Trial Information

RIT-I-000/RIT-I-000A: Phase I Study of Radiolabeled Monoclonal Antibody Anti B1 for the Treatment of B Cell Lymphomas & RIT-I-000B: Extended Phase I/II Study to Determine the Safety and Efficacy of Coulter Clone® 131Iodine-B1 Radioimmunotherapy of Advanced Non-Hodgkin's Lymphoma

Phase I/II, single-center, dose-escalation study of the safety, pharmacokinetics, dosimetry,
and efficacy of TST/I-131 TST for the treatment of patients with chemotherapy-refractory or
resistant low-grade, intermediate-grade, or high-grade B-cell lymphoma. Subjects received 1
to 3 dosimetric doses followed by a therapeutic dose of TST/I-131 TST. Study BEX104526 was
a follow-up study of the long-term safety and efficacy data from the surviving patients who
completed at least 2 years of follow-up following administration of TST/I 131 TST on Study
BEX104728.

Dosimetric dose: Subjects received 1 to 3 dosimetric doses of TST/I-131 TST, followed by a
therapeutic dose of TST/I-131 TST. Subjects received various doses of unlabeled TST (0, 95
or 475 mg) to determine the dose of unlabeled TST that optimized the radiation dose
delivered to the tumor by TST/I-131 TST. The unlabeled TST was followed by 5 milliCurie
(mCi) of I-131 TST. Serial whole body sodium iodide scintillation probe counts were
obtained daily, for at least 5 days, in order to determine the rate of whole body clearance
of radioactivity (residence time). The residence time was used to determine the radioactive
clearance for the subject and the activity (in mCi) of I-131 required to deliver the desired
TBD of radiation during the therapeutic dose. Because 475 mg was determined to be the
optimal pre-dose of TST in the first subjects entered, the last 34 subjects received a
single dosimetric dose that was preceded by an infusion of 475 mg of TST.

Therapeutic dose: Groups of 3-6 subjects were enrolled at successively higher whole-body
radiation dose levels beginning at a total body dose (TBD) of 25 centiGray (cGy). The TBD
of each subsequent dose level was escalated by 10 cGy. Subjects who had undergone bone
marrow transplantation (BMT) underwent a separate dose escalation (10 cGy TBD increase per
dose level) beginning at a TBD level of 65 cGy. The MTD was defined as the highest dose
level at which 0/3 or 1/6 subjects experienced dose-limiting toxicity (DLT).

DLT was defined as follows:

Any Grade 4 hematologic toxicity (National Cancer Institute [NCI] criteria) lasting greater
than 7 days, or Any Grade 3 hematologic toxicity lasting greater than 2 weeks, or Any Grade
3 or 4 nonhematologic toxicity Redosing: Subjects who achieved tumor regression were
considered for re-dosing, using the original therapeutic dose of TST/I-131 TST, at the time
the tumor was no longer shrinking in an attempt to upgrade their response.

Retreatment: Subjects who achieved a partial response (PR) or complete response (CR) were
considered for retreatment following relapse of their NHL, if progression occurred ≥6 weeks
following the therapeutic dose. The original therapeutic dose of TST/I-131 TST was given
unless a grade 2 or greater toxicity had been encountered, in which case a reduced dose was
administered for the repeat therapeutic dose.

Subjects who completed at least 2 years of follow-up in BEX104728 were enrolled in LTFU
Study BEX104526 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 and disease status,
including subsequent therapy for NHL, and for long-term safety, including the development of
hypothyroidism, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and any
other secondary malignancies. Additionally, subjects were followed for the development of
any adverse event(s) (AEs) deemed by the Principal Investigator as being possibly or
probably related to a subject's treatment with TST/I-131 TST. Laboratory evaluations,
consisting of thyroid stimulating hormone (TSH) level and complete blood cell count with a
differential and platelet count, were obtained annually through year 10 post-treatment.

Study assessments included demographic and baseline characteristics; tumor response,
duration of response, survival (progression-free survival [PFS] and overall survival [OS]),
adverse events (AEs), incidence of human anti-murine antibody (HAMA), incidence of
hypothyroidism, and serious (fatal and non-fatal) adverse events (SAEs).

Dosing;"Dosimetric Doses", Intravenous (IV) administration of unlabeled TST (0, 95 or 475
mg) was administered to determine the dose of unlabeled TST that optimized the radiation
dose to the tumor. This was followed by 5 mCi of I-131 TST. Serial whole body sodium iodide
scintillation probe counts were obtained daily, for at least 5 days, in order to determine
the rate of whole body clearance of radioactivity (residence time). The residence time was
used to determine the radioactive clearance from the subject and subsequently the activity
(in mCi) of Iodine-131 required to deliver the desired TBD of radiation during the
therapeutic dose of TST/I-131 TST. Because 475 mg was determined to be the optimal pre-dose
of tositumomab in the first subjects entered, the last 34 subjects received a single
dosimetric dose that was preceded by an infusion of 475 mg of tositumomab (Source Data:
Listing 13).

"Therapeutic Dose", Groups of 3-6 subjects were treated at successively higher therapeutic
whole body radiation doses, beginning at a TBD of 25 cGy. The TBD was escalated in 10 cGy
increments in subsequent dose level cohorts until the MTD was achieved. A separate
determination of MTD was conducted for subjects who had undergone prior BMT. This was
initiated at a TBD of 65 cGy TBD and increased in 10 cGy increments until determination of
the MTD. The MTD was defined as the dose at which fewer than 1/3 or 2/6 subjects experienced
DLT, i.e. any Grade 4 hematologic toxicity (absolute neutrophil count [ANC], platelets,
hemoglobin, white blood count [WBC] lasting > 7 days or any Grade 3 hematologic toxicity
lasting > 14 days, as defined in Section 4.1.

Re-Dosing; Subjects who achieved tumor regression were considered for re-dosing, using the
original therapeutic dose of TST/I-131 TST, at the time the tumor was no longer shrinking in
an attempt to upgrade their response. Patients were not redosed sooner than 6 weeks
following a therapeutic dose.

Retreatment (≥6 weeks following therapeutic dose); Subjects who achieved a PR or CR were
considered for retreatment following relapse of their NHL. The original therapeutic dose of
TST/I-131 TST was given unless a Grade 2 or greater toxicity had been encountered, in which
case the dose level immediately below the original dose was administered.