A Randomized Study of Iodine-131 Anti-b1 Antibody Versus Anti-b1 Antibody in Chemotherapy-relapsed/Refractory Low-grade or Transformed Low-grade Non-Hodgkin's Lymphoma (NHL)

NCT01573000 | Completed Phase 2 Results DMC

• 1 other identifier: 104515
• Study Type: interventional
• Target: 78
• Locations: 0 countries
• Sites: N/A

Brief Summary

Subjects were randomized to receive either tositumomab (Anti-B1 Antibody) and iodine I 131 tositumomab (Arm A) or unlabeled tositumomab (Arm B). Subjects randomized to Arm B were allowed to cross over and receive I 131 tositumomab once their disease had progressed as long as they still fulfilled the protocol entry criteria (except for exclusion criterion 12, prior monoclonal antibody therapy) and were human anti-murine antibody (HAMA) negative. Study endpoint assessments of response were conducted by a Masked Independent Randomized Radiographic and Oncologic Review (MIRROR) panel and the Study Investigators' assessments of safety and survival. Subjects who completed at least two years of follow-up in Protocol BEX104515 (formerly Corixa Protocol RIT-II-002) were enrolled in long term follow-up Protocol BEX104526 (formerly Corixa Protocol CCBX001-051), an administrative protocol, for continued radiographic response evaluations and safety evaluations every 6 months for years 3 through 5 post-treatment and annually for years 6 through 10 post-treatment. Subjects in BEX104526 were assessed for survival, disease status, subsequent therapy for NHL, and long-term safety, including the use of thyroid medication, development of hypothyroidism, human anti murine antibody (HAMA), myelodysplastic syndrome, acute myelogenous leukemia, and all other secondary malignancies. Additionally, subjects were followed for the development of any adverse event(s) deemed by the Principal Investigator as being possibly or probably related to a subject's previous treatment with Iodine I-131 tositumomab. Laboratory evaluations consisting of a thyroid stimulating hormone level and a complete blood cell count, with a differential and platelet count, were obtained annually through year 10 post-treatment. Dosimetric Dose: Subjects received 450 mg of tositumomab IV followed by 5.0 mCi of Iodine I-131 and 35 mg of tositumomab. Following the dosimetric dose, whole body dosimetry was performed on each subject using a total body gamma camera. Whole body anterior and posterior whole body images were obtained at the following timepoints.

1. 1.Within one hour of infusion of the dosimetric dose and prior to urination
2. 2.2-4 days after infusion of the dosimetric dose, following urination
3. 3.6-7 days after infusion of the dosimetric dose, following urination Therapeutic Dose: The total body residence time, derived from total body gamma camera counts obtained at the 3 time points, was used to calculate the iodine-131 activity (mCi) to be administered to deliver the therapeutic total body irradiation dose of 65 or 75 cGy. The therapeutic step was administered 7-14 days after the dosimetric step and consisted of tositumomab 450 mg followed by an activity (mCi) of iodine-131 calculated to deliver 75 cGy or 65 cGy of total body irradiation, depending on platelet count, and 35 mg of tositumomab.

Conditions

Lymphoma, Non-Hodgkin

Keywords

Bexxar; Non-Hodgkin's Lymphoma; Tositumomab; Anti-B1 Antibody; Radioimmunotherapy; Iodine I-131; Iodine-131

Outcome Measures

Primary Outcomes (11)

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

  Responses had to be confirmed by 2 separate evaluations occurring \>=4 weeks apart. Par. with confirmed response include those with Complete Response (CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease), Clinical Complete Response (CCR: complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present), or Partial Response (PR: \>=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions).

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

• Number of Participants With Confirmed Response Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator

  Participants receiving Unlabeled TST with progressive disease (defined as a \>=25% increase from the nadir value of the sum of the products of the longest perpendicular diameters of all measureable lesions or the appearance of any new lesion. Individual lesions must be \>2 centimeters \[cm\] in diameter by radiographic evaluation or \>1 cm in diameter by physical examination.) were assessed separately before and after receiving the crossover treatment of I 131 TST for confirmed response, which included participants with CR, CCR, and PR.

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

• Number of Participants With Confirmed Complete Response (CR) as Assessed by the Investigator

  CR is defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease.

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

• Number of Participants (Par.) With a Confirmed Complete Response as Assessed by the Masked Independent Randomized Radiology and Oncology Review (MIRROR) Panel

  Responses had to be confirmed by 2 separate evaluations occurring \>=4 weeks apart. Par. with confirmed response include those with Complete Response (CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease), Clinical Complete Response (CCR: complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present), or Partial Response (PR: \>=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions).

  The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001

• Number of Participants With Confirmed Complete Response (CR) Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator

  Participants receiving Unlabeled TST with progressive disease were assessed separately before and after receiving the crossover treatment of I 131 TST for CR. CR is defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease.

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

• Number of Participants With Confirmed Clinical Complete Response (CCR) as Assessed by the Investigator

  CCR is defined as the complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present. Generally, an unchanging lesion =\<2 cm in diameter by radiographic evaluation or =\<1 cm in diameter by physical examination can be considered scar tissue.

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

• Number of Participants With Confirmed Clinical Complete Response (CCR) Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator

  Participants receiving Unlabeled TST with progressive disease were assessed separately before and after receiving the crossover treatment of I 131 TST for CCR. CCR is defined as the complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present. Generally, an unchanging lesion =\<2 cm in diameter by radiographic evaluation or =\<1 cm in diameter by physical examination can be considered scar tissue.

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

• Number of Participants With Confirmed Complete Response Plus Clinical Complete Response (CR + CCR) as Assessed by the Investigator

  CCR is defined as the complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present. Generally, an unchanging lesion =\<2 cm in diameter by radiographic evaluation or =\<1 cm in diameter by physical examination can be considered scar tissue. The extent of disease must be unchanged or decreased upon follow-up evaluations. If the extent of disease was unchanged or if further decreases occurred for 6 months or longer, the participant was reclassified as having a CR.

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

• Number of Participants With Confirmed Complete Response Plus Clinical Complete Response (CR + CCR) Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator

  Participants receiving Unlabeled TST with progressive disease were assessed separately before and after receiving the crossover treatment of I 131 TST for CR + CCR.

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

• Number of Participants With Confirmed Partial Response (PR) as Assessed by the Investigator

  Confirmed PR is defined as a \>=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, with no new lesions.

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

• Number of Participants With Confirmed Partial Response (PR) Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator

  Participants receiving Unlabeled TST with progressive disease were assessed separately before and after receiving the crossover treatment of I 131 TST confirmed PR. Confirmed PR is defined as a \>=50 percent reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, with no new lesions.

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

Secondary Outcomes (25)

• Number of Participants (Par.) With a Confirmed Response (CR, CCR, or PR) as Assessed by the MIRROR Panel

  The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001

• Duration of Response for All Confirmed Responders, Confirmed Complete Responders, and Confirmed Partial Responders

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

• MIRROR Panel Assessments of Duration of Complete Response (Time From the First Documented Response to the First Documented Progression)

  The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001

• MIRROR Panel Assessments of Duration of Confirmed Response (Time From the First Documented Response to the First Documented Progression)

  The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001

• Time to Progression of Disease or Death as Assessed by the Investigator

  Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.

Study Arms (2)

Open-label, two-arm, Arm A and Arm B Crossover

EXPERIMENTAL

Arm A Dosimetric Dose: 450 mg of TST infused over 70 minutes (inclusive of a 10-minute flush) immediately followed by 5 milliCurie (mCi) (35 mg) of I-131 TST infused over 30 minutes (inclusive of a 10-minute flush).• Therapeutic Dose: Seven to 14 days after the dosimetric dose, 450 mg of TST infused over 70 minutes (inclusive of a 10-minute flush) immediately followed by a subject-specific mCi activity (35 mg) of I-131 TST to deliver the desired total body dose (TBD) infused over 30 minutes (inclusive of a 10-minute flush). The desired TBD was 65 cGy for subjects with a baseline platelet count of 100,001-149,999 cells/mm3 and 75 cGy for subjects with a baseline platelet count ≥150,000 cells/mm3. Obese subjects (subjects weighing more than 137% of their calculated lean body weight) were dosed based upon 137% of their calculated lean body mass

Biological: Iodine-131 Anti-B1 Antibody Versus Anti-B1 Antibody in Chemotherapy-Relapsed/Refractory Low-Grade or Transformed Low-Grade Non-Hodgkin's Lymphoma (NHL)

Arm B Crossover

EXPERIMENTAL

Arm B Dosimetric Dose: 450 mg of TST infused over 70 minutes (inclusive of a 10-minute flush) immediately followed by 35 mg of TST infused over 30 minutes (inclusive of a 10-minute flush).Therapeutic Dose: Seven to 14 days after the dosimetric dose, 450 mg of TST infused over 70 minutes (inclusive of a 10-minute flush) immediately followed by 35 mg of TST infused over 30 minutes (inclusive of a 10-minute flush). Subjects randomized to Arm B were allowed to cross-over and receive TST/ I-131 TST once their disease had progressed.

Biological: Iodine-131 Anti-B1 Antibody Versus Anti-B1 Antibody in Chemotherapy-Relapsed/Refractory Low-Grade or Transformed Low-Grade Non-Hodgkin's Lymphoma (NHL)

Interventions

Iodine-131 Anti-B1 Antibody Versus Anti-B1 Antibody in Chemotherapy-Relapsed/Refractory Low-Grade or Transformed Low-Grade Non-Hodgkin's Lymphoma (NHL) BIOLOGICAL

Subjects will be randomized to receive tositumomab and iodine-131 tositumomab (Arm A) or unlabeled tositumomab (Arm B). Subjects randomized to receive unlabeled tositumomab may crossover and receive radiolabeled Iodine-131 tositumomab following progression of their lymphoma. Response in both arms will be assessed at 7 weeks, 13 weeks, and then at 3-monthly intervals for up to 2 years.

Arm B Crossover; Open-label, two-arm, Arm A and Arm B Crossover

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed low-grade or transformed NHL with evaluable, measurable disease
• Tumor had to express CD20 antigen
• One to three prior chemotherapy regimens
• Karnofsky performance score ≥60% and anticipated survival ≥3 months
• Absolute neutrophil count (ANC) \>1500/mm3 and platelet count \>100,000/mm3
• Adequate renal and hepatic function
• years of age or older.
• Written informed consent and sign an IRB-approved Informed consent from prior to study entry.

You may not qualify if:

• More than an average of 25% of the intratrabecular marrow space involved by lymphoma in bone marrow biopsy specimens as assessed microscopically within 42 days of study entry. Bilateral posterior iliac crest core biopsies are required if the percentage of intratrabecular space involved exceeds 10% on a unilateral biopsy. The mean of bilateral biopsies must be no more than 25%.
• Received cytotoxic chemotherapy, radiation therapy, immunosuppressants, or cytokine treatment within FOUR weeks prior to study entry (6 weeks of nitrosourea compounds) or who exhibit persistent clinical evidence of toxicity. The use of steroids must be discontinued at least 1 week prior to study entry.
• Have undergone prior stem cell transplant.
• Active obstructive hydronephrosis.
• Evidence of active infection requiring intravenous antibiotics at the time of study entry.
• New York Heart Association class III or IV heart disease or other serious illness that would preclude evaluation.
• Prior malignancy other than lymphoma, except for adequately-treated skin cancer, in situ cervical cancer, or other cancer for which subject has been disease-free for 5 years.
• Known HIV infection.
• Known brain or leptomeningeal metastases.
• Pregnant or nursing. Subjects of childbearing potential must undergo pregnancy test within 7 days of study entry and antibody is not to be administered until a negative result is obtained. For those subjects in Arm B, the pregnancy test must be repeated within 7 days of crossover. Male and female must agree to use effective contraception for 6 months following the therapeutic dose, as applicable.
• Previous allergic reactions to iodine. This does not include reactions to intravenous iodine-containing contrast materials.
• Previously given any monoclonal or polyclonal antibodies of any non-human species for either diagnostic or therapeutic purpose. This includes engineered chimeric and humanized antibodies.
• Previously received radioimmunotherapy .
• Progressive disease within one year of irradiation arising in a field that has been previously irradiated with \>3500 cGy.
• de novo intermediate or high-grade lymphoma.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Related Publications (1)

• Knox SJ, Goris ML, Davis TA, Trisler KD, Saal J, Levy R. Randomized controlled study of Iodine-131 Anti-B1 Antibody vs. unlabeled-Anti-B1 Antibody in subjects with chemotherapy refractory low-grade non-Hodgkin's Lymphoma [abstract]. Int J Radiat Oncol Biol Phys 1997;39(Suppl):326.

  RESULT

Related Links

• 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

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 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 8, 2012
• First Posted: April 6, 2012
• Study Start: September 1, 1998
• Primary Completion: April 1, 2001
• Study Completion: April 1, 2010
• Last Updated: January 18, 2017
• Results First Posted: October 5, 2012

Record last verified: 2016-11

Data Sharing

• IPD Sharing: Will share