Study of Radiolabeled Monoclonal Antibody Anti-B1 for the Treatment of B-Cell Lymphomas and Extended Study to Determine the Safety and Efficacy of Coulter Clone® 131Iodine-B1 Radioimmunotherapy of Advanced Non-Hodgkin's Lymphoma

NCT01536561 | Completed Phase 1 Results DMC

• 1 other identifier: 104728
• Study Type: interventional
• Target: 59
• Locations: 0 countries
• Sites: N/A

Brief Summary

Phase I/II, single-center, dose-escalation study of the safety, pharmacokinetics, dosimetry, and efficacy of TST/I-131 TST for the treatment of patients with chemotherapy-refractory or resistant low-grade, intermediate-grade, or high-grade B-cell lymphoma. Subjects received 1 to 3 dosimetric doses followed by a therapeutic dose of TST/I-131 TST. Study BEX104526 was a follow-up study of the long-term safety and efficacy data from the surviving patients who completed at least 2 years of follow-up following administration of TST/I 131 TST on Study BEX104728. Dosimetric dose: Subjects received 1 to 3 dosimetric doses of TST/I-131 TST, followed by a therapeutic dose of TST/I-131 TST. Subjects received various doses of unlabeled TST (0, 95 or 475 mg) to determine the dose of unlabeled TST that optimized the radiation dose delivered to the tumor by TST/I-131 TST. The unlabeled TST was followed by 5 milliCurie (mCi) of I-131 TST. Serial whole body sodium iodide scintillation probe counts were obtained daily, for at least 5 days, in order to determine the rate of whole body clearance of radioactivity (residence time). The residence time was used to determine the radioactive clearance for the subject and the activity (in mCi) of I-131 required to deliver the desired TBD of radiation during the therapeutic dose. Because 475 mg was determined to be the optimal pre-dose of TST in the first subjects entered, the last 34 subjects received a single dosimetric dose that was preceded by an infusion of 475 mg of TST. Therapeutic dose: Groups of 3-6 subjects were enrolled at successively higher whole-body radiation dose levels beginning at a total body dose (TBD) of 25 centiGray (cGy). The TBD of each subsequent dose level was escalated by 10 cGy. Subjects who had undergone bone marrow transplantation (BMT) underwent a separate dose escalation (10 cGy TBD increase per dose level) beginning at a TBD level of 65 cGy. The MTD was defined as the highest dose level at which 0/3 or 1/6 subjects experienced dose-limiting toxicity (DLT). DLT was defined as follows: Any Grade 4 hematologic toxicity (National Cancer Institute \[NCI\] criteria) lasting greater than 7 days, or Any Grade 3 hematologic toxicity lasting greater than 2 weeks, or Any Grade 3 or 4 nonhematologic toxicity Redosing. Subjects who achieved tumor regression were considered for re-dosing, using the original therapeutic dose of TST/I-131 TST, at the time the tumor was no longer shrinking in an attempt to upgrade their response. Retreatment. Subjects who achieved partial (PR) or complete response (CR) were considered for retreatment following relapse of their NHL, if progression occurred ≥6 weeks following the therapeutic dose. The original therapeutic dose of TST/I-131 TST was given unless a grade 2 or greater toxicity had been encountered, in which case a reduced dose was administered for the repeat therapeutic dose.

Conditions

Lymphoma, Non-Hodgkin

Keywords

Tositumomab and/or Iodine I 131 Tositumomab; B-cell non-Hodgkin's lymphoma; Dose-limiting toxicity; Bexxar

Outcome Measures

Primary Outcomes (4)

• Number of Participants (Par.) During Initial Treatment Exposed to the Indicated Dose Levels of the Therapeutic Dose (TD), Re-dose, and Total Dose (TD + Re-dose)

  Par. (groups of 3-6) received the TD at a total body dose (TBD) of 25 centiGray (cGy) or 65 cGy (par. who had bone marrow transplantation), increasing by 10 cGy increments at each dose level, until the maximum tolerated dose (MTD) was achieved. The MTD was defined as the highest dose level at which 0/3 or 1/6 par. experienced dose-limiting toxicity (DLT): any Grade 4 hematologic toxicity (National Cancer Institute criteria) lasting \>7 days, any Grade 3 hematologic toxicity lasting \>2 weeks, or any Grade 3/4 nonhematologic toxicity. Not Applicable (NA) indicates that no par. were re-dosed.

  Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.

• Number of Participants During Retreatment Exposed to the Indicated Dose Levels of the TD, Re-dose, and Total Dose (TD + Re-dose)

  Retreatment was administered to participants either at the initial TD of TST/I 131 TST or at a reduced dose if a \>=Grade 2 toxicity had occurred after initial treatment, until the MTD was achieved. The MTD was defined as the highest dose level at which 0/3 or 1/6 participants experienced DLT: any Grade 4 hematologic toxicity (National Cancer Institute criteria) lasting \>7 days, any Grade 3 hematologic toxicity lasting \>2 weeks, or any Grade 3/4 nonhematologic toxicity. Not Applicable (NA) indicates that no participants were re-dosed.

  Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.

• Maximum Tolerated Dose (MTD) of TST/I 131 TST Evaluated in the Study

  Participants who had prior bone marrow transplantation (BMT) initiated TD at 65 cGy TBD, whereas those who had no prior BMT initiated TD at 25 cGy TBD. The MTD was defined as the highest dose level at which 0/3 or 1/6 par. experienced DLT: any Grade 4 hematologic toxicity (National Cancer Institute criteria) lasting \>7 days, any Grade 3 hematologic toxicity lasting \>2 weeks, or any Grade 3/4 nonhematologic toxicity. Not Applicable (NA) indicates that no par. were re-dosed.

  Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.

• Tumor/Organ Dosimetry of TST/I 131 TST for All Predoses (Initial Treatment)

  Serial whole body sodium iodide scintillation probe counts were obtained from participants approximately 1 hour after the administration of the dosimetric dose and then daily for at least 5 days. Gamma camera images of participants were used to calculate the amount of radiation that accumulated in the target tumor and normal organs (tumor/organ dosimetry). Spleen volume may vary based on disease status, and volume correction allows for a comparison of spleen dose across participants.

  Serial anterior and posterior gamma whole body scans were obtained 1 hour after the administration of the dosimetric dose (on Day 0), and then daily for at least 5 days until Day 7

Secondary Outcomes (18)

• Tumor/Organ Dosimetry at the Indicated Predoses of 475 mg, 95 mg, and 0 mg (Initial Treatment)

  Serial anterior and posterior gamma whole body scans were obtained 1 hour after the administration of the dosimetric dose (on Day 0), and then daily for at least 5 days until Day 7

• Number of Participants (Par.) With the Indicated Response as Assessed by the Investigator

  Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.

• Number of Participants (Par.) With Confirmed Response as Assessed by the Investigator

  Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.

• Duration of Response for All Unconfirmed Responders (CR, CCR, or PR) as Assessed by the Investigator

  Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.

• Time to Progression of Disease or Death

  Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.

Study Arms (1)

open-label, dose escalation

EXPERIMENTAL

Each subject will undergo two phases of study. The first phase, termed "tracer Study", involves the injection of low-radioactivity doses (about 5 mCi) of 131-I anti-B1 for the purposes of determining the rate of whole body clearance of radiation so that a whole body radiation can be calculated. The calculated whole-body radiation dose per mCi administered can then be used to determined how many mCi will be required to deliver a specified whole-body radiation dose in the second phase of the study for each patient, termed radio-immunotherapy dose in a tracer-projected whole-body radiation dose will be used for dose escalation with a minimum of three subjects per dose level.

Biological: Radiolabeled Monoclonal Antibody Anti-B1 for the Treatment of B-Cell Lymphomas (Tositumomab and Iodine I 131 Tositumomab)

Interventions

Radiolabeled Monoclonal Antibody Anti-B1 for the Treatment of B-Cell Lymphomas (Tositumomab and Iodine I 131 Tositumomab) BIOLOGICAL

131-I anti-B1 is the product of 131-I labeling of the anti-CD20 murine monoclonal antibody and the anti-B1 antibody itself is an intact IgG2a murine monoclonal antibody which has specificity far the CD20 antigen on human B cells. Anti-B1 is a clear, colorless liquid. 131-I labeling of the anti-B1 antibody will be carried out by iodogen technique. Trace labeling of the antibody will involve the labeling of approximately 1 to 3 mg of antibody with 5 mCi of 131-I.

open-label, dose escalation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects had histologically-confirmed NHL.
• Subjects with low-, intermediate-, or high-grade histologies, according to the International Working Formulation.
• Subjects had relapsed after or had failed to respond to at least 1 prior chemotherapy regimen.
• Subjects had evidence that their tumor tissue expressed the CD20 antigen.

You may not qualify if:

• ≥25% bone marrow involvement.
• Absolute granulocyte count ≥1500 cells/mm3 or platelet count ≤100,000 platelets/mm3.
• Creatinine ≥2.0 mg/dL, bilirubin ≥2.0 mg/dL.
• Cytotoxic chemotherapy, radiation therapy, immunosuppressants, or cytokine treatment within 4 weeks of study entry.
• Active infection, collagen vascular disease, vasculitis, glomerulonephritis, New York Heart Association class II or IV heart disease and/or serious illness.
• Prior external beam radiation therapy such that the maximum tolerated dose level for any normal organ would be exceeded by additional irradiation.
• Pregnancy.
• Allergy to iodine or previous sensitization to mouse protein as documented by positive anti-mouse antibody ELISA test.
• Known brain metastases.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Related Publications (1)

• Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, Tuck M, Regan D, Fisher S, Gutierrez J, Kroll S, Stagg R, Tidmarsh G, Wahl RL. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood. 2000 Aug 15;96(4):1259-66.

  PMID: 10942366 BACKGROUND

Related Links

• Results for study 104728 can be found on the GSK Clinical Study Register.
• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Lymphoma, B-Cell

Interventions

tositumomab I-131

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 26, 2012
• First Posted: February 22, 2012
• Study Start: April 24, 1990
• Primary Completion: July 2, 1997
• Study Completion: October 16, 2009
• Last Updated: August 31, 2017
• Results First Posted: March 30, 2012

Record last verified: 2017-08

Data Sharing

• IPD Sharing: Will share