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

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ClinicalTrials.gov Identifier: NCT02483000
Recruitment Status : Active, not recruiting
First Posted : June 26, 2015
Last Update Posted : April 12, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Tracking Information
First Submitted Date  ICMJE June 23, 2015
First Posted Date  ICMJE June 26, 2015
Last Update Posted Date April 12, 2019
Actual Study Start Date  ICMJE February 1, 2017
Estimated Primary Completion Date November 17, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 22, 2017)
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 [ Time Frame: Up to 30 days after transplant ]
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%.
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2015)
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 [ Time Frame: Up to 30 days after transplant ]
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%.
Change History Complete list of historical versions of study NCT02483000 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 22, 2017)
  • Dosimetry of yttrium Y 90 DOTA-biotin [ Time Frame: Up to 7 days after infusion ]
    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.
  • Incidence of toxicity, defined according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after transplant ]
    Descriptive statistics on the number and percent toxicities will be calculated.
  • Overall response rate [ Time Frame: Up to 4 years ]
    Descriptive statistics on the responses will be calculated.
  • Overall survival [ Time Frame: Up to 4 years ]
    Overall survival will be estimated.
  • Progression free survival (PFS) [ Time Frame: 1 year from autologous stem cell transplant ]
    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%.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2015)
  • Overall response rate [ Time Frame: Up to 4 years ]
    Descriptive statistics on the responses will be calculated.
  • Overall survival [ Time Frame: Up to 4 years ]
  • Progression free survival (PFS) [ Time Frame: 1 year from autologous stem cell transplant ]
    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%.
  • Incidence of toxicity, defined according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after transplant ]
    Descriptive statistics on the number and percent toxicities and responses will be calculated.
  • Dosimetry of yttrium Y 90 DOTA-biotin [ Time Frame: Up to 7 days after infusion ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Anti-CD20 Radioimmunotherapy Before Chemotherapy and Stem Cell Transplant in Treating Patients With High-Risk B-Cell Malignancies
Official Title  ICMJE Evaluation of Pretargeted Anti-CD20 Radioimmunotherapy Combined With BEAM Chemotherapy and Autologous Stem Cell Transplantation for High-Risk B-Cell Malignancies
Brief Summary 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

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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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  ICMJE
  • 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
  • Procedure: Autologous Hematopoietic Stem Cell Transplantation
    Undergo autologous PBSCT
    Other Name: Autologous Stem Cell Transplantation
  • Drug: Carmustine
    Given IV
    Other Names:
    • BCNU
    • Becenum
    • Becenun
    • BiCNU
    • Bis(chloroethyl) Nitrosourea
    • Bis-Chloronitrosourea
    • Carmubris
    • Carmustin
    • Carmustinum
    • FDA 0345
    • Gliadel
    • N,N'-Bis(2-chloroethyl)-N-nitrosourea
    • Nitrourean
    • Nitrumon
    • SK 27702
    • SRI 1720
    • WR-139021
  • Drug: Clearing Agent
    Given IV
  • 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: Etoposide
    Given IV
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16-213
    • VP-16
    • VP-16-213
  • Radiation: Indium In 111-DOTA-Biotin
    Given IV
    Other Name: In 111-DOTA-Biotin
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Melphalan
    Given IV
    Other Names:
    • Alanine Nitrogen Mustard
    • CB-3025
    • L-PAM
    • L-Phenylalanine Mustard
    • L-Sarcolysin
    • L-Sarcolysin Phenylalanine mustard
    • L-Sarcolysine
    • Melphalanum
    • Phenylalanine Mustard
    • Phenylalanine Nitrogen Mustard
    • Sarcoclorin
    • Sarkolysin
    • WR-19813
  • Procedure: Peripheral Blood Stem Cell Transplantation
    Undergo autologous PBSCT
    Other Names:
    • PBPC transplantation
    • PBSCT
    • Peripheral Blood Progenitor Cell Transplantation
    • Peripheral Stem Cell Support
    • Peripheral Stem Cell Transplant
    • Peripheral Stem Cell Transplantation
  • Other: Pharmacological Study
    Correlative studies
  • Radiation: Yttrium Y 90-DOTA-Biotin
    Given IV
    Other Names:
    • 90Y-DOTA-Biotin
    • yttrium Y 90 DOTA-biotin
Study Arms  ICMJE 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.

Interventions:
  • 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
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 10, 2019)
3
Original Estimated Enrollment  ICMJE
 (submitted: June 23, 2015)
44
Estimated Study Completion Date  ICMJE November 17, 2020
Estimated Primary Completion Date November 17, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02483000
Other Study ID Numbers  ICMJE 9189
NCI-2015-00299 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9189 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P01CA044991 ( U.S. NIH Grant/Contract )
P30CA015704 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Ajay Gopal Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Research Center
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP