Iodine-131 Anti-B1 Antibody (Tositumomab and Iodine I 131 Tositumomab) for Previously Untreated, Advanced-stage, Low Grade Non-Hodgkin's Lymphoma
- Conditions
- Lymphoma, Non-Hodgkin
- Interventions
- Biological: Tositumomab and Iodine I 131 Tositumomab (Anti-B1 Antibody and Iodine-131 Anti-B1 Antibody)
- Registration Number
- NCT00996996
- Lead Sponsor
- GlaxoSmithKline
- Brief Summary
This is a single-arm, single-institution, phase II study of Iodine-131 Anti-B1 Antibody for patients with previously untreated, advanced-stage (stage III or IV) low-grade non-Hodgkin's B-cell lymphoma. A total of 75-80 patients will be enrolled.
Patients will undergo two phases of the study. In the first phase, termed the "dosimetric dose", patients will receive an infusion of unlabeled Anti-B1 Antibody (450 mg) over 70 minutes (including a 10-minute flush) immediately followed by a 30-minute infusion (including a 10-minute flush) of Anti-B1 Antibody (35 mg) which has been trace-labeled with 5 mCi of Iodine-131. Whole body gamma camera scans will be obtained 5 to 8 times between Days 0 and 7 following the dosimetric dose. Using the dosimetric data from 3 imaging timepoints (the imaging timepoints to be used in decreasing order of preference depending on availability of data are Days 0, 3, and 7; Days 0, 4, and 7; Days 0, 3 and 6; Days 0, 4, and 6; Days 0, 2, and 7; and Days 0, 2, and 6), a patient-specific dose of Iodine- 131 to deliver the desired total body dose of radiotherapy will be calculated. In the second phase, termed the "therapeutic dose", patients will receive a 70-minute infusion (including a 10-minute flush) of unlabeled Anti-B1 Antibody (450 mg) immediately followed by a 30-minute infusion (including a 10-minute flush) of Anti-B1 Antibody (35 mg) labeled with the patient-specific dose of Iodine-131 to deliver a whole body dose of 75 cGy. Patients who are obese will be dosed based upon 137% of their calculated lean body mass. Patients 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 Anti-B1 Antibody (i.e., dosimetric dose) and continuing for 14 days following the last infusion of Iodine-131 Anti-B1 Antibody (i.e., therapeutic dose).
The primary endpoint of the study is the determination of the response rate with Iodine-131 Anti-B1 Antibody in previously untreated patients with low-grade non-Hodgkin's lymphoma (NHL). The secondary endpoints include duration of response, safety, radiation dosimetry, and the predictive value of detection of the presence or absence minimal residual disease by molecular techniques on response duration.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 77
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description open-label, single arm Tositumomab and Iodine I 131 Tositumomab (Anti-B1 Antibody and Iodine-131 Anti-B1 Antibody) Tositumomab and Iodine I 131 Tositumomab
- Primary Outcome Measures
Name Time Method Number of Participants With Confirmed Response, Including Participants With Complete Response (CR), Clinical Complete Response (CCR), and Partial Response (PR) From Study Day 0 (start of treatment) up to 12 years (long-term follow up) Confirmed response required CR, CCR, or PR, which were confirmed by 2 separate response evaluations \>=4 weeks apart. CR: Complete resolution of all disease-related radiological abnormalities and disappearance of all signs and symptoms related to the disease. CCR: Complete resolution of all disease-related symptoms, but residual foci, thought to be residual scar tissue, are present. PR: \>=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 Response, Including Participants With Complete Response (CR), Clinical Complete Response (CCR), or Partial Response (PR) From Study Day 0 (start of treatment) up to 12 years (long-term follow up) CR: Complete resolution of all disease-related radiological abnormalities and disappearance of all signs and symptoms related to the disease. CCR: Complete resolution of all disease-related symptoms, but residual foci, thought to be residual scar tissue, are present. PR: \>=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 Complete Response (CR, CCR, and CR+CCR) and Partial Response (PR) From Study Day 0 (start of treatment) up to 12 years (long-term follow up) Responses were confirmed by two separate response evaluations at least 4 weeks apart. CR: Complete resolution of all disease-related radiological abnormalities and disappearance of all signs and symptoms related to the disease. CCR: Complete resolution of all disease-related symptoms, but residual foci, thought to be residual scar tissue, are present. PR: \>=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 Complete Response (CR, CCR, and CR+CCR) and Partial Response (PR) From Study Day 0 (start of treatment) up to 12 years (long-term follow up) CR: Complete resolution of all disease-related radiological abnormalities and disappearance of all signs and symptoms related to the disease. CCR: Complete resolution of all disease-related symptoms, but residual foci, thought to be residual scar tissue, are present. PR: \>=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions.
- Secondary Outcome Measures
Name Time Method The Estimated Value Represents the Percentage of Participants With a PR From Study Day 0 (start of treatment) up to 12 years (long-term follow up) Duration of response (CR, CCR, or PR) is defined as the time from the first documented response to the first documented progression. Progressive Disease (PD) is defined as a \>=25% increase from the nadir value of the sum of the products of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion.
Overall Survival From Study Day 0 (start of treatment) up to 12 years (long-term follow up) Overall survival is defined as the time from the treatment start date to the date of death from any cause.
Time to Progression of Disease or Death (Progression-free Survival) From Study Day 0 (start of treatment) up to 12 years (long-term follow up) Time to progression is defined as the time from the treatment start date to the first documented progression or death. Progressive Disease is defined as a \>=25% increase from the nadir value of the sum of the products of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion.
Number of Participants With Resolution of All Baseline B-symptoms by the End of the Study Baseline and up to 12 years (long-term follow up) The Ann Arbor staging system of lymphomas is used to summarize the extent of the cancer's spread. Stages are classified by Roman numerals I (less spread) to IV (more spread). If the following symptoms (called B-symptoms) are present, a "B" classification is added to the stage: night sweats, intermittant fever, and weight loss. B-symptoms indicate the presence of systemic symptoms. The presence or absence of B-symptoms has prognostic significance and is reflected in the staging of these lymphomas.
Number of Participants Who Were Polymerase Chain Reaction (PCR)-Positive at Baseline With Bone Marrow Conversion to a Status of PCR Positive and Negative Any Time After Treatment Baseline and up to 12 years (long-term follow up) PCR is a scientific technique in molecular biology to amplify a single copy or a few copies of a piece of deoxyribonucleic acid (DNA) across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence. Applications of PCR technique include: selective DNA isolation, amplification and quantification of DNA, and the diagnosis of diseases. PCR positive: interchromosomal translocation t(14;18) is present. PCR negative: t(14;18) is absent.
Duration of Response (the Time From the First Documented Response to the First Documented Progression) for Participants Who Were PCR Positive at Baseline and Converted to PCR Negative Status After Treatment Baseline and up to 12 years (long-term follow up) PCR is a scientific technique in molecular biology to amplify a single copy or a few copies of a piece of deoxyribonucleic acid (DNA) across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence. Applications of PCR technique include: selective DNA isolation, amplification and quantification of DNA, and the diagnosis of diseases. PCR positive: interchromosomal translocation t(14;18) is present. PCR negative: t(14;18) is absent.
Progression-free Survival (PFS) Based on Participants' Baseline PCR Status Baseline and up to 12 years (long-term follow up) PCR is a scientific technique in molecular biology to amplify a single copy or a few copies of a piece of deoxyribonucleic acid (DNA) across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence. Applications of PCR technique include: selective DNA isolation, amplification and quantification of DNA, and the diagnosis of diseases. PCR positive: interchromosomal translocation t(14;18) is present. PCR negative: t(14;18) is absent. PFS is defined as the time from the dosimetric dose to the first documented occurrence of disease progression or death.
Initial Half-life (t1/2alpha) 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) t1/2 alpha is the estimated initial or alpha phase half-life in a two-compartmental pharmacokinetic model. Half-life measures how long it takes for the concentration of drug in the blood to decrease by half.
Terminal Half-life (t1/2beta) 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) t1/2 beta is the estimated terminal or beta phase half-life in a two-compartmental pharmacokinetic model. Half-life measures how long it takes for the concentration of drug in the blood to decrease by half.
Area Under the Curve (AUC) at 0 to 120 Hours and 0 to Infinity Hours 0-120 hours and 0-infinity hours from the dosimetric dose (given only on Day 0) and 0-120 hours and 0-infinity hours from the therapeutic dose (given only on Day 7) Area under the concentration-time curve for I-131 tositumomab from time 0 to 120 hours and time 0 to infinity hours (extrapolated) after the end of the dosimetric dose infusion was measured. Unit: %ID\*h/ml, where %ID/ml is the percentage of the injected dose per milliliter of blood. AUC measures how much drug is in the system over time after infusion.
Clearance Values 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) Clearance of I-131 tositumomab after intravenous administration was measured. The clearance of a drug measures the rate at which the drug is removed from the body after the dose.
Maximum Concentration (Cmax) Values 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) Cmax is the maximum observed I-131 tositumomab concentration from time zero (end of the dosimetric dose infusion) to 120 hours after the end of the infusion. Unit: %ID/ml, where %ID/ml is the percentage of the injected dose per milliliter of blood. Cmax is the highest drug concentration in the blood after infusion.
Volume of Distribution at Infusion Time 0 (Vd0) and Steady State (Vdss) 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) Volume of distribution at the start of infusion and at steady state of I-131 tositumomab. The volume of distribution measures how much the drug spreads through the body after the dose. Steady state is defined as that state at which the overall intake of a drug is fairly in dynamic equilibrium with its elimination.
Total Body Effective Half-life (EHL) 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) Total body EHL is the time required for a radioactive element in the body to be diminished by 50% as a result of radioactive decay and biologic elimination. The EHL is equal to the product of the biologic half-life (BHL) and the radioactive half-life (RHL) divided by the sum of the BHL and the RHL: EHL=(BHL \* RHL)/(BHL + RHL). BHL is the time it takes for a drug to lose half of its pharmacologic, physiologic, or radiologic activity. RHL is the time taken for half of the radioactive nuclei to decay.
Normal Organ Dosimetry for the Indicated Organs 0-120 hours from the dosimetric dose (given only on Day 0) and 0-120 hours from the therapeutic dose (given only on Day 7) Organ dosimetry was performed in participants using the kidneys, liver, lungs, spleen, red marrow, urinary bladder, and the remainder of the body as source organs. Organ doses and Iodine I-131 Anti-B1 Antibody biodistribution were comparable across the three Anti-B1 Antibody manufacturers. 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). For the spleen (corrected) category, participant-specific corrections were made to account for individual spleen size.
Number of Participants With the Indicated Fatal Serious Adverse Events (SAE) From Baseline up to 12 years from the start of treatment (long-term follow up) 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. A fatal SAE is a medical event that results in death.
Number of Participants Evaluable and Not Evaluable for Human Anti-Murine Antibodies (HAMA) From Baseline up to 2 years from the start of treatment Tositumomab is a murine (mouse) antibody (immunoglobulin) of the IgG2a subclass. Participants 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 HAMA above the HAMA assay threshold, and a negative HAMA value indicates either the absence or below threshold level of HAMA.
Number of Participants With Conversion to HAMA Positivity Any Time During the Study From Baseline From Baseline up to 2 years from the start of treatment Tositumomab is a murine (mouse) antibody (immunoglobulin) of the IgG2a subclass. Participants 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 HAMA above the HAMA assay threshold, and a negative HAMA value indicates either the absence or below threshold level of HAMA. HAMA assays were conducted in the laboratory to measure conversion to HAMA positivity following treatment.
Time to HAMA Positivity From the First Dosimetric Dose From Baseline up to 2 years from the start of treatment Tositumomab is a murine (mouse) antibody (immunoglobulin) of the IgG2a subclass. Participants 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 HAMA above the HAMA assay threshold, and a negative HAMA value indicates either the absence or below threshold level of HAMA. HAMA assays were conducted in the laboratory to measure conversion to HAMA positivity following treatment.
Number of Participants With Elevated, Low, and Normal Thyroid Stimulating Hormone (TSH) Levels at Baseline Baseline TSH is a hormone that stimulates the thyroid gland to produce thyroxine (T4) and then triiodothyronine (T3), which stimulates the metabolism of almost every tissue in the body. Participants were considered to have normal, high, or low TSH levels per the standard TSH ranges of the testing laboratory.
Participants With Elevated TSH Levels at Baseline With Post Baseline TSH Levels of Low/Normal and Elevated Baseline and up to 12 years (long-term follow up) TSH is a hormone that stimulates the thyroid gland to produce thyroxine (T4) and then triiodothyronine (T3), which stimulates the metabolism of almost every tissue in the body. Participants were considered to have normal, high, or low TSH levels per the standard TSH ranges of the testing laboratory.
Time to Elevated TSH Post Baseline for Participants Who Had Low or Normal TSH Levels at Baseline and Elevated Levels Post Baseline Baseline and up to 12 years from the start of treatment TSH is a hormone that stimulates the thyroid gland to produce thyroxine (T4) and then triiodothyronine (T3), which stimulates the metabolism of almost every tissue in the body. Participants were categorized to have elevated or normal/low TSH values per the standard TSH ranges of the testing laboratory.
Number of Participants With the Adverse Event (AEs) of Hypothyroidism Baseline and up to 12 years from the start of treatment Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone and is defined as either developing elevated TSH levels or initiating thyroid medication. An AE is defined as any unfavorable and unintended sign, including an abnormal laboratory finding, symptom, or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered to be related to the medical treatment or procedure, that occurs during the course of the study.
Number of Participants With Low or Normal Baseline TSH Levels That Developed Hypothyroidism Baseline and up to 12 years from the start of treatment Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone and is defined as either developing elevated TSH levels or initiating thyroid medication.
Number of Participants Who Received Thyroid Medication After Treatment From Study Day 0 (start of treatment) up to 12 years (long-term follow up) Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone and is defined as either developing elevated TSH levels or initiating thyroid medication.