drug: Carmustine; Given IV; Other Names: BCNU; BiCNU; Becenum; Becenun; Bis(chloroethyl) Nitrosourea; Bis-Chloronitrosourea; Carmubris; Carmustin; Carmustinum; FDA 0345; N,N'-Bis(2-chloroethyl)-N-nitrosourea; Nitrourean; Nitrumon; SK 27702; SRI 1720; WR-139021; Gliadel; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo autologous PBSCT; Other Names: Autologous Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo autologous PBSCT; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant; Biological: Anti-CD20 B9E9 scFv-Streptavidin Fusion Protein; Given IV; Other Names: Anti-CD20 B9E9 scFv-SA Fusion Protein; Anti-CD20 B9E9-SA Fusion Protein; B9E9 scFvSA Fusion Protein; Recombinant Anti-CD20 B9E9 scFvSA Fusion Protein; scFv B9E9-streptavidin Fusion Protein; Drug: Clearing Agent; Given IV; Radiation: Indium In 111-DOTA-Biotin; Given IV; Other Names: In 111-DOTA-Biotin; Radiation: Yttrium Y 90-DOTA-Biotin; Given IV; Other Names: 90Y-DOTA-Biotin; yttrium Y 90 DOTA-biotin

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2017
• Primary Completion (Actual): November 17, 2019
• Study Completion (Actual): September 2, 2020

Study Registration Dates

• First Submitted: June 23, 2015
• First Submitted That Met QC Criteria: June 23, 2015
• First Posted (Estimate): June 26, 2015

Study Record Updates

• Last Update Posted (Actual): November 23, 2020
• Last Update Submitted That Met QC Criteria: October 30, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Virus Diseases; Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; DNA Virus Infections; Tumor Virus Infections; Epstein-Barr Virus Infections; Herpesviridae Infections; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Burkitt Lymphoma; Lymphoma, Mantle-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Micronutrients; Vitamins; Keratolytic Agents; Vitamin B Complex; Chelating Agents; Sequestering Agents; Etoposide; Etoposide phosphate; Podophyllotoxin; Melphalan; Cytarabine; Carmustine; Biotin; Mechlorethamine; Nitrogen Mustard Compounds; 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• Other Study ID Numbers: 9189 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); P01CA044991 (U.S. NIH Grant/Contract); P30CA015704 (U.S. NIH Grant/Contract); NCI-2015-00299 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No