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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)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01573000
First received: March 8, 2012
Last updated: September 6, 2012
Last verified: April 2012
  Purpose

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. Within one hour of infusion of the dosimetric dose and prior to urination
  2. 2-4 days after infusion of the dosimetric dose, following urination
  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.

For subjects with ≥150,000 platelets/mm3, the recommended dose was the activity of iodine-131 calculated to deliver 75 cGy of total body irradiation; for subjects with NCI Grade 1 thrombocytopenia (platelet counts ≥100,000 but <150,000 platelets/mm3), the recommended dose was the activity of iodine-131 calculated to deliver 65 cGy of total body irradiation.


Condition Intervention Phase
Lymphoma, Non-Hodgkin
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)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II 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)

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants (Par.) With Confirmed Response as Assessed by the Investigator [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    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).

  • 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 [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Confirmed Complete Response (CR) as Assessed by the Investigator [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    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.

  • Number of Participants (Par.) With a Confirmed Complete Response as Assessed by the Masked Independent Randomized Radiology and Oncology Review (MIRROR) Panel [ Time Frame: The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001 ] [ Designated as safety issue: No ]
    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).

  • 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 [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Confirmed Clinical Complete Response (CCR) as Assessed by the Investigator [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Confirmed Complete Response Plus Clinical Complete Response (CR + CCR) as Assessed by the Investigator [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Participants receiving Unlabeled TST with progressive disease were assessed separately before and after receiving the crossover treatment of I 131 TST for CR + CCR.

  • Number of Participants With Confirmed Partial Response (PR) as Assessed by the Investigator [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Number of Participants (Par.) With a Confirmed Response (CR, CCR, or PR) as Assessed by the MIRROR Panel [ Time Frame: The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001 ] [ Designated as safety issue: No ]
    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).

  • Duration of Response for All Confirmed Responders, Confirmed Complete Responders, and Confirmed Partial Responders [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    For all participants with CR, CCR, or PR, duration of response was defined as the time from first documented response to first documented progression. All confirmed responders included participants with CR, CCR, and PR, whereas confirmed complete responders included participants with CR and CCR.

  • MIRROR Panel Assessments of Duration of Complete Response (Time From the First Documented Response to the First Documented Progression) [ Time Frame: The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001 ] [ Designated as safety issue: No ]
    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).

  • MIRROR Panel Assessments of Duration of Confirmed Response (Time From the First Documented Response to the First Documented Progression) [ Time Frame: The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001 ] [ Designated as safety issue: No ]
    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).

  • Time to Progression of Disease or Death as Assessed by the Investigator [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Progression-free survival or time to progression is defined as the time from the dosimetric dose to the first documented occurrence of disease progression or death.

  • Time to Progression of Disease or Death in Participants Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Progression-free survival or time to progression is defined as the time from the dosimetric dose to the first documented occurrence of disease progression or death.

  • MIRROR Panel Assessed Time to Response (Time From the Date of Enrollment to the First Documented Response (PR, CR, CCR) [ Time Frame: The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001 ] [ Designated as safety issue: No ]
    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).

  • MIRROR Panel Assessed Progression-free Survival [ Time Frame: The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001 ] [ Designated as safety issue: No ]
    Time from the date of enrollment (the date of randomization) to the first documented progression or death.

  • Overall Survival [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Overall survival is defined as the time from the treatment start date to the date of death by any cause.

  • Number of Participants With the Indicated Drug-Related (DR) Adverse Events (AEs) Experienced by 3 or More Participants [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Causality of AEs was determined by the investigators as "none," "remote," "possible," "probable," or "highly probable." AEs considered by the investigator as being at least remotely related to the study treatment were considered to be DR AEs. White blood cell (WBC) count and absolute neutrophil count (ANC) were measured as cells per millimeters cubed (mm^3); hemoglobin was measured in grams per deciliter (g/dL).

  • Number of Participants With the Indicated Type of Infection [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    An infection is the colonization of a host organism by a parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease. Specimen samples of the body fluid are cultured for testing whether the infectious organism is present and grown in the culture media to assess the growth pattern of the organisms present in the specimen. The culture results could be positive or negative. The positive culture results indicate that the tested participant has the infection under investigation, in which case therapeutic treatment with anti-infective is required.

  • Number of Participants With an Infection for Which Anti-infectives Were Administered [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Anti-infectives are capable of acting against infection, by inhibiting the spread of an infectious agent or by killing the infectious agent outright. Anti-infective is a general term that encompasses antibacterials, antibiotics, antifungals, antiprotozoans, and antivirals.

  • Number of Participants With the Indicated Grade 3 or Grade 4 AEs Experienced by 3 or More Participants [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    AEs were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No adverse event or within normal limits; 1 = Mild adverse event; 2 = Moderate adverse event; 3 = Severe and undesirable adverse event; 4 = Life-threatening or disabling adverse event; 5 = Death related to adverse event.

  • Number of Participants With the Indicated Grade 3 or Grade 4 Drug-related AEs Experienced by 3 or More Participants [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    AEs were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No adverse event or within normal limits; 1 = Mild adverse event; 2 = Moderate adverse event; 3 = Severe and undesirable adverse event; 4 = Life-threatening or disabling adverse event; 5 = Death related to adverse event.

  • Number of Participants With the Indicated Primary Cause of Death [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Participants were categorized according to their primary cause of death. Deaths due to progressive disease or to another reason ("Other") were not captured as serious adverse events (SAEs) and are thus not included in the SAE module.

  • Number of Participants With a Time to Death From the Last Dose of Study Drug Less Than or Equal to 30 Days or More Than 30 Days [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Time to death from the last dose of study drug is the time from the last dose of study drug administered to the date of death. Deaths due to progressive disease or to another reason ("Other") were not captured as serious adverse events (SAEs) and are thus not included in the SAE module.

  • Number of Participants With the Indicated Serious Adverse Events (SAE) Related to Study Drug [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    An SAE is any event occurring at any dose that results in any of the following: death, a life-threatening adverse drug experience (ADE; at immediate risk of death from the experience as it occurred), inpatient hospitalization/prolongation of existing hospitalization, a persistent/significant disability/incapacity, or a congenital anomaly/birth defect. Medical events that may not result in death, be life-threatening, or require hospitalization may be considered to be a serious ADEs when based upon appropriate medical judgment. Relatedness was based on the investigator's medical judgement.

  • Number of Participants With the Indicated Fatal SAEs Related to Study Drug [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    An SAE is any event occurring at any dose that results in any of the following: death, a life-threatening adverse drug experience (ADE; at immediate risk of death from the experience as it occurred), inpatient hospitalization/prolongation of existing hospitalization, a persistent/significant disability/incapacity, or a congenital anomaly/birth defect. Medical events that may not result in death, be life-threatening, or require hospitalization may be considered to be a serious ADEs when based upon appropriate medical judgment. Relatedness was based on the investigator's medical judgement.

  • Time to Nadir and Time to Recovery to Baseline in Hematologic Laboratory Evaluations [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Nadir is defined as the lowest laboratory value recorded following the administration of the study medication. Time to recovery to baseline in hematologic laboratory evaluations is the time required for recovery from nadir values to baseline values. Hematologic laboratory evaluations included ANC, hemoglobin (Hb), platelets (Plt), and WBC count.

  • Nadir Values for ANC, a Hematologic Parameter [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Nadir is defined as the lowest laboratory value recorded following the administration of study medication. ANC is a measure of the number of neutrophil granulocytes present in the blood. Neutrophils are a type of white blood cell that fights against infection.

  • Nadir Values for Hemoglobin, a Hematologic Parameter [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Nadir is defined as the lowest laboratory value recorded following the administration of study medication. Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells.

  • Nadir Values for the Hematologic Parameters Platelets and WBC Count [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Nadir is defined as the lowest laboratory value recorded following the administration of study medication. Platelets and WBCs are types of blood cells.

  • Number of Participants With the Indicated Grade 3 or Grade 4 Hematologic Toxicities [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Adverse events were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No adverse event or within normal limits; 1 = Mild adverse event; 2 = Moderate adverse event; 3 = Severe and undesirable adverse event; 4 = Life-threatening or disabling adverse event; 5 = Death related to adverse event.

  • Duration of the Indicated Grade 3 or Grade 4 Hematologic Toxicities [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Adverse events were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No adverse event or within normal limits; 1 = Mild adverse event; 2 = Moderate adverse event; 3 = Severe and undesirable adverse event; 4 = Life-threatening or disabling adverse event; 5 = Death related to adverse event.

  • Time to Human Anti-Murine Antibodies (HAMA) Positivity From the First Dosimetric Dose [ Time Frame: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526. ] [ Designated as safety issue: No ]
    Tositumomab is a murine (mouse) antibody (immunoglobulin) of the IgG2a subclass. Participants in this study were evaluated to determine whether they developed an immune response to study treatment as evident by human anti-mouse antibodies (HAMA) after administration of tositumomab and iodine I 131 tositumomab. A positive HAMA value indicates that the participant developed human anti-mouse antibodies above the HAMA assay threshold, and a negative HAMA value indicates either the absence or below threshold level of human anti-mouse antibodies.


Enrollment: 78
Study Start Date: September 1998
Study Completion Date: April 2010
Primary Completion Date: April 1999 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Open-label, two-arm, Arm A and Arm B Crossover
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)
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.
Experimental: Arm B Crossover
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)
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.

Detailed Description:

This is a Phase II randomized, controlled, two-arm, open-label, multicenter study comparing the safety and efficacy of tositumomab and iodine I 131 tositumomab to tositumomab for the treatment of chemotherapy-relapsed or refractory low-grade or transformed low-grade B-cell NHL.

Treatment Arm A: Subject will undergo 2 phases of study. In the first phase, termed "dosimetric dose", subjects will receive tositumomab (450 mg) followed by tositumomab (35 mg) that has been trace labeled with 5mCi) Iodine-131 tositumomab. Whole body gamma camera scans will be obtained on day 0, day 2, 3, or 4, and day 6 or 7 following the dosimetric dose. Using the dosimetric data from three imaging time points, a subject-specific dose of iodine I 131 tositumomab to deliver the desired total body dose of radiotherapy will be calculated. In the second phase of the study, termed "therapeutic dose", subjects will receive unlabeled tositumomab (450mg) followed by iodine tositumomab (35mg) labeled with the subject-specific dose of iodine I-131 to deliver a whole body dose of 75 cGy to subjects. Subjects with platelet counts of 100,001 - 149,999 cells/mm3, will receive 65 cGy and subjects who are obese will be doses based on 137% of their lean body mass. Subjects will be treated with either saturated solution potassium iodide (SSKI), Lugol's solution, or potassium iodide tablets starting at least 24 hours prior to the first infusion of the Iodine-131 tositumomab (i.e., the dosimetric dose) and continuing for 14 days following the last infusion of radiolabeled tositumomab (i.e., the therapeutic dose).

Treatment Arm B: Subjects will receive the same amount of unlabeled tositumomab (450 + 35 mg) administered over the same time-frame as Arm A on the study Days 0 and 7 (the day 7 dose may be delayed but no longer than 14 days after the first dose).

Crossover treatment Arm B: Subjects in Arm B may crossover and receive Iodine-131 tositumomab following progression of their lymphoma if they still fulfill the protocol inclusion exclusion criteria (except exclusion criteria#12) and are HAMA-negative.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
  • 18 years of age or older.
  • Written informed consent and sign an IRB-approved Informed consent from prior to study entry.

Exclusion Criteria:

  • 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.
  • Received >3 chemotherapy regimens (different or identical agents).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01573000

Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications:
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01573000     History of Changes
Other Study ID Numbers: 104515
Study First Received: March 8, 2012
Results First Received: April 12, 2012
Last Updated: September 6, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
Bexxar
Non-Hodgkin's Lymphoma
Tositumomab
Anti-B1 Antibody
Radioimmunotherapy
Iodine I-131
Iodine-131

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Antibodies
Antibodies, Monoclonal
Cadexomer iodine
Immunoglobulins
Iodine
Iodine-131 anti-B1 antibody
Anti-Infective Agents
Anti-Infective Agents, Local
Antineoplastic Agents
Growth Substances
Immunologic Factors
Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Trace Elements

ClinicalTrials.gov processed this record on November 20, 2014