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)
Condition: Lymphoma, Non-Hodgkin
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin
Intervention: Iodine-131 Anti-B1 Antibody Versus Anti-B1 Antibody in Chemotherapy-Relapsed/Refractory Low-Grade or Transformed Low-Grade Non-Hodgkin's Lymphoma (NHL)
Intervention description: 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.
Intervention MeSH terms: Tositumomab I-131; Antibodies; Immunoglobulins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 78.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Bexxar; Non-Hodgkin's Lymphoma; Tositumomab; Anti-B1 Antibody; Radioimmunotherapy; Iodine I-131; Iodine-131

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. 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.
    

Eligibility 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).