Comparison Of Rituximab Versus Tositumomab and Iodine I 131 Tositumomab (BEXXAR® Therapeutic Regimen) For Patients With Relapsed Follicular Non-Hodgkins Lymphoma

GlaxoSmithKline14 enrolled

Overview

Comparison of rituximab versus Iodine I 131 Tositumomab Therapeutic Regimen (Tositumomab and Iodine I 131 Tositumomab or the Bexxar Therapeutic Regimen, formerly called Iodine-131 Anti-B1 Antibody) in subjects with follicular non Hodgkins B cell lymphoma. 506 subjects will be enrolled at 30 to 40 sites in the US, Canada, and Europe. Subjects will be randomly assigned to one of two treatment arms. In Arm A, subjects will receive 375 milligrams/meter2 (mg/m2 )of rituximab, given as an intravenous (IV) infusion once weekly for 4 weeks. In Arm B, subjects will undergo a two-phase treatment. In the first phase, termed the "dosimetric dose," subjects will receive an infusion of unlabeled Tositumomab (450 mg) immediately followed by an infusion of 5 millicuries (mCi) (0.18 gigabecquerel \[GBq\]) of Iodine 131 Tositumomab (35 mg). Whole body gamma camera scans will be obtained three times (Day 0; Day 2, 3, or 4; and Day 6 or 7) following the dosimetric dose. The information derived from the scans will enable a patient specific dose to be calculated to deliver the desired total body dose of radiation (65 or 75 centigray \[cGy\]). In the second phase, termed the "therapeutic dose," subjects in Arm B will receive an infusion of unlabeled Tositumomab (450 mg) immediately followed by an infusion of the subject specific activity of Iodine 131-conjugated Tositumomab (35 mg). Thyroid blockade will be implemented 24 hours prior to the dosimetric dose and continued for 14 days following the therapeutic dose. Subjects on study will be followed for response and safety at Week 7, Week 13, and every three months for the first and second year, every six months for the third year, and then annually for the forth and fifth years; and then for vital status, additional therapy, and long term safety events through year ten. Follow Up after subsequent NHL therapy will be carried out to assess tolerance of next anti-lymphoma therapy, development of myelodysplasia (MDS)/acute myelogenous leukemia (AML), HAMA or hypothyroidism, unexpected safety issues, and death.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion criteria: * Histologically confirmed diagnosis of follicular lymphoma * Recurrent lymphoma after one or two qualifying therapy regimen(s) * Patients must not have progressed within 4 weeks of their last chemotherapy dose * Rituximab may have been used once as a single agent, in one continuous course of 4-8 weekly infusions (10-week period), or in combination with chemotherapy in a single prior treatment * Patients whose prior therapy includes rituximab must have had a 6 month or greater response duration following the rituximab-containing regimen. * Performance status of at least 70% on the Karnofsky Scale and an anticipated survival of at least three months * Adequate absolute neutrophil count and platelet count within 21 days of study entry without support of blood products/growth factors * Adequate renal function and adequate hepatic within 21 days of study entry * Measurable disease, with at least one lesion measuring \>/=2.0 cm x 2.0 cm by CT scan * Human Anti Mouse Antigen negative * Written informed consent prior to study entry Exclusion criteria: * Histologic transformation to diffuse, large cell lymphoma. * History of more than one course of Rituximab * Disease limited to single lymph node or single group of nodes * Involvement of 25% of the intratrabecular marrow by bone marrow biopsy specimen. * Active infection requiring IV antibiotics at the time of study entry * New York Heart Association Class III/IV heart disease * Prior chemotherapy, biologic, radiation or steroid therapy for NHL within 8 weeks * Any prior radioimmunotherapy * Prior history of malignancy other than lymphoma (except for treated basal cell, squamous cell skin cancer, in situ cervical cancer, or other cancer that is disease-free for 5 years) * Known HIV infection * Hepatitis B positive * Known central nervous system involvement

Outcomes

Primary Outcomes

Event-free Survival (EFS)

Event-free survival is defined as the time from the date of randomization to the first occurrence of (whichever came first) progressive disease, death, or additional Non-Hodgkins Lymphoma (NHL) therapy due to disease-related symptoms, threatened end-organ function, cytopenias secondary to NHL, massive bulk disease, or steady progression over at least 6 months. Progressive disease is defined as at least a 50% increase in the sum of the perpendicular diameters of all measurable lesions and the appearance of new lesions at least 1.4 centimeters (cm) x 1.4 cm (i.e., 2.0 cm\^2) by radiographic evaluation or greater than 1.0 cm by palpation upon physical examination.

Time frame: From the date of randomization to the first occurrence of progressive disease, death, or additional Non-Hodgkins Lymphoma (median follow-up for the Rituximab and TST/I-131 TST groups was 62 and 91.5 months, respectively)

Progression-free Survival

Progression-free survival is defined as the time from the initial date of dosing to the first documented disease progression or death. Disease assessment was based on the International Workshop to Standardize Response Criteria (IWSRC) for Non-Hodgkin's Lymphoma (NHL). Progression is defined as at least a 50% increase in the sum of the perpendicular diameters of all measurable lesions and the appearance of new lesions at least 1.4 centimeters (cm) x 1.4 cm (i.e., 2.0 cm\^2) by radiographic evaluation or greater than 1.0 cm by palpation upon physical examination.

Time frame: From first dose of treatment until disease progression or death, whichever came first (median follow-up for the Rituximab and TST/I-131 TST groups was 62 and 91.5 months, respectively)

Secondary Outcomes

Number of Participants Achieving Response

Complete response (CR) is defined as the complete disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms (by the IWSRC) if present before therapy, and normalization of those biochemical abnormalities definitely assignable to NHL. Confirmation of response was carried out by an independent reviewer

Time frame: Participants were followed for response at Week 7, Week 13, every 3 months for the first and second year, every 6 months for the third year, and then annually

Duration of Response

Response duration is defined as the time from the first documented response (complete response, complete response unconfirmed, or partial response) until disease progression. Partial response is defined as at least a 50% decrease in the product of two perpendicular diameters of all measurable lesions; no increase in the size of other nodes, liver, or spleen; and no new disease sites.

Time frame: Participants were followed for response at Week 7, Week 13, every 3 months for the first and second year, every 6 months for the third year, and then annually

Time to Death

Time to death is defined as the time from treatment start to the date of death. As a median time to death is not presented for either group, see the outcome measure entitled "Number of Participants Who Had Died by the Month Indicated" for data regarding time to death.

Time frame: From first dose of treatment until disease progression or death, whichever came first (median follow-up for the Rituximab and TST/I-131 TST groups was 62 and 91.5 months, respectively)

Number of Participants Who Had Died by the Month Indicated

The median time to death could not be calculated for participants in either treatment group; thus, data are shown as the number of participants who had died by the month indicated.

Time frame: From first dose of treatment until disease progression or death, whichever came first (median follow-up for the Rituximab and TST/I-131 TST groups was 62 and 91.5 months, respectively)

Time to Next Treatment

Time to next treatment is defined as time from the date of randomization until the new treatment is needed for NHL. Because too few evaluable participants were enrolled/treated, analysis of the time to next treatment was not conducted as planned.