Title: Randomized Study of Iodine I 131 Tositumomab vs. Anti-B1 Antibody Alone in Chemotherapy-Relapsed and Refractory Low-Grade or Transformed Low-Grade NHL.

Design

Study RIT-II-002 was a randomized two-arm, open-label, multi-center study conducted in patients with chemotherapy-relapsed or refractory low-grade or transformed low-grade NHL. The study was designed to determine the incremental benefit of the radioconjugate compared to the unlabeled antibody. The study compared the safety and efficacy of the radiolabeled labeled antibody (Arm A) versus the unlabeled antibody (Arm B). A one-way cross-over at the time of disease progression was permitted for patients in the unlabeled arm (to receive iodine I-131 tositumomab).

Protocol activated- March 18, 1996

Accrual was from September 18,1996 to June 1, 2000

Principal Investigators and Study Sites

John Leonard, M.D., New York Hosp.-Cornell Medical Center
Arnold Friedman M.D., Dana-Farber Cancer Institute
Mary Wilkinson M.D. Inova Fairfax Hospital
Stanley Frankel M.D., Georgetown University
Andrew Zelenetz M.D. , Ph.D., Memorial Sloan-Kettering Cancer Center
Rush-Presbyterian-St. Luke’s Medical Center
Susan Know M.D., Ph.D., and Ronald Levy M.D., Stanford University Medical Ct.
Mark Kaminiski, M.D. & Richard Wahl M.D., University of Michigan Medical Ctr.
Aldo Serafini, M.D. , University of Miami Hospital and Clinic
Frank Hsu, M.D. Yale University School of Medicine

Objectives (Final protocol)

Primary objective:

The comparison of the rates of complete response between the Iodine I-131 Anti-B1 antibody (iodine – I 131 tositumomab) and the unlabeled anti-B1 ("cold" tositumomab) arms.

Randomization was performed at an external site. There were no stratification criteria specified and no details regarding the randomization procedure in the protocol other than that the randomization would allocate patients equally (1:1) to the two study arms.

The treatment program consisted of two intravenous infusions; an initial dosimetric infusion followed in 7 to 14 days by a therapeutic infusion.

• The first day of the dosimetric phase was designated as study day 0. The dosimetric [tracer dose] infusion contained 450 mg of Anti-B1 antibody infused over 70 minutes (includes a 10 minute flush) immediately followed by 5 mCi (35 mg) of Iodine –131 Anti-B1 Antibody infused over 30 minutes (includes a 10 minute flush).
• Seven to 14 days later, the therapeutic dose consisting of 450 mg of Anti-B1 antibody was infused over 70 minutes (includes a 10 minute flush) immediately followed by the patient –specific milliCurie activity (35 mg) of Iodine-131 Anti-B1 Antibody calculated to deliver a total body dose of 75 cGy and infused over thirty minutes. The calculation of the patient specific dose was base on the information obtained from the dosimetric infusion and is detailed in the protocol.
• The therapeutic dose was calculated to deliver 75 cGy TBD in patients with platelet counts ³ 150,000/mm³. Patients with platelet counts between 100,001 and 150,000/mm³ were administered a therapeutic dose calculated to deliver 65 cGy TBD. Obese patients were dosed based upon 137% of their lean body mass.
• Starting 24 hours before the dosimetric dose and continuing for 14 days after the last infusion of radiolabeled antibody, either Lugol’s solution or potassium iodide tablets were given to all patients.
• Thirty minutes prior to both the dosimetric dose and the therapeutic dose, patients were pre-medicated with acetaminophen 650 mg p.o. and diphenhydramine 50 mg p.o.
• Patients were tested for HAMA at day 5 and HAMA+ subjects were not given the therapeutic infusion.

Concomitant medications:

• Thirty minutes prior to both the dosimetric dose and the therapeutic dose, patients were pre-medicated with acetaminophen 650 mg p.o. and diphenhydramine 50 mg p.o.

Dose modifications

• Patients with conversion to HAMA+ could not receive the therapeutic infusion.
• Dose adjustments of radiolabeled antibody for obesity and for thrombocytopenia were as described in study report for RIT-II-004

Monitoring Plan

(Final study protocol, after the inclusion of amendments 1-6):

Tumor response was assessed at baseline, at 6 weeks, 3 months and then at 3-month intervals until 2 years. AE, SAE and morbidity/mortality data were collected at each contact. Hematologic data were obtained at baseline, and weeks 3 through 13 unless more frequent counts were indicated. After grade 0 toxicity has been observed on 2 or more occasions the protocol stated that weekly hematology testing could be discontinued. After week 13, the follow up phase began with collection of hematology & serum chemistry test samples, TSH levels, physical and history and HAMA every 13 weeks until year two or death or the patient is withdrawn from study for disease progression or concomitant therapy. The final HAMA measurement was at week 26. Withdrawn patients were entered into long term follow up [LTFU] which collected information on disease and vital status, history of thyroid medication, history regarding myelodysplastic disease or other malignancy and any subsequent therapy for NHL. In amendment 1 samples for HAMA and TSH were added to LTFU requirements.

Original analytic plan

A sample size of 28 patients was selected based on a comparison of CR rates between Arms A and B. The sample size was stated to be sufficient to detect a clinically important difference in CR rates with a one-sided test at the 0.05 level. Comparisons of complete response duration, overall response rates, overall response durations, and time to progression between study arms were planned, however the timing and statistical methods to be employed were not provided. In addition, CR rates, ORR, response durations and TTP would be compared in the subset of patients enrolled in Arm B who progressed and crossed over to anti-B1 radioimmunotherapy following progression. Formal hypotheses to be tested and the timing of the analyses were not stated. Comparisons of response rates would be performed using a Fisher’s exact test and time to event comparisons (response durations, TTP, TTF) were to be performed using the log-rank test. Comparisons of ³ grade 3 adverse events would be performed using Fisher’s exact test. Comparison of the changes in laboratory values from baseline would be compared using the log-rank test.

Final Analytic Plan

(Final study protocol, after the inclusion of amendments 1-6):

The primary endpoint was the comparison (using Fischer’s Exact Test) of the complete response rates between the two treatment arms (A and B), as determined by the assessment of an independent review of films and medical information (MIRROR Panel). A single interim analysis was performed by the Data Safety Monitoring Board (DSMB), who applied the Lan-DeMets implementation of O’Brien-Fleming boundary for correction for the interim look; based on this interim analysis, the final analysis level of significance was adjusted to 0.049.

The secondary endpoints included comparison of overall response rate, the duration of response, time to progression and time to death. Based on results from RIT-I-000 and RIT-II-001, a 30% CR rate was estimated for treatment arm patients (Arm A) and a 5% rate for Arm B patients exposed to the "cold" antibody. Using a 2 sided alpha of 5%, it was calculated that equal randomization of 78 patients would result in 80% power to demonstrate a difference in CR rate. The primary analysis was a comparison of the complete response rate between arms of the intent-to-treat population with calculation of 2 sided 95% confidence intervals. P values would be calculated without adjustments except for any interim analyses. Secondary analyses would be performed for crossover patients for response rate and duration of response (McNemar’s test). Mean and median durations of response, time to treatment failure and survival will also be calculated.

Based on amendment 6 to the protocol, the analyses of study endpoints were based upon the determination of responses and response durations derived from an assessment of the CRFs and clinical data by an independent reviewer (MIRROR) panel. The MIRROR panel was composed of two teams of radiologists and oncologists who reviewed the CTs and determined the response assignment and duration of response. MIRROR panel radiographs were masked as to information on treatment arm of the patient and to investigators’ assessment of response.

AMENDMENTS TO THE STUDY (BY DATE OF ACTIVATION)

Amendment 1- -------------------

Amendment 2- -------------------------

• Primary endpoint changed from comparison, between arms, of rates of complete response [CR] and the durations of CR to only rates of complete response. Duration of response became a secondary endpoint.
• Inclusion criteria changed from, "histologically confirmed diagnosis of low grade NHL according to IWF Formulation…" to "histologically confirmed initial diagnosis of low grade NHL according to IWF Formulation".
• Inclusion criteria three and four were rewritten to read: "Patients must have received at least one chemotherapy regimen that included an anthracycline, an anthracenedione, or an alkylating agent. Patients must have progressive disease (at least 25% increase in tumor size at one or more sites of disease or new sites of disease) within 12 months of receiving their last chemotherapy regimen. Patients who have received > 3 chemotherapy regimens are excluded".
• Recalculation of extinction coefficient for anti-B1. It is now -----.
• Crossover patients must fulfill the same initial inclusion and exclusion criteria and be crossed over within 3 months of progression.
• All SAE within the 12 weeks after study entry must be reported. After 12 weeks only SAE probably or possibly related to study agent are to be tracked.
• Sample size increased from 28 to 78.
• Study converted from single center to multi-center study.
• The analytic plan was extensively revised.
• Addition of 2 new response categories (Best Response and Prolonged Response) with retention of the original definition of Response (requiring a duration of response of at least 4 weeks),
• Addition of a DSMB permitted to perform at least one and possibly two interim analyses.
• Analyses in "patients completing therapy" in addition to analyses in the ITT population.
• Inclusion of Cox model in the analyses of secondary endpoints

Amendment 3- ----------------

• Measurable lesions for evaluating tumor response are defined as any lesion ³ 2 cm in both perpendicular diameters at baseline.

Amendment 4- ----------------

Amendment 5- --------------

No significant changes

Amendment 6- -------------------

• Time to treatment failure removed from abstract, MIRROR Panel assessments, statistical techniques, and endpoints sections
• Long term follow up added TSH and HAMA monitoring. Final HAMA on week 26 removed.
• MIRROR panel assessment added to determine primary endpoint ( Section 9.9). Statistical section 10.7 expanded to include analyses adjusting for prognostic factors (Cox model). .

RESULTS

Conduct of the Study

Bioresearch Monitoring

FDA did not conduct audits of this study at clinical sites.

Disclosure: Financial Interests and Arrangements of clinical Investigators

The following are investigators disclosing (Form FDA 3455) any significant payments of other sorts made on or after February 2, 1999 from the sponsor of the covered study such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria.

• Mark Kaminski, M.D.- Principal Investigator, University of Michigan
• Richard Wahl, M.D. – Principal Investigator, University of Michigan
• Susan Knox, M.D.- Principal Investigator, Stanford University

Patient disposition

A total of 78 subjects were enrolled. One subject was removed from study due to reactivation of hepatitis prior to receipt of the therapeutic dose. Of the 78, 42 were randomized to receive Iodine I 131 tositumomab (Arm A) and 36 to received unlabelled tositumomab (Arm B). At the time of the study report, 31 patients had withdrawn from Arm A (29 for disease progression) and 33 had withdrawn from Arm B (32 for disease progression). No patient dropped out due to adverse events.

Patients randomized to unlabeled antibody (Arm B) who experienced disease progression within 3 months of treatment with unlabeled antibody were permitted to receive I 131 tositumomab (the tositumomab therapeutic regimen) in a cross-over arm (denoted Arm X). Among the 36 patients randomized to arm B, there were 32 who experienced progressive disease. Nineteen of the 32 withdrawn subjects were crossed over to Arm X. The remaining 13 were not crossed over for a variety of reasons; the major reason was development of a human anti-murine antibody (HAMA) immune response after exposure to cold anti-B1 antibody. Three patients randomized to Arm B had not experienced disease progression and one patient withdrew from the study.

Reasons cited for 13 patients with progressive disease who did not cross over were:

Protocol Violations:

Thirty-one violations were reported in 29 patients. Patient 200-030-004 [arm B] and 200-030-904*[arm X] were reported to have had protocol violations both during participation in Arm B and after being crossed over to arm X. Two protocol violations were reported for Patient 002-034-009. Eligibility or treatment/dosing reasons are listed below. Serious eligibility violations were encountered for 002-011-002 (question of disease progression at baseline), possibly for 002-030-004 and 002-030-015 (question of appropriate studies for disease staging) and patient 002-034-007 (progressive disease not shown until 18 months after last chemotherapy).The number of discrepancies in therapeutic dose and incorrect SSKI dosing were substantial.

Study Population

A total of 78 patients with previously treated low-grade or transformed low-grade NHL were enrolled in this multi-center study. The median follow up was 24.9 months (range: 1.9–52.0 months).

The baseline entry characteristics for the study population by treatment arm and for the patients who cross-over in Arm B are presented in the table below.

Efficacy Results

There was a significantly higher complete response rate in patient randomized to Arm A as compared to Arm B as well as a significantly increased overall response rate in Arm A. The duration of response however, not significantly different in the two arms; 10 of the 23 responding patients have relapsed in Arm A and 4 of the 7 responding patients have relapsed in Arm B. There was also no difference in overall survival between the two study arms. The median survival has not been reached in either study arm, with 16 of 42 patients dead in Arm A and 12 of 36 patients dead in Arm B. However, there was a significant difference in time to death or progression between the study arms (p=0.031). The survival curves for duration of response, time to progression or death, and time to death are displayed below.

Per-patient incidence of adverse events regardless of severity or relationship to study agent

The most frequent adverse event (all severity) and the most frequent severe adverse events were hematologic. In the 19 subjects in arm X there were 11 patients with documented hematologic toxicity and 3 with undocumented toxicity for a cumulative total of 14 (74%). Source was FDA analysis using CRTs submitted ------------.

Hematologic toxicity in crossover population: The table below compares documented hematologic toxicity in the three arms and shows a higher incidence of grade 3-4 toxicity in arm A as compared to B, as well as a higher incidence of hematologic grade 3-4 toxicity in arm X as compared to Arm A. Notable is the rate of grade 3-4 neutropenia (8%) with the unlabeled tositumomab, which exceeds that generally observed with other anti-CD20 antibodies. If this is a real finding, the mechanism is unclear. In addition, the incidence of severe cytopenias and of bleeing events in patients who were treated in Arm B and crossed over to treatment with iodine I 131 tositumomab in the 3-month interval permitted in this study is higher than observed in patients in Arm A (initial treatment with the iodine I 131 tositumomab therapeutic regimen. Again, given the small patient numbers it is unclear whether this finding is real or a chance event.

Recovery from hematologic toxicity was evaluated at week 13. There were 35 (of the 42 patients) actively followed in Arm A for hematologic toxicity at week 13. Two patients among the 35 had persistent hematologic toxicity (grade 3 and one grade 4 neutropenia). There were 2 patients, among the 22 being actively followed for toxicity at week 13 in Arm B, who had persistent toxicity (both had Grade 4 neutropenia).

HAMA: HAMA was detected at week 7 (5 cases), week 13 (2 cases) and at 6 months in one case. As noted, 32 patients in Arm B with progressive disease had an option of a one-way cross-over to Arm X. Nineteen of the 32 patients crossed over to arm X (to receive iodine I 131 tositumomab therapy). The 13 patients with progressive disease who did not crossover included 8 who could not be crossed over because of positive HAMA tests.

There were 15 patients in the randomized portion of the study who suffered one or more serious adverse events. The iodine I 131 tositumomab arm had an approximately 2-fold higher rate of SAE. A similarly high rate of SAE were observed in the patients who crossed over to iodine I 131 tositumomab after disease progression on Arm B.

• 11% (4/36) patients randomized to unlabelled tositumomab experienced at least one SAE. Four patients (11%) were hospitalized for the following adverse events: chest and abdominal pain; syncope /dehydration and hypothermia; retroperitoneal bleed; hydronephrosis; bacteremia; fungemia; febrile neutropenia.

• 37% (7/19) of patients who crossed over to receive I-131 tositumomab (crossed-over after progression) experienced one or more SAEs. Five patients (21%) were hospitalized for the following adverse events: ulcerated node; thrombocytopenia; basal cell carcinoma; bronchitis; abdominal bloating and dyspnea and edema. The patients with SAEs not requiring hospitalization experienced CML and gastric adenocarcinoma, respectively.

Deaths: There were 13 total deaths in RIT-II-002 of which 2 were prior to day 90, 3 by day 189, 4 by day 270, and 8 by one year. Arm A had 2 deaths (weeks 8 & 10) and 6 patients who withdrew (weeks 3, 6, 7,9 and 11) during the first 90 study days.

002-030-002 69 F L A 54

002-030-009 51 M T A 69

002-030-018 62 F T B 53

Study initiated April 24, 1990

Phase B initiated October 5, 1994

Closed on January 17, 1996

Date cut-off: Dec. 1, 2000

Study Sites:

University of Michigan Medical Center

Objectives:

Inclusion Criteria

Treatment Plan:

The study was modified numerous times over the course of the study.

Phase A: The general treatment plan for Phase A remained unchanged, however the dose cohorts were modified several times. All patients were to receive two or more dosimetric doses of anti-B1 antibody. The dosimetric doses were administered 7-14 days apart. The amount of unlabeled antibody was varied (generally increased) between the initial and subsequent dosimetric doses given to an individual patient so that an assessment of the impact of the amount of unlabeled antibody [administered within 30 minutes prior to the radiolabeled tracer dose] on the biodistribution could be assessed and compared within an individual patient. In addition, the dose of unlabeled antibody on the initial dosimetric dose was increased in successive groups of patients in a manner not prospectively defined in the protocol, although the analytic plan indicated that intra-patient comparisons in groups of 3 to 6 patients should be sufficient to identify within patient differences in biodistribution.

The dosimetric dose consisted of 35 mg of unlabeled anti-B1 antibody administered intravenously (IV) over one or more hours, following by an IV dose over 1-2 hours, followed 30-60 minutes later with 1 mg of B1 antibody labeled with 5 mCi I 131 co-administered with additional unlabeled anti-B1antibody (10-15 mg of antibody total) as an IV infusion over minutes to hours.

The amount of unlabeled antibody administered in the initial part of the dosimetric infusion varied over the course of the study. The unlabeled doses of antibody administered at the initial dosimetric infusion included 0 mg, 95 mg, 475 mg,

In addition, the therapeutic dose was increased in successive cohorts of 3-6 patients to determine the maximum tolerated therapeutic dose. Although modified several times, the treatment plan incorporated the scheme of starting at 25 cGy total body dose (TBD) and increasing by 10 cGy TBD in subsequent cohorts until the MTD was reached or exceeded. Gamma counts were measured daily for 7 days following the dosimetric dose. The gamma count data were then used to determine each patient’s clearance of the drug (i.e., total body residence time: TBRT), which was utilized to determine the patient-specific activity (mCi) required to deliver a desired uniform TBD (cGy) of radiation.

Phase B was introduced by an amendment to the protocol in ------------------. During Phase B, there was exploration of the activity of treatment regimen at the MTD for 131-Iodine labeled anti-B1 and the optimal dose of unlabeled antibody in the dosimetric/therapeutic in 12 patients with CD20 positive NHL who had not undergone a prior hematopoeitic stem cell transplantion. In addition, during Phase B, the MTD of the therapeutic dose of 131-Iodine labeled anti-B1 was determined in patients with CD20 expressing NHL with a history of prior hematopoeitic stem cell transplantion. The treatment plan was not described for these patients, however a range of doses beginning at a dose of 45 cGy TBD and escalating/de-escalating in 10 cGy increments was administered in groups of patients (1-3).

Analytic Plan

The analytic plan was modified over time. The major objectives were to determine the optimal biologic dose of unlabeled antibody as a component of the dosimetric dose and the maximum tolerated dose (MTD) of the therapeutic dose. The definition of dose-limiting toxicity (DLT), upon which the MTD was based, was revised during the course of the study. The final protocol defined the MTD as the level below the dose level at which there was a one-third or greater incidence of DLT. DLT was defined as any non-hematologic Grade 3 or 4 dose-related toxicity, any Grade 3 hematologic toxicity of >2 weeks duration, or any Grade 4 hematologic toxicity of >1 week duration. The determination of the optimal biologic dose of unlabeled antibody was described in qualitative terms in the analytic plan.

There were 3 amendments to Phase A [dated --------------------------------------------------------------------] and 2 amendments to Phase B [----------------------------]

RESULTS:

Conduct of the study:

The results of this study were not audited by FDA at the clinical study sites

The sponsor reports 11 protocol violations among 9 patients; all were violations of the eligibility criteria.

Disclosure: Financial Interests and Arrangements of clinical Investigators

The following are investigators disclosing (Form FDA 3455) any significant payments of other sorts made on or after February 2, 1999 from the sponsor of the covered study such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria.

• Mark Kaminski, M.D.- Principal Investigator, University of Michigan
• Richard Wahl, M.D. – Principal Investigator, University of Michigan

Patient Enrollment and Disposition:

A total of 59 patients were enrolled. The first 47 were enrolled in Phase A and 12 additional patients were enrolled in Phase B.

• 59 patients received ³ 1 one dosimetric dose,
• 53 patients received a therapeutic dose; of these, 14 were re-treated

Dropouts

Patient Disposition

In Phase A, patients were sequentially enrolled into treatment cohorts, which included a simultaneous intra-patient escalation of the dose of unlabeled tositumomab, administered as multiple dosimetric doses, and intra-patient dose escalation, in cohorts of three to six patients, of the total body dose of iodine I 131 tositumomab. The enrollment into the various cohorts are summarized in the table below.

During Phase B, there were 15 additional patients without a history of prior bone marrow transplantation enrolled at a fixed dose of 75mCi TBD. There was a separate dose ranging assessment in patients with prior bone marrow transplantation. Dose cohorts and number of patients enrolled are summarized in the following table. This approach was not well described in the protocol and the enrollment did not appear to follow entry into sequential cohorts with dose escalation between cohorts. Rather, dose selection appeared to be somewhat random.

Study Population:

The study population contained a mixture of patients with chemosensitive and chemotherapy-refractory disease. Of the 59 patients enrolled, 30 (51%) had responded to the most recent chemotherapeutic regimen. Of these 19 (33% of the overall study population) had achieved a complete or clinical complete response to the most recent treatment regimen.

BASELINE ENTRY CHARACTERISTICS

The study enrolled a heterogenous group of patients and was not intended to provide more than anectodotal information on clinical activity. In addition, because of the patient heterogeneity and the small numbers of patients who received a particular TBD, it is difficult to draw conclusions regarding the dose-response relationship. The data presented below are not an ITT analysis. For example, no patient was intended to receive "0 cGy" TBD- each of these patients was unable to receive study drug in a treatment cohort for various reasons, including toxicity with dosimetric infusion, development of HAMA, and/or disease progression. The dose selected by the sponsor for use in Phase 2 studies is based upon determination of the MTD and not necessarily the optimal biologic dose (OBD), which cannot be determined in a study of this size and with this degree of heterogeneity. The data presented in the table below are provided only for information.

Study RIT-I-000 was designed to determine the optimal unlabeled (cold) predose of Anti-B1 Antibody to maximize tumor targeting and the maximum tolerated non-myeloablative radiation dose level.

The sponsor anticipated that bone marrow toxicity would be dose limiting. The sponsor elected the dose escalation design based on whole body radiation-absorbed dose, on the assumption that the whole body radiation dose would be more closely related to levels of bone marrow toxicity as compared to an escalation based on mCi/kg, mCi/m², or mCi.

Because the direct estimation of radiation dose to bone marrow is not feasible with unsealed source radiation therapy and marrow dosimetry from blood is not considered to be reliable in NHL subjects with normal B-cell populations as well as variable bone marrow involvement, the Total Body Dose (TBD) of radiation exposure was utilized as a surrogate for bone marrow dosimetry. Therefore, dose cohorts were escalated based on TBD and subjects were followed for dose-limiting toxicity (DLT) with expectations that the DLT would be related to declines in peripheral blood assessments, e.g. neutropenia, thrombocytopenia and anemia.

The MTD was set at one level below the dose level at which there was a one-third or greater incidence of DLT. The DLT was defined as any non-hematologic Grade 3 or 4 dose-related toxicity, a Grade 3 hematologic toxicity of >2 week’s duration, or a Grade 4 hematologic toxicity of >1 week duration.

The dose escalation was performed in subjects without prior bone marrow transplantation (BMT).

The maximum non-myeloablative TBD level was established in study RIT-I-000, based on 2 of 3 patients who had a DLT at 85 cGy TBD. Therefore, the MTD was established to be 75 cGy TBD for patients with no prior BMT

Narrative summaries of Serious Adverse Events

• Patient 000-002-031 (---)- Leukemia This patient was identified as having - no description of this provided in the summary.
• Patient 000-002-044 (---)- Superficial bladder cancer. The subject was a 48 year old male at study entry, with a diagnosis of low grade NHL in October 1981 and a diagnosis of low grade papillary transitional cell carcinoma of the bladder on October 19, 1995. Cystosopy was performed on Oct. --, 1995 (study day 253) reviewed papillary lesions. Patient underwent TURB October 20, 1995. Of note, a CT scan report of January 24, 1994 had noted a thick-walled bladder in a focal fashion in several areas, "etiology uncertain, bladder neoplasm cannot be excluded". In April 1996, new papillary lesions noted on cystoscopy. The patient underwent TURB and intravesical mitomycin C.
• Patient 000-002-046: 33 y/o female with transformed NHL at enrollment, developed pancytopenia, Coombs negative hemolytic anemia, and hospitalized for febrile neutropenia on study day 47. Patient remained culture negative, responded to antibiotics and discharged on study day 57. Received packed RBC x 4, but no platelets. Duration of pancytopenia approximately 20 days; anemia unresolved at day 77.
• Patient 000-002-050: 50 y/o female at entry, extensive prior history of chemotherapy, received 2 therapuetic doses of iodine I 131 tositumomab (114 mCi [75 cGy] and 84 mCi [75 cGy]) in June and Oct. 1995, respectively. Patient diagnosed with squamous cell carcinima of the rectum in March 1996, treated with APR. Patient diagnosed with MDS in Feb. 1998 and died August 1998.
• Patient 000-002-052: 57 y/o male diagnosed with follicular mixed NHL in 1982. He received 2 therapeutic doses of iodine I 131 tositumomab (106 mCi [65 cGy] and 70 mCi [65 cGy]) in August 1995 and April 1996 respectively. He was diagnosed with superficial bladder cancer in October 1996, treated with TURB. The patient died of progressive lymphoma in May 1997.
• Patient 000-002-055: 66 y/o male diagnosed in 1982 with follicular mixed NHL, extensive pretreatment history. He received therapeutic dose of iodine I 131 tositumomab (90 mCi [75 cGy]) in Nov. 1995. Patient had a pretreatment bone marrow that was normocellular with 3% blasts and 31% monocytes in Oct. 1995. At the time of entry, the patient appears to have been ineligible based on modest cytopenias (ANC 1083, Hgb 9.5 gm/dL, platelets 73, 000) on study day –2 [study day 0 – ANC 1474, Hgb 10.0 gm/dL, platelets 75, 000]. The post-treatment course was complicated by development of cellulitis on study day 20, treated with oral antibiotics and was hospitalized for fever and new skin lesions that responded to antibiotic therapy on study day 61; subsequently diagnosed with Sweet’s syndrome on biopsy. The patient received filgrastim post-iodine I 131 tositumomab and remained anemic and thrombocytopenic, through study day 68, with intermittent transfusions. The patient was diagnosed with MDS on study day 96, in Feb. 1996. He died on February 1997 (study day 470 due to secondary leukemia, and infectious complications.
• Patient 000-002-056: 70 y/o female with a diagnosis of follicular, small cleaved NHL in January 1989. The patient had an extensive pretreatment history for NHL. She was also diagnosed with ductal carcinoma of the R breast, treated with lumpectomy (patient refused further therapy). She received one therapeutic infusion of iodine I 131 tositumomab (61 mCi [75 cGy]) in Dec. 1995. At the time of entry she had a slightly hypocellular marrow and mild thrombocytopenia (platelets 138,000). The patient achieved a CR and received no additional treatment for NHL on study. She development disease progression and was withdrawn from study in May 1997. The patient developed pancytopenia and was diagnosed with MDS in January 1999, although bone marrow biopsies in 1997 revealed a hypocellular marrow and abnormal cytogenetics (monosomy 8).

Study initiated December 5, 1995

Study closed to enrollment November 20, 1996

Date cut-off December 1, 2000

Study Sites

Objectives

The primary objective of this multi-center study was to demonstrate that each independent site could reproducibly and accurately conduct the whole body dosimetry. Additional objectives of this study were to evaluate the efficacy and safety of iodine I 131 tositumomab therapy in a multicenter study. Dosimetry methods and calculations from each participating site were validated by a central dosimetry center at the University of Michigan.

Eligibility

Patients were eligible if they had progressive disease of either low-grade or transformed low-grade lymphoma within one year of completion of the last chemotherapy regimen administered. At least one of the previous chemotherapy regimens was required to contain an anthracycline or anthracenedione. Progression after single-agent steroids was not sufficient for study entry. Patients who were treated with chemotherapy for low-grade lymphoma and subsequently transformed to a higher grade were eligible even if they had not received specific treatment for their transformed lymphoma.

Treatment Plan

As described in RIT-II-OO2 for Arm A.

Patient Monitoring

Monitoring was similar to the other studies with the exception that gamma camera images for calculation of dosimetry were obtained daily on study days 0-7.

Analysis plan:

Descriptive statistics for assessment of toxicity, response rates and durations.

Bioresearch Monitoring Inspections

The University of Nebraska study site was inspected for Protocol RIT-II-001, entitled "Multicenter, Phase II Dosimetry/Validation Study of 131Iodine-AntiB1(murine) Radioimmunotherapy for Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade Lymphomas that have Transformed to Higher Grades" after the sponsor reported that data was missing. The inspections were conducted in accordance with CPGM 7348.811, the Inspection Program for Clinical Investigators. Specific questions concerning the studies were included.

Disclosure: Financial Interests and Arrangements of clinical Investigators

The following are investigators disclosing (Form FDA 3455) any significant payments of other sorts made on or after February 2, 1999 from the sponsor of the covered study such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria.

• Mark Kaminski, M.D.- Principal Investigator, University of Michigan
• Richard Wahl, M.D. – Principal Investigator, University of Michigan
• Susan Knox, M.D.- Principal Investigator, Stanford University
• David Colcher, Ph. D.- Investigator, University of Nebraska

The results of bioresearch monitoring inspections indicate that the deviations are not substantive, with the exceptions noted (failure to calculate residual activity, eligibility entry violations), and that the submitted data can be considered reliable and accurate.

Patient Enrollment and Disposition

Forty-seven patients with relapsed/refractory low-grade or transformed low-grade NHL were enrolled. All 47 patients received the dosimetric dose, and 98% (46/47) of the patients received the therapeutic dose. The median follow-up from the dosimetric dose was 34.0 months (range: 0.2–58.3 months).

Assessment of all of the onsite calculations and the administered activity of iodine I 131 tositumomab (mCi) by the independent dosimetry center indicated that the calculations performed at the treating centers were within 10% of those calculated at the dosimetry center.

The overall response rate was 49% (23/47). The complete response rate (CR + CCR) was 30% (14/47).

Non-hematologic toxicities were qualitatively similar to that reported in other studies. Hematologic toxicities were somewhat more frequent than in the other studies.

Narrative descriptions of serious adverse events