## OVERVIEW OF CLINICAL Studies 

The primary efficacy data supporting the proposed indication for the
treatment of chemotherapy-refractory patients with low grade and
follicular NHL, with or without transformation are derived from Study
RIT‑II‑004. The primary efficacy data supporting the indication for the
treatment of Rituxan-refractory patients with low grade and follicular
NHL, with or without transformation, are derived from Study
CP‑97‑012.Three additional studies (RIT‑I‑000, RIT-II-001, and
RIT‑II‑002) provide supportive anti-tumor activity data for the proposed
indications.

Safety information relevant to single agent use of Iodine I-131
tositumomab in this patient population were obtained from the five
efficacy/activity studies, the interim results of an additional study
(RIT-II-003) conducted as an exploratory, Phase 2 study of initial
treatment in patients with low grade, follicular NHL. Additional,
limited safety data are provided from the expanded access experience
under Protocol CP-98-020 and supplement by data provided to the sponsor
from \-\-- sponsor-investigator INDs for the treatment of individual
patients.

## individual CLINICAL study results 

## Study RIT‑II‑004 

Title: Multicenter, Pivotal Phase 3 Study of Iodine I 131 tositumomab
(Murine) Radioimmunotherapy for Chemotherapy-Refractory Low‑Grade B‑Cell
Lymphomas and Low‑Grade Lymphomas that Have Transformed to Higher Grade
Histologies.

Design: A multicenter, historically-controlled, single-arm trial in
patients with chemotherapy-refractory low grade or follicular NHL, with
or without transformation.

Study opened- November 22, 1996

Study closed to accrual - March 6, 1998

Data cut-off- January 28, 2002

Study Sites

-   Christie Hospital (UK)

-   Cornell Medical Center

-   Dana-Farber Cancer Institute

-   Georgetown University

-   Kaiser Permanente Medical Center

-   Memorial Sloan-Kettering Cancer Center

-   Rush-Presbyterian-St. Luke's Medical Center

-   St. Bartholomew's Hospital (UK)

-   Stanford University Medical Center

-   University of Alabama at Birmingham

-   University of Michigan Medical Center

-   University of Nebraska Medical Center

-   University of Washington

-   Yale University School of Medicine

Specific Aims and Objectives (original protocol)

1.  To establish the response rate, response duration, time to
    progression, time to treatment failure and survival after treatment
    with iodine I-131 tositumomab Radioimmunotherapy (RIT) in patients
    with chemotherapy-refractory low-grade or transformed non-Hodgkin's
    lymphoma

2.  To compare these endpoints to the patient's previous chemotherapy
    outcome

3.  To assess the safety of iodine I-131 tositumomab RIT

4.  To assess the quality of life of treated patients using the
    \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-- validated
    questionnaire.

Eligibility criteria (original protocol)

Inclusion Criteria

1.  Histologically confirmed diagnosis of CD20 positive low-grade or
    transformed low-grade non-Hodgkin's lymphoma.

2.  Treatment with at least two cycles of a qualifying chemotherapy
    regimen (6 weeks of single agent therapy) (see below), with failure
    to achieve an objective response, or relapse/progression within 6
    months after completion of the last qualifying chemotherapy (LQC)
    regimen. Patients must have [objective]{.underline} evidence of
    relapse or failure to respond.

3.  Karnofsky Performance Status  60%; anticipated survival of 3 months.

4.  Absolute granulocyte count \> 1500/mm3 and a platelet
    count \> 100,000/mm3.

5.  Adequate renal (creatinine \<2.0 mg/dL) and hepatic function
    (bilirubin \<2.0 mg/dL).

6.  Bidimensionally measurable disease or evaluable disease.

7.  Copies of original medical notes and radiographic studies
    documenting the chemotherapy drugs, number of courses and dates of
    their LQC, response to the LQC and, for responders, the date of
    disease progression.

### Exclusion Criteria

1.  An average of \>25% of the intratrabecular marrow space involved
    with lymphoma.

2.  Prior hematopoietic stem cell transplant.

3.  Active obstructive hydronephrosis.

4.  Pregnant or nursing females.

5.  Disease progression within one year, arising in a field previously
    irradiated with \>3500 cGy.

6.  Concurrent treatment with any other anti‑cancer drugs or biologics.

Qualifying chemotherapy regimens

Original protocol

-   Low grade NHL: CVP, COP-Bleo, CP, cytoxan, chlorambucil, fludarabine

-   Intermediate grade NHL: C-MOPP, BACOP, CHOP, CHOP-Bleo,
    ProMACE-MOPP, CHOP-Bleo + alpha interferon, COMLA, MINE, ESHAP,
    DHAP, EPOCH, CEPP, ProMACE-CytoBOM, ICE, COP-BLAM, CNOP, FND,
    MACOP-B, m-BACOD

Added in amendment 1 (\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--)

-   Intermediate grade NHL: VAPEC-B, IM-VP16

Added in amendment 2 (\-\-\-\-\-\-\-\-\-\-\-\-\-\--)

-   CF, cladribine

Monitoring Plan (Original Protocol)

1.  Baseline (Within 2 weeks of Enrollment)

History and Physical with Karnofsky Status; Lab -- CBC, Serum Chemistry
(Creatinine, Total Bilirubin, Na K, Cl, Bun, LDH, Urinalysis Thyroid
functions, HAMA);Tumor Staging consisting of Bone Marrow within 42 days
of entry; CT and other radiographs as needed of the chest, abdomen,
pelvis within 28 days of entry

2.  Days 0; Day 2, 3, or 4; and Day 7

> Whole body biodistribution, Whole body dosimetry, and calculation of
> therapeutic dose

3.  Treatment phase

CBC weekly for weeks 3-9, 13 & 25; Serum Chemistry weeks 3, 7, 13 & 25;
tumor restaging (physical examination, radiologic studies, and bone
marrow biopsy \[if positive at baseline\]) weeks 7,13, and 25; HAMA
weeks 7 & 25

4.  Follow-up (Every 13 weeks up to 2 years or until discontinuation)

> History and Physical with Karnofsky Status; CBC, Serum Chemistry,
> HAMA; Tumor restaging studies including radiologic evaluations and
> bone marrow biopsy

5.  Long-term follow-up: Disease status and vital status every 6 months

    Treatment Plan

The treatment 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 infusion contained 450 mg of tositumomab infused over
    70 minutes (includes a 10 minute flush) immediately followed by 5
    mCi (35 mg) of iodine I-131 tositumomab Iodine infused over 30
    minutes (includes a 10 minute flush).

-   Seven to 14 days later the therapeutic dose consisting of 450 mg of
    tositumomab was infused over 70 minutes (includes a 10 minute flush)
    immediately followed by the patient --specific mCi activity (35 mg)
    of iodine I-131 tositumomab 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 150,000/cu mm. Patients with platelet
    counts between 100,001 and 150,000/cu mm were administered a
    therapeutic dose calculated to deliver 65 cGy TBD. Obese patients
    were dosed based upon 137% of their lean body mass.

Dose Modifications

-   Obesity

Excessively obese patients (defined as patients weighing more than 137%
of the calculated lean body mass) the calculations to determine the
iodine I-131 tositumomab activity will be performed using an upper limit
of mass (maximum effective mass) based upon height and gender (Table for
determination of max effective mass included as Appendix 2 to the
protocol).

-   Baseline Thrombocytopenia

The administered dose for patients with platelet counts between 100,001
and 150,000/cu mm will be adjusted to deliver an estimated activity of
65cGy TBD. An additional adjustment for obesity may be performed, if
indicated.

-   Toxicity

    -   The infusion rate was to be decreased by 50% for fever of
        385.-38.9C, mild to moderate rigors, mild to moderate mucosal
        congestion/edema, [or]{.underline} 30-49% drop in systolic blood
        pressure

    -   The infusion was to be stopped until resolution of toxicity and
        then resumed at 25-50% of the original infusion rate for fever
        \>39C, severe rigors, severe mucosal congestion/edema,
        [or]{.underline} 50% decrease in systolic blood pressure.

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-   Patients who have not received at least 3 doses of SSKI, 3 doses of
    Lugol's solution, or 130 mg of potassium iodide at least 24 hours
    prior to the dosimetric dose, may not receive the dosimetric dose

-   Patients who are seropositive for HAMA at day 5 may not receive the
    therapeutic infusion.

Concomitant Medications

-   All patients were required to receive either Lugol's solution or
    potassium iodide tablets, beginning 24 hours before the dosimetric
    dose and continuing until 14 days after the last infusion of
    radiolabeled antibody.

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

# 

Analytic Plan (Original Protocol)

#### Primary and Secondary Endpoints

The primary efficacy endpoint for this study will be the Overall
Response Rate and duration established on this study.

Secondary efficacy endpoint analyses for this study will be survival,
time-to-progression, time-to-treatment failure established on this
study. Quality of life and safety analyses will also be included as
secondary endpoint analyses. In addition, the response rate, response
duration, time to progression and time to treatment failure will be
compared with the patient's last qualifying chemotherapy regimen.

# 

# Statistical Considerations

The proposed sample size of 60 patients was selected to enable response
rates to be estimated with a maximum standard error of 0.065.The
protocol stated that any patient who is enrolled but does not complete
both the trace and therapeutic dose of Anti-B1, will be replaced so that
a total of 60 radioimmunotherapy treated patients will be enrolled.
Projected completion of accrual was September 1997.

# Establishing of Response Rate, Best Response Rate and Duration Measures

Estimates of the rates of response, complete response and overall
response (complete, clinical complete and partial), will be estimated
from the study response rates. All acquired data will be analyzed by
intention-to-treat. Point estimates and two-sided 95% confidence
intervals will be calculated. One-sided 95% confidence intervals for
minimum response rates will also be calculated. Mean and median duration
response, time-to-progression, time-to-treatment failure, and survival
will be calculated. If the study evaluation is performed before all data
have reached their respective endpoints, right censored data for
duration estimates will be treated as independent censoring and
Kaplan-Meier survival estimates will be employed. Time-to-progression
analyses will treat patients' withdrawals and interventions for reasons
other that progression or death as independent censoring. Subgroup
analyses by number of previous therapies, time from diagnosis,
histology, and previous response will be performed.

# Efficacy Analyses: Patients As Their Own Control

Although the eligibility criteria restrict the study to patients who
completed their previous qualify chemotherapy regimen so that the
appropriate comparison is based on patients who complete treatment, all
acquired data will be analyzed by intention-to-treat methods. Two-sided
paired-sample tests of equivalency of the response rates following RIT
with the last previous qualifying chemotherapy response will be
performed at the 5% level. Paired t-test and non-parametric Wilcoxon
signed rank tests comparing the duration of response,
time-to-progression, and tine-to-treatment failure will be performed. If
right-censoring is present, pair-matched censored survival tests will be
performed. No stratification is present in the study as the patients as
their own control performs this function. Subgroup analyses by number of
previous therapies, time from diagnosis, histology, and previous
response will be performed.

Revised, Final Analytic Plan

The primary endpoint of the study was a comparison of the number of
patients having a longer duration of response (i.e., \>30 days longer)
after iodine I 131 tositumomab therapy compared to the number of
patients having a longer duration of response after their LQC regimen.
For the purposes of the primary efficacy endpoint, efficacy outcomes
after the LQC and iodine I 131 tositumomab therapies were assessed by
the MIRROR Panel. Secondary efficacy endpoints were response rate,
complete response rate, and time to progression or death.

The original sample size of 60 patients is adequate to detect a a
difference of 25% in the proportion of patients experiencing a longer
duration of response (greater than 30 days) when treated with iodine I
131 tositumomab therapy compared to the proportion of patients
experiencing a longer duration of response (greater than 30 days) to the
LQC.

There are two dichotomous treatment outcomes that are assessed in this
analysis

-   Durations equivalent- defined as [\<]{.underline} 30 days difference
    in response durations to Iodine I-131 tositumomab and to prior
    chemotherapy for an individual patients

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-   Durations non-equivalent- defined as \> 30 days difference in the
    durations of response to Iodine I-131 tositumomab and to prior
    chemotherapy.

Only the non-equivalent cases contribute to the test statistic in this
approach. The null hypothesis is that the durations of response are the
following the most recent chemotherapy regimen and following Iodine-131
Anti-B1 Antibody therapy.

##### Statistical Test Method - McNemar's test

The assumptions used in this trial were that the expected proportion of
patients responding to therapy decreases with each successive therapy.
Under this assumption, it is expected that the proportion of patients
responding to Iodine-131 Anti-B1 Antibody would be smaller than the
proportion of patients who responded to the most recent, preceding
chemotherapeutic regimen.

A test incorporating the expected decrease in response was named a
modified McNemar's test and, under the null hypothesis, the McNemar's
test statistic was expected to equal 0.375. This corresponds to 75% of
the 0.5 expected under the test, which ignores the order of therapies
described in the previous paragraph. A one-sided exact binomial test was
used.

![](media/image1.png){width="5.497916666666667in"
height="1.363888888888889in"}

The McNemar's test is a test of the equality of the probability of each
of these two groups. The response rate on the comparative chemotherapy
is equal to that on Iodine-131 Anti-B1 Antibody if the number of
patients in Group B equals the number of patients in Group C.McNemar's
test statistic equals the proportion of patients in Group C of the
patients in Group B or Group C. Under the null hypothesis, this equals
0.5.

Efficacy analyses were to be conducted on a modified intent-to-treat
basis, i.e., the analyses of efficacy include all patients who received
any portion of the study drug including only the dosimetric dose.

### MIRROR Panel

The MIRROR Panel was composed of two radiologists and two oncologists.
All were board certified in their respective disciplines. The panel
reviewed both patient radiographs and patient medical notes, while
masked to the investigators' assessments of response. Efficacy endpoints
include response rate, complete response rate, duration of response and
time to progression based on the MIRROR Panel independent review
assessment. The independent review process was coordinated by an
independent CRO. The representative from the CRO facilitated the review
process and ensured appropriate masking of the data and completion of
the CRFs.

Amendments to the protocol and dates of amendment

Amendment 1- \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

-   Expanded aims and objectives of the study defined the primary
    endpoint (overall response rate) and expanded the secondary
    endpoints to include 3 types of response rates (Best Response
    \[regardless of durability\], Response, and Prolonged Response),
    duration of unmaintained response, TTP, TTF, and survival. The
    results for each of these endpoints following Iodine I-131
    tositumomab would be compared to that observed following the LQC,
    except for survival.

-   Inclusion criteria modified to permit CD20 expression using any
    commercial antibody similar to the \-\-\-- or anti-B1 antibody; to
    allow for a limited exposure to treatment between the LQC and study
    entry, if the patient progressed on or after the intervening therapy
    and was enrolled within 6 months of completion of the LQC; added LDH
    \<500 IU/mL; required that all patients have measurable disease;
    required patients with intervening chemotherapy to provide
    radiographic studies documenting baseline, best response, and

Amendment 2 - \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

-   Aims and Objectives section revised to add the following "To compare
    the response rates, duration of responses, and time to treatment
    failure after 131-Iodine anti-B1 antibody RIT" to the patients
    previous qualifying chemotherapy outcome."

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-   Endpoints revised to read as follows: "The primary efficacy endpoint
    of the study is the comparison of the number of patients having a
    longer duration of response on Iodine-131 Anti-B1 antibody therapy
    to the number of patients having a longer duration of response on
    their last qualifying chemotherapy regimen. Secondary efficacy
    endpoint analyses are to establish response rates, complete response
    rates, time-to-progression, time-to-treatment failure, and survival
    established on this study. The comparison of the response rate and
    the TTF following RIT with the response rate and the time to
    treatment failure following the last qualifying chemotherapy regimen
    are additional secondary endpoint analyses. Qualify of life and
    safety analyses will also be included as secondary endpoint
    analyses. Survival will be analyzed following RIT only. "

-   Eligibility criteria modified to (1) delete requirement for testing
    tumor biopsy material for CD20 antigen expression, (2) require that
    patients must have failed to respond or progressed within 6 months
    of completion of any additional therapy (after last qualifying
    therapy but prior to study entry) (3) delete LDH \<500 IU/mL and WBC
    \>3500/mm^3^, (4) adds stated that "at least one lesion must be at
    least 2 cm diameter" to requirement that patients have
    bidimensionally measurable disease, (5) changes requirement for
    baseline radiographic study for evaluation of LQC and any interval,
    non-qualifying therapy, to be obtained with 10 weeks prior to
    initiation of that therapy \[previously required within 6 weeks
    prior to therapy\] and also requires that medical notes documenting
    the patient's course on the LQC must be available, (6) broadens
    exclusion criteria to exclude patients receiving approved or
    non-approved anti-cancer drugs or biologics (previously excluded
    only non-approved drugs) (7) deletes exclusion criterion for
    patients who have been exposed to non-human monoclonal or polyclonal
    antibodies \[such patients may be enrolled in seronegative for
    HAMA\]

-   Correction in of antibody dose administered based on more accurate
    protein measurement

-   Permits multiple use of Anti-B1 vials (i.e., to prepare doses for
    more than one patient from the same vial)

-   Treatment plan modified to require use of an in-line filter for
    infusion of study drug

-   Limits collection of information on concomitant medications to the
    first 12 weeks of study, unless medication used to treat a
    drug-related adverse experience

-   Revision of patient monitoring schema: (1) Expands follow-up for
    patients with disease progression. Patients who progress or have
    been followed without progression for 2 years will be evaluated
    every 6 months by physical exam and staging studies, evidence of
    toxicity (particularly pulmonary toxicity) and "thyroid function
    will be determined periodically"; (2) Adds 2 microglobulin to
    baseline and on-study evaluations; (3) Blood sampling for
    pharmacokinetic analyses to be performed at one study site
    (\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--); (4) States that
    HAMA assessment may be performed at study sites rather than by a
    central lab.

-   Modifies duration of assessment for serious adverse events from
    first 12 weeks on study to 12 weeks or administration of alternative
    therapy for lymphoma, whichever occurs first

-   Extensive changes to statistical analysis section, including brief
    description of the procedures for review of medical records and
    radiographs to assess response and response duration to LQC and to
    Iodine I-131 tositumomab.

-   Common Toxicity Criteria added as supplemental grading sale

-   Modifies criteria for LQC to state that patients must receive at
    least 2 cycles of combination chemotherapy or 6 weeks of single
    agent therapy of the LQC, allows addition of agents to single agent
    and combination regimens or deletion of a drug (that drug or drug in
    that class) from a combination regimen if patient is known to be
    intolerant of, or have disease that is refractory to, the drug.

Amendment 3 \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

-   Change title from "Phase II/III" to "Phase III"

-   Radiolabeled anti-B1 (dosimetric and therapeutic doses) shipped as
    patient-specific doses from \-\-\-\-\-\-\-\-\-\-\-\-\-\-- to the
    study site.

-   Definition of measurable disease modified in section of Response
    criteria to state "measurable lesions are defined as any lesion \>2
    cm in both perpendicular diameters at baseline."

-   Addition of cladiribine to LQC regimens

Amendment 4 \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

-   Inclusion criteria modified with regard to documentation of response
    to last qualifying regimen. Written documentation must be provided
    from the referring physician (i.e., copies of original medical notes
    and radiographic reports) specifying the agents in the LQC, the
    number of course administered, the start and stop dates of LQC, the
    response to LQC, the date of response to LQC if applicable, and the
    date that stable or progressive disease. The same written
    documentation must be provided for any intervening non-qualifying
    therapy. Written documentation to be submitted to Coulter with the
    eligibility checklist and prior to enrollment, the documentation
    will undergo independent review to ensure that it is adequate. In
    addition, all radiographic studies for assessment of disease status
    at baseline, at best response (if applicable), and at progressive
    disease must be supplied to
    \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
    for the LQC and any intervening non-qualifying chemotherapy regimen
    before the patient is enrolled. Evaluations that constitute evidence
    of disease progression after the last chemotherapy may also be used
    as the baseline for this study.

-   Revision in definition of TTF; treatment failure to include "the
    decision to seek additional therapy" as an event, in addition to
    treatment withdrawal, study removal, \[disease\] progression,
    alternative therapy for patient's lymphoma, or death.

Amendment 5 - \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

-   Revised study endpoints to specify that (1) the primary efficacy
    endpoint will be based on response and response duration as assessed
    by the independent review panel; (2) all efficacy analyses will be
    performed using both Investigator-assessed and masked, independent
    review panel-assessed data.

-   Modifies study population to state that any patient who is
    "determined to be HAMA-positive at baseline according to the
    validated, centralized HAMA assay will be replaced so that a total
    of 60 HAMA-negative patients who have received radioimmunotherapy
    will be enrolled."

-   Modifies eligibility criteria to (1) permit baseline neutrophil and
    platelet counts to be obtained within 14 days (from 7 days) of study
    entry; (2) require that patients with low-grade NHL that has
    undergone transformation to a higher grade histology must have been
    treated with a prior therapy for intermediate-grade lymphoma.
    Re-biopsy to rule out transformation and to confirm low grade
    histology will be required only for those patients who have not
    received appropriate therapy for intermediate-grade lymphoma.

-   Monitoring plan specifies thyroid function tests (total T3, free T4,
    and TSH) and timing of assessment (baseline, week 25, and at
    follow-up)

-   Deletes determination of "best" response rates and comparisons of
    "best" response rates between Iodine I-131 tositumomab and LQC.

-   Interim analysis plan expanded to state that analysis will include
    data on chemotherapy refractory status and on LQC as assessed by the
    independent review panel, percent of patients with non-equivalent
    durations of response following the LQC and Iodine I-131
    tositumomab. The percent of patients contributing to the primary
    endpoint analysis will be calculated. The sample size will be
    adjusted if the percent suggests that primary endpoints analysis sis
    underpowered.

-   Objectives for independent-review panel specified. They are to
    obtain an independent confirmation of investigator-assessed response
    to therapy (LQC and Iodine I-131 tositumomab) and to verify the
    investigator's assessment of each patient's chemotherapy refractory
    status.

Amendment 6 - \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

-   Eligibility criteria modified to (1) to state that patients must
    *objective* evidence of disease progression or failure to
    respond; (2) requirement for baseline creatinine changed from \<2.0
    mg/dL to \<1.5 times the upper limit of normal (ULN), requirement
    for baseline bilirubin changed from \<2.0 mg/dL to \<1.5 x ULN, and
    new requirement for AST and ALT \< 5 times ULN added.

-   Addition of CRO for data management responsibilities of independent
    review panel activities

Amendment 7 -- \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

-   Modifies endpoints and analytic plan to state that the Independent
    review panel only reviews the fully assess the comparison of
    duration of response (primary study endpoint). All efficacy analyses
    will be performed using the investigator assess and *when
    appropriate*, the masked, independent review panel-assessed data.

-   Study population modified at FDA's request to include all patients
    who received at least a portion of the dosimetric dose in the
    primary efficacy analysis. Patients who are HAMA-seropositive will
    not be replaced and these patients will be included in the efficacy
    analysis.

-   Revision of criteria for "removal from study". Patients with adverse
    experiences that "require discontinuation of therapy" will not be
    removed from study.

-   Definition of response revised from CR, CCR or PR confirmed by two
    separate response evaluations at least 4 weeks apart to "best
    response evaluation (ordered by CR, CCR, PR, SD, then PD) and does
    not require subsequent confirmation. Adds definition of "confirmed
    response" that requires CR, CCR or PR be confirmed by two separate
    response evaluations at least 4 weeks apart

-   Modification of definition of "intent-to-treat" population, adding
    the phrase "including all patients who received at least a portion
    of the dosimetric dose"

-   Appendix titled "Independent Review of Efficacy Data" deleted and
    replaced with "the Prior contents of the appendix have been
    superseded by the "Charter for the Independent Review of Efficacy
    and Chemotherapy-refractory Status in Study RIT-II-004".

Amendment 8 -- \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

-   Administrative changes reflecting acquisition of Coulter
    Pharmaceuticals by Corixa Corp.

-   Modification to plan for long-term follow-up (LTFU)- plan now
    requires TSH and HAMA testing every 12 months.

-   Modification to informed consent document describing risks of
    hypothyroidism as a delayed toxicity and of the additional testing
    requirements for LTFU.

Amendment to the Statistical analysis plan, not identified as a protocol
amendment in the BLA \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

-   The independent review of data was expanded from the assessment of
    the primary endpoint to include the assessments of secondary
    endpoints in study RIT-II-004 ("Expanded MIRROR Panel").

### STUDY RESULTS

Patient Disposition

Sixty-one patients were enrolled at 8 centers.

-   One patient (004-015-002) was not administered any study drug. The
    patient was enrolled on Feb. \-\--, 1997 and withdrew consent. The
    date of last follow-up for this patient is April 29, 1997.

-   60 patients received the dosimetric dose

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-   One patient (004-018-001) received the dosimetric dose; the patient
    was withdrawn from study for encephalopathy on study day 13 prior to
    receiving the therapeutic dose.

-   One patient (004-015-005) received the dosimetric dose but
    experienced an infusion‑related adverse experience on the day of the
    therapeutic dose infusion. The event occurred during administration
    of the unlabeled tositumomab, resulting in termination of treatment
    prior to administration of the radiolabeled portion of the
    therapeutic dose.

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-   58 patients received both the dosimetric dose and the therapeutic
    dose.

Study RIT-II-004: Enrollment by Protocol Amendment

+--------------------------+-----------------+--------------------------+
| **Submission**           | **Submission**  | **Cumulative Number of** |
|                          |                 |                          |
|                          | **Date**        | **Subjects Enrolled**    |
+--------------------------+-----------------+--------------------------+
| > **Original Protocol**  | **\-\-\-        | **4**                    |
|                          | \-\-\-\-\-\--** |                          |
+--------------------------+-----------------+--------------------------+
| > **Amendment 1**        | **\-\-\-        | **21**                   |
|                          | \-\-\-\-\-\--** |                          |
+--------------------------+-----------------+--------------------------+
| > **Amendment 2**        | **\-\-\-        | **22**                   |
|                          | \-\-\-\-\-\--** |                          |
+--------------------------+-----------------+--------------------------+
| > **Amendment 3**        | **\-\-\-        | **26**                   |
|                          | \-\-\-\-\-\--** |                          |
+--------------------------+-----------------+--------------------------+
| > **Amendment 4**        | **\-\-\-        | **53**                   |
|                          | \-\-\-\-\-\--** |                          |
+--------------------------+-----------------+--------------------------+
| > **Amendment 5**        | **\-\-\-        | **58**                   |
|                          | \-\-\-\-\-\--** |                          |
+--------------------------+-----------------+--------------------------+
| > **Amendment 6**        | **\-\-\-        | **61**                   |
|                          | \-\-\-\-\-\--** |                          |
+--------------------------+-----------------+--------------------------+
| > **Amendment 7**        | **\-\-\-        | **61**                   |
|                          | \-\-\-\-\-\--** |                          |
+--------------------------+-----------------+--------------------------+
| > **Amendment 8**        | **\-\-\-        | **61**                   |
|                          | \-\-\-\-\-\--** |                          |
+--------------------------+-----------------+--------------------------+
| > **Total Enrollment**   |                 | **61**                   |
+--------------------------+-----------------+--------------------------+

Conduct of the Study

FDA's review of the case report forms for study RIT-II-004 noted the
following unreported protocol violations of eligibility criteria for
Subject No: 004-014-001, 004-018-001 and 004-020-007. These violations
were discovered in the course of the review of case report forms.

The subject was enrolled on December \-\--, 1996. The subject received
fludarabine from June 3 through August 2, 1996. CT scan evaluations
obtained prior to fludarabine were interpreted by the MIRROR as an SPPD
of 66.66 cm². CT scans following fludarabine on Aug 21, 1996 were read
with an SPPD of 43.16 cm². Baseline enrollment CT scans on study entry,
December\-\--, 1996, were read with an SPPD of 22.00 cm², documenting a
decrease in the SPPD of 67%. Thus the subject had a PR to fludarabine at
study entry, in violation of the eligibility criteria.

004-018-001: This 39 yo female experienced rapidly progressive disease
through prior therapy. Prior treatment included cytarabine 1 gm/m^2^ and
etoposide 100 mg/m^2^ IV on days 1-5, administered on October \-\--,
(cycle 1) and November \-\-\--, 1996 (cycle 2). The second cycle was
complicated by catheter-related sepsis (Staph aureus) treated with
catheter removal. CBC, creatinine and liver functions were normal during
that admission. The patient was re-admitted for the dosimetric dose on
November \-\--,1996 (study day --2) with increasing pleural effusions.
Following administration of the dosimetric dose on Nov. \-\--, 1996 (day
0), she underwent thoracentesis and chest tube placement. On study day
6, the patient was noted to have hyperbilirubinemia and increased LFTs.
On Dec. \-\-- 1996 (study day 10), she was admitted for the therapeutic
dose with a history of increasing lethargy and 2-3 day history of
confusion described as "trouble finding the right words". Examination
reports extensive expressive and receptive dysphasia with slight
impairment of memory. The patient was mildly thrombocytopenic (77,000)
with worsening LFTs, notably LDH of 11, 640 IU/ml. A diagnosis of
hepatic encephalopathy was made on study day 12, with progressive
hepatic deterioration and death on study day 14.

004-020-007: 45 yo male with diagnosis of NHL in Dec. 1994 and multiple
chemotherapeutic regimens prior to study entry, received therapeutic
dose of 82 mCi (75 cGy TBD) on Jan \--, 1998. Baseline CBC (12/12/97)
revealed ANC 5.6, hemoglobin 12 gm/dL, and platelets 116,000. The
patient responded to treatment (apparent CR) but suffered persistent
thrombocytopenia through 1998 and 1999 with development of leukopenia in
1999 and a diagnosis of **MDS** in September 1999. The patient suffered
subdural hematoma in June 2000 (secondary to thrombocytopenia) and died
with progressive hemorrhage and hemoptysis on
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--.

Subjects for whom protocol violations were identified by the sponsor,
are summarized in the following table.

+-----------------+--------+---------+---+--------+------------------+
| **Patent ID**   | *      | *       | * | ###### | **Description**  |
|                 | *NHL** | *Dose** | * | ## Vio |                  |
|                 |        |         | S | lation |                  |
|                 | **sub  | **      | t |        |                  |
|                 | type** | (cGy)** | u | **     |                  |
|                 |        |         | d | type** |                  |
|                 |        |         | y |        |                  |
|                 |        |         | * |        |                  |
|                 |        |         | * |        |                  |
|                 |        |         |   |        |                  |
|                 |        |         | * |        |                  |
|                 |        |         | * |        |                  |
|                 |        |         | d |        |                  |
|                 |        |         | a |        |                  |
|                 |        |         | y |        |                  |
|                 |        |         | * |        |                  |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| Violation of    |        |         |   |        |                  |
| Eligibility     |        |         |   |        |                  |
| Criteria        |        |         |   |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-013-004   | **T**  | **75**  | * | **E    | **WBC = 2.9,     |
| 66F T75C**      |        |         | * | NTRY** | current protocol |
|                 |        |         | 0 |        | required \>3.5   |
|                 |        |         | * |        | but was being    |
|                 |        |         | * |        | amended**        |
+-----------------+--------+---------+---+--------+------------------+
| **004-016-002   | **T**  | **65**  | * | **E    | **WBC = 3.5,     |
| 80M T65C**      |        |         | * | NTRY** | current protocol |
|                 |        |         | - |        | required \>3.5   |
|                 |        |         | 1 |        | but was being    |
|                 |        |         | * |        | amended**        |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-016-009   | **T**  | **75**  | * | **E    | **Bone marrow    |
| 68M T75L**      |        |         | * | NTRY** | involvement      |
|                 |        |         | - |        | based on         |
|                 |        |         | 8 |        | unilateral       |
|                 |        |         | * |        | biopsy           |
|                 |        |         | * |        | (20-25%)**       |
+-----------------+--------+---------+---+--------+------------------+
| **004-013-017   | **T**  | **65**  | * | **E    | **Patient        |
| 65M T65L**      |        |         | * | NTRY** | received oral    |
|                 |        |         | 0 |        | prednisone 13    |
|                 |        |         | * |        | days prior to    |
|                 |        |         | * |        | study entry**    |
+-----------------+--------+---------+---+--------+------------------+
| **004-020-002   | **T**  | **75**  | * | **E    | **CT scans 29    |
| 50M T75C**      |        |         | * | NTRY** | days prior to    |
|                 |        |         | 0 |        | enrollment       |
|                 |        |         | * |        | (protocol        |
|                 |        |         | * |        | requires 28      |
|                 |        |         |   |        | days)**          |
+-----------------+--------+---------+---+--------+------------------+
| #               |        |         |   |        |                  |
| Violations of I |        |         |   |        |                  |
| nformed Consent |        |         |   |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-014-006   | **L**  | **75**  | * | **E    | **Verbal         |
| 48M L75L**      |        |         | * | NTRY** | informed consent |
|                 |        |         | - |        | given, not       |
|                 |        |         | 2 |        | signed until     |
|                 |        |         | * |        | after enrollment |
|                 |        |         | * |        | (9/4/97)**       |
+-----------------+--------+---------+---+--------+------------------+
| **004-018-001   | **T**  | **0**   | * | **E    | **Informed       |
| 39F T00C**      |        |         | * | NTRY** | consent not      |
|                 |        |         | - |        | approved by      |
|                 |        |         | 1 |        | ethics committee |
|                 |        |         | * |        | when signed**    |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| # Viola         |        |         |   |        |                  |
| tion of Eligibl |        |         |   |        |                  |
| e NHL Histology |        |         |   |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-021-001   | **I**  | **75**  | * | **E    | **Mantle cell,   |
| 51M I75C**      |        |         | * | NTRY** | pathology        |
|                 |        |         | 0 |        | re-read**        |
|                 |        |         | * |        |                  |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| # Violation     |        |         |   |        |                  |
| of Thyroid Prot |        |         |   |        |                  |
| ection Protocol |        |         |   |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-013-003   | **T**  | **65**  | * | #####  | **SSKI started   |
| 43M T65C**      |        |         | * | ## TRE | on same day as   |
|                 |        |         | 0 | ATMENT | dosimetric       |
|                 |        |         | * |        | dose**           |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-013-004   | **T**  | **75**  | * | *      | **Pt was started |
| 66F T75C**      |        |         | * | *TREAT | on SSKI plus     |
|                 |        |         | 0 | MENT** | potassium        |
|                 |        |         | * |        | perchlorate      |
|                 |        |         | * |        | rather than      |
|                 |        |         |   |        | protocol         |
|                 |        |         |   |        | regimen**        |
+-----------------+--------+---------+---+--------+------------------+
| **004-013-005   | **T**  | **75**  | * | *      | **SSKI started   |
| 63M T75L**      |        |         | * | *TREAT | on same day as   |
|                 |        |         | 0 | MENT** | dosimetric       |
|                 |        |         | * |        | dose**           |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-013-006   | **L**  | **75**  | * | *      | **SSKI started   |
| 38F L75L**      |        |         | * | *TREAT | on same day as   |
|                 |        |         | 0 | MENT** | dosimetric       |
|                 |        |         | * |        | dose**           |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-013-007   | **L**  | **75**  | * | *      | **SSKI started   |
| 55M L75L**      |        |         | * | *TREAT | on same day as   |
|                 |        |         | 0 | MENT** | dosimetric       |
|                 |        |         | * |        | dose**           |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-013-009   | **L**  | **75**  | * | *      | **SSKI started   |
| 61M L75L**      |        |         | * | *TREAT | on same day as   |
|                 |        |         | 0 | MENT** | dosimetric       |
|                 |        |         | * |        | dose**           |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-013-012   | **L**  | **75**  | * | *      | **SSKI started   |
| 66F L75L**      |        |         | * | *TREAT | on same day as   |
|                 |        |         | 0 | MENT** | dosimetric       |
|                 |        |         | * |        | dose**           |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-020-008   | **L**  | **65**  | * | *      | **Lugols         |
| 71M L65L**      |        |         | * | *TREAT | solution dosed   |
|                 |        |         | 0 | MENT** | at 5 gtts tid,   |
|                 |        |         | * |        | protocol         |
|                 |        |         | * |        | requires 20      |
|                 |        |         |   |        | gtts/day**       |
+-----------------+--------+---------+---+--------+------------------+
| **Violation of  |        |         |   |        |                  |
| Timing for Dose |        |         |   |        |                  |
| Assessment or   |        |         |   |        |                  |
| Administration  |        |         |   |        |                  |
| of Therapeutic  |        |         |   |        |                  |
| Dose**          |        |         |   |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-021-002   | **L**  | **65**  | * | #####  | **Therapeutic    |
| 51M L65L**      |        |         | * | ## TRE | dose given 15    |
|                 |        |         | 1 | ATMENT | days after       |
|                 |        |         | 5 |        | dosimetric       |
|                 |        |         | * |        | dose**           |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-029-003   | **L**  | **75**  | * | *      | **Second total   |
| 39M L75L**      |        |         | * | *TREAT | body count       |
|                 |        |         | 1 | MENT** | performed on day |
|                 |        |         | * |        | 1 and third on   |
|                 |        |         | * |        | day 5**          |
+-----------------+--------+---------+---+--------+------------------+
| #               |        |         |   |        |                  |
|  Violation of T |        |         |   |        |                  |
| herapeutic Dose |        |         |   |        |                  |
|  Administration |        |         |   |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-020-005   | **L**  | *       | * | ####   | **Calculated     |
| 66M L88L**      |        | *87.8** | * | ## TRE | dose 104 mCi,    |
|                 |        |         | 8 | ATMENT | actual dose 125  |
|                 |        |         | * |        | mCi**            |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-020-006   | **L**  | **75**  | * | *      | **Enrolled at 65 |
| 60M L75L**      |        |         | * | *TREAT | cGy, treated at  |
|                 |        |         | 8 | MENT** | 75 cGy**         |
|                 |        |         | * |        |                  |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+
| **004-020-007   | **L**  | **75**  | * | *      | **Enrolled at 65 |
| 45M L75L**      |        |         | * | *TREAT | cGy, treated at  |
|                 |        |         | 1 | MENT** | 75 cGy**         |
|                 |        |         | 4 |        |                  |
|                 |        |         | * |        |                  |
|                 |        |         | * |        |                  |
+-----------------+--------+---------+---+--------+------------------+

Financial Disclosure

Under 21 CFR 54, an applicant is required to certify all investigators
and consultants have disclosed any financial arrangements that could
influence the study outcome.

The following investigators disclosed one or more of the above types of
financial arrangements meeting:

-   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

FDA Assessment of Potential Conflicts- There was no evidence that the
data from these sites were significantly different from other study
sites or altered the results of the study.

Bioresearch Monitoring Inspection Results

Inspections of five clinical sites were performed in support of BLA
99-0813 for Protocol RIT-II-004 entitled "Multicenter, Pivotal Phase III
Study of Iodine-131 Anti-B1 Antibody (Murine) Radioimmunotherapy for
Chemotherapy-Refractory Low-Grade B-Cell Lymphomas and Low-Grade
Lymphomas that have Transformed to Higher Grade Histologies." In
addition one of the sites (University of Nebraska) was also 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. Data audits
were performed at the following five sites:

+---------------+---------------+---------------+---------------------+
| **Site**      | **I           | **Form 483**  | **Classification**  |
|               | nvestigator** |               |                     |
+---------------+---------------+---------------+---------------------+
| Kaiser -      | Dr.           | No            | VAI                 |
|               | Fehrenbacher  |               |                     |
| Vallejo       |               |               |                     |
+---------------+---------------+---------------+---------------------+
| Stanford      | Dr. Knox      | Yes           | VAI                 |
| University    |               |               |                     |
+---------------+---------------+---------------+---------------------+
| University of | Dr. Kaminski  | Yes           | VAI                 |
| Michigan      |               |               |                     |
+---------------+---------------+---------------+---------------------+
| University of | Dr. Press     | Yes           | VAI                 |
| Washington    |               |               |                     |
+---------------+---------------+---------------+---------------------+
| University of | Dr. Vose      | Yes           | VAI                 |
| Nebraska      |               |               |                     |
+---------------+---------------+---------------+---------------------+

[]{.mark}

[]{.mark}

Inspectional Summary Statement

The results of bioresearch monitoring inspections indicate that the
deviations are not substantive, with the exceptions noted (verification
of dose delivered), and that the submitted data can be considered
reliable and accurate.

Study Population:

The study population consists of low grade and follicular NHL;
approximately 1/3 of the patients have disease, which has transformed to
a higher histologic subtype. The population has been heavily pretreated
with chemotherapy (median number of prior regimens --4) but not
radiotherapy. None of the patients have undergone dose-intensive
chemotherapy with prior stem cell support. The majority had advance
disease (stage III and IV) and 11% have bulky lesions. The
characteristics of the population at study entry are summarized in the
following table.

### 

######### Baseline Characteristics for Patient Population in Study RIT‑II‑004

+----------------------------------------------+-----------------------+
| **Baseline Characteristic**                  | **ITT population**    |
|                                              |                       |
|                                              | **n=61**              |
+----------------------------------------------+-----------------------+
| Age (years)                                  |                       |
+----------------------------------------------+-----------------------+
| Median(range)                                | 59 (38-82)            |
+----------------------------------------------+-----------------------+
| Q1; Q3                                       | 52; 68                |
+----------------------------------------------+-----------------------+
| Gender                                       |                       |
+----------------------------------------------+-----------------------+
| Males (%)                                    | 38 (62%)              |
+----------------------------------------------+-----------------------+
| Race                                         |                       |
+----------------------------------------------+-----------------------+
| Caucasian (%)                                | 59 (97%)              |
+----------------------------------------------+-----------------------+
| Histologic diagnosis at entry                |                       |
+----------------------------------------------+-----------------------+
| W/o transformation                           |                       |
+----------------------------------------------+-----------------------+
| Low grade                                    | 37 (61%)              |
+----------------------------------------------+-----------------------+
| Intermediate grade                           | 1 (2%)                |
+----------------------------------------------+-----------------------+
| High grade                                   | 0                     |
+----------------------------------------------+-----------------------+
| With transformation                          |                       |
+----------------------------------------------+-----------------------+
| Low grade                                    | 0                     |
+----------------------------------------------+-----------------------+
| Intermediate grade                           | 23 (37%)              |
+----------------------------------------------+-----------------------+
| High grade                                   | 0                     |
+----------------------------------------------+-----------------------+
| Stage of disease                             |                       |
+----------------------------------------------+-----------------------+
| I                                            | 0                     |
+----------------------------------------------+-----------------------+
| II                                           | 1(2%)                 |
+----------------------------------------------+-----------------------+
| III                                          | 13 (21%)              |
+----------------------------------------------+-----------------------+
| IV                                           | 47 (77%)              |
+----------------------------------------------+-----------------------+
| Missing                                      | 0                     |
+----------------------------------------------+-----------------------+
| IPI category                                 |                       |
+----------------------------------------------+-----------------------+
| 0                                            | 0                     |
+----------------------------------------------+-----------------------+
| 1                                            | 7 (12%)               |
+----------------------------------------------+-----------------------+
| 2                                            | 22 (36%)              |
+----------------------------------------------+-----------------------+
| 3                                            | 22 (36%)              |
+----------------------------------------------+-----------------------+
| 4                                            | 7 (12%)               |
+----------------------------------------------+-----------------------+
| 5                                            | 1 (2%)                |
+----------------------------------------------+-----------------------+
| Missing                                      | 2 (3%)                |
+----------------------------------------------+-----------------------+
| Max. tumor diameter                          |                       |
+----------------------------------------------+-----------------------+
| \< 5 cm                                      | 25 (41%)              |
+----------------------------------------------+-----------------------+
| 5, [\<]{.underline}10 cm                     | 29 (48%)              |
+----------------------------------------------+-----------------------+
| \> 10 cm                                     | 7 (11%)               |
+----------------------------------------------+-----------------------+
| \# Prior chemo regimens                      |                       |
+----------------------------------------------+-----------------------+
| Median (range)                               | 4 (2-13)              |
+----------------------------------------------+-----------------------+
| 25^th^, 75^th^ quartiles                     | 3, 5                  |
+----------------------------------------------+-----------------------+
| \# Prior RT regimens                         |                       |
+----------------------------------------------+-----------------------+
| Median (range)                               | 0 (0-7)               |
+----------------------------------------------+-----------------------+
| 25^th^, 75^th^ quartiles                     | 0, 1                  |
+----------------------------------------------+-----------------------+
| No Prior BMT                                 | 61 (100%)             |
+----------------------------------------------+-----------------------+
| Time from diagnosis to entry (mos)           |                       |
+----------------------------------------------+-----------------------+
| Median (range)                               | 4.4 (0.8, 27.8)       |
+----------------------------------------------+-----------------------+
| 25^th^, 75^th^ quartiles                     | 2.6, 7.2              |
+----------------------------------------------+-----------------------+

Primary Efficacy Outcome:

The response to treatment and response duration for the most recent
qualifying chemotherapy regimen and for Iodine I-131 tositumomab was
determined by the Expanded MIRROR panel for 60 patients; data were not
reviewed for the patient who withdrew from study and received neither
the dosimetric nor therapeutic dose. There were 7 patients who responded
to the LQC for an ORR of 12% and a CR/CCR of 2%. There were 28 subjects
who responded to Iodine I-131 tositumomab for an ORR of 47% and a CR/CCR
of 20%. The response determinations by the MIRROR panel are summarized
in the table below.

+---------------------+------------------------+-----------------------+
| **Treatment         |                        |                       |
| Response by         |                        |                       |
| Expanded MIRROR     |                        |                       |
| Panel (Effoutm      |                        |                       |
| dataset)**          |                        |                       |
|                     |                        |                       |
| **According to      |                        |                       |
| Treatment for       |                        |                       |
| Patients enrolled   |                        |                       |
| in RIT-II-004**     |                        |                       |
+---------------------+------------------------+-----------------------+
| ####                | **Last Qualifying      | **IODINE I-131        |
| # Response Category | Chemotherapy**         | TOSITUMOMAB**         |
+---------------------+------------------------+-----------------------+
| Complete Response   | 1                      | 8                     |
+---------------------+------------------------+-----------------------+
| Complete Clinical   | 0                      | 4                     |
| Response            |                        |                       |
+---------------------+------------------------+-----------------------+
| Partial Response    | 6                      | 16                    |
+---------------------+------------------------+-----------------------+
| Stable Disease      | 5                      | 4                     |
+---------------------+------------------------+-----------------------+
| Progressive disease | 48                     | 28                    |
+---------------------+------------------------+-----------------------+
| Total Patients      | 60                     | 60                    |
+---------------------+------------------------+-----------------------+

There were 28 patients whose disease did not respond to either therapy
or for whom the duration of response to either therapy was roughly
equivalent (\< 30 days difference in the duration of response to either
treatment). This group was classified as "Duration Equivalent".

+-----------------+---------------------+----------------------+------+
|                 | **Response to**     | **No Response**      |      |
|                 |                     |                      |      |
|                 | **Iodine I-131      | **to Iodine I-131    |      |
|                 | tositumomab**       | tositumomab**        |      |
+-----------------+---------------------+----------------------+------+
| **Responded to  | 3                   | 4                    | 7    |
| LQC**           |                     |                      |      |
+-----------------+---------------------+----------------------+------+
| **No Response   | 25                  | **28**               | 53   |
| to LQC**        |                     |                      |      |
+-----------------+---------------------+----------------------+------+
|                 | 28                  | 32                   |      |
+-----------------+---------------------+----------------------+------+

The remaining 32 patients achieved an objective tumor response (CR, CCR,
or PR) following Iodine I-131 tositumomab, the last qualifying
chemotherapy regimen, with a difference in the durations of response to
Iodine I-131 tositumomab and to the last qualifying chemotherapy regimen
of more than 30 days. Among these 32 patients, 27patients experienced a
longer duration of response to Iodine I-131 tositumomab (difference in
the durations 30 days) as compared to the duration of response to last
qualifying chemotherapy regimen. This group of 27 consisted of 25
patients who failed to respond to the LQC but did respond to Iodine
I-131 tositumomab and 2 patients who responded to both the LQC and to
Iodine I-131 tositumomab but had a longer duration of response to Iodine
I-131 tositumomab than to LQC (difference in response durations 30
days).

+-----------------+---------------------+----------------------+------+
|                 | **Response to**     | **No Response**      |      |
|                 |                     |                      |      |
|                 | **Iodine I-131      | **to Iodine I-131    |      |
|                 | tositumomab**       | tositumomab**        |      |
+-----------------+---------------------+----------------------+------+
| **Responded to  | (**2** + 1)         | 4                    | 7    |
| LQC**           |                     |                      |      |
+-----------------+---------------------+----------------------+------+
| **No Response   | **25**              | 28                   | 53   |
| to LQC**        |                     |                      |      |
+-----------------+---------------------+----------------------+------+
|                 | (**27** + 1)        | 32                   |      |
+-----------------+---------------------+----------------------+------+

The remaining 5 patients experienced a longer duration of response to
the last qualifying chemotherapy regimen (difference in the durations 30
days) as compared to the duration of response to Iodine I-131
tositumomab. This group was comprised of 4 patients who responded to the
LQC but not to Iodine I-131 tositumomab and one patient who responded to
both the LQC and Iodine I-131 tositumomab, in whom the duration of
response to LQC was longer than to Iodine I-131 tositumomab.

+-----------------+--------------------+----------------------+--------+
|                 | **Response to**    | **No Response**      |        |
|                 |                    |                      |        |
|                 | **Iodine I-131     | **to Iodine I-131    |        |
|                 | tositumomab**      | tositumomab**        |        |
+-----------------+--------------------+----------------------+--------+
| **Responded to  | (2 + **1**)        | **4**                | 7 (2 + |
| LQC**           |                    |                      | **5**) |
+-----------------+--------------------+----------------------+--------+
| **No Response   | 25                 | 28                   | 53     |
| to LQC**        |                    |                      |        |
+-----------------+--------------------+----------------------+--------+
|                 | 28                 | 32                   |        |
+-----------------+--------------------+----------------------+--------+

##### 

##### Based on the Expanded MIRROR Panel assessment of response and response duration as described above, the following proportions were generated for use in the primary efficacy analysis: 

#####  

##### 28/60 (47%) patients had an equivalent duration of response 

##### 32/60 (53%) patients had a non-equivalent duration of response

-   27/32 (84%) patients had a longer duration of response to Iodine
    I-131 tositumomab

-   5/32 (16%) patients had a longer duration of response to the last
    qualifying chemotherapy regimen

Primary Efficacy Analysis

The primary efficacy endpoint of the study was the comparison, as
assessed by the Masked Independent Randomized Radiology and Oncology
Review (MIRROR) panel, of the number of patients having a longer
duration of response (i.e., more than 30 days) on their last qualifying
chemotherapy regimen to the number of patients having a longer duration
of response on IODINE I-131 TOSITUMOMAB™.

FDA followed the protocol defined primary endpoint and compared the
duration of response on I-131 Antibody therapy to prior chemotherapy.
The duration of response is linked with the response. If there is no
response (SD, PD) on both (Bexaar & Prior Chemo) then these patients
were classified as equivalent regardless of how long their Stable
Disease (in favor of either Iodine I-131 tositumomab or prior Chemo) was
or if they had a response (CR, CCR or PR), but the difference in the
duration of response between Bexaar and prior Chemo was lass than 30
days. There were 28 patients in this group. The remaining 32 patients
had a CR or CCR or PR on either therapy and the difference in the
duration of response was more than 30 days. There were 27 patients from
these 32 whose the duration of response was longer than 30 days on
Iodine I-131 tositumomab as compared to Prior Chemo, and 5 from these 32
whose duration of response was longer than 30 days on prior chemo as
compared to Bexaar.

Using this algorithm, the following table provides a summary of the
results for the primary endpoint for confirmed responses:

> Response Frequency % of 60

\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

> Equivalent duration 28 47 %
>
> Longer response with 27 45 %

Iodine I-131 tositumomab

Longer response with Chemo 5 8 %

The sign-rank test takes all data into account, equivalent as well as
non- equivalent cases, and tests the hypothesis that overall there is a
statistically change. Then two proportions can be compared.

**p \< 0.0001 using sign-rank test in favor of Bexaar.**

Analysis of Proportions

Let p~1~ = proportions of equivalent responses

p~2~ = proportions of responses favoring Iodine I-131 tositumomab

p~3~ = proportions of responses favoring prior chemotherapy

Of interest is to test the null hypothesis H~0~ : p~2~ = p~3~
conditioned on equivalent response, i.e., ignoring equivalent response,
and n becomes 32, and test is . H~0~ : p~2~ = p~3~ = 0.5 versus H~1~ :
p~2~ ≠ p~3\ .~ The p-value for testing this H~0~ is \< 0.0001 (Exact
Binomial test) **in favor of Bexaar**

**Note: FDA's analysis differs slightly from the analysis of the primary
efficacy endpoint as performed by the sponsor.**

While, FDA and the sponsor used different approaches to assess the
primary endpoint, the results of both tests were similar; both
demonstrating a highly significant increase in the durations of response
after Iodine I-131 tositumomab. The sponsor applied the one-sided exact
McNemar\'s test for comparing the number of patients with longer
response on Iodine I-131 tositumomab compared to the number of patients
with longer response on chemotherapy. This test only accounts for
patients with nonequivalent durations of response. FDA applied the
Wilcoxon signed rank test using all response duration data. As the
Wilcoxon signed rank test includes the magnitude of the duration of
response, it is more powerful in this study (as the higher response rate
after Iodine I-131 tositumomab is also associated with a longer duration
of response). The sponsor approach accounts for the paired censored
data. As the censored values were almost exclusively with the longest
durations of response, the censoring effect is minimal. Thus, while the
statistical approaches used by FDA and the sponsor differed, the
conclusions were similar.

##### 

##### Secondary Efficacy Outcomes

1.  Comparison of other efficacy outcomes between Iodine I-131
    tositumomab and LQC:

> The protocol identified several secondary endpoints, including
> comparisons between efficacy outcomes following Iodine I-131
> tositumomab as compared to the most recent qualifying chemotherapy
> regimen. These outcomes included comparisons of overall response
> rates, complete response rates, durations of overall response and of
> complete responses. For each of these analyses, the differences were
> in favor of Iodine I-131 tositumomab and were significantly different.

MIRROR Panel--Assessed Secondary Efficacy Endpoint Data:

Study RIT‑II‑004 (N = 60)

+--------------------------------+------------------+------------------+
| **Secondary Efficacy           | **Last           | **Iodine I 131   |
| Endpoints**                    | Qualifying       | tositumomab\     |
|                                | Chemotherapy\    | (N = 60)**       |
|                                | (N = 60)**       |                  |
+--------------------------------+------------------+------------------+
| **Overall Response Rate**      | **7/60 (12%)**   | **28/60 (47%)**  |
+--------------------------------+------------------+------------------+
| > **Median (95% CI) duration   | **4.1\           | **11.7\          |
| > of response for responders   | (3.0--5.4)**     | (6.9--NR)**      |
| > (months)**                   |                  |                  |
+--------------------------------+------------------+------------------+
| **Complete response Rate**     | **1/60 (2%)**    | **12/60 (20%)**  |
+--------------------------------+------------------+------------------+
| > **Median (95% CI) duration   | **4.8\           | **NR\            |
| > of response for complete     | **               | (12.5--NR)**     |
| > responders (months)**        |                  |                  |
+--------------------------------+------------------+------------------+

##### 

##### 

Exploratory Analyses

##### Subset analyses of the primary efficacy analysis in patients whose disease has undergone transformation and in patients whose disease has not undergone transformation to a higher histologic subtype of NHL. 

> Subset analyses were done comparing Last Qualifying Chemotherapy
> Response -- Original & Expanded MIRROR Assessed to Iodine I-131
> tositumomab Confirmed Response -- expanded MIRROR Assessed to evaluate
> if the original and expanded MIRROR assessment made any difference to
> the efficacy of the primary endpoint for each of the following two
> subset populations.

(1) Patients with low grade non-Hodgkin's lymphoma (NHL) that has not
    undergone transformation (36 patients) -- Not Transformed

(2) Patients with intermediate grade, follicular NHL that has not
    undergone transformation (1 patient)

(3) Patients with low grade non-Hodgkin's lymphoma (NHL) that has
    undergone transformation (23 patients) -- Transformed

> Last Qualifying Chemotherapy Response Versus Iodine I-131 tositumomab
> Confirmed Response -- expanded MIRROR Assessed
>
> Using previously defined algorithm, the following table provides a
> summary of the results of the subset analysis for the primary endpoint
> (the patient with an intermediate grade histologic subtype of NHL was
> not classified as not transformed, this patient was a non-responder):
>
> Low Grade/follicular Transformed
>
> Response Frequency % of 37 Frequency % of 23
>
> \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
>
> Equivalent response duration 11 30 % 17 74 %
>
> Longer duration with 22 59 % 5 22 %
>
> Iodine I-131 tositumomab
>
> Longer duration with Chemo 4 11 % 1 4 %
>
> p-value (sign-rank test) \<0.0001 0.0625
>
> **Conclusions:** There is a significant difference in favor of Iodine
> I-131 tositumomab for patients with low grade, untransformed NHL (p
> \<0.0001 ), but not significantly different in patients with NHL with
> transformation, (p=0.0625, trend in favor of Iodine I-131
> tositumomab). Iodine I-131 tositumomab activity is different in two
> sub-populations. The patients with NHL without transformation (all but
> one with low grade histologic subtype) benefit significantly more from
> Iodine I-131 tositumomab than transformed patients (p=0.0071, Fisher's
> exact test).

##### Assessment of response to Iodine I-131 tositumomab in patient subsets (patients with and without evidence of histologic transformation to a more aggressive (higher grade) histologic subtype. 

##### 

##### At the initiation of the study, the sponsor was urged to limit the patient population to a more homogeneous group. Specifically, the sponsor was asked to exclude subjects with evidence of histologic transformation since FDA felt this was a biologically different disease than low grade and follicular lymphoma. The sponsor declined, stating that evidence of histologic transformation was a prognostic factor but only one of many in this chemotherapy refractory population. As a result of these discussions, the protocol was to include a plan for analysis of the study results in patient subsets, i.e., those with and those without evidence of histologic transformation. As can be seen in the table below, the likelihood of achieving a response was much lower in the transformed subset. 

+-----------------+-------------------------+-------------------------+
| Response        | Response Rate in Subset | Response Rates in       |
|                 | without Transformation  | Subset with             |
| Category        |                         | Transformation          |
|                 |                         |                         |
|                 |                         | N =23                   |
+-----------------+-------------------------+-------------------------+
| CR              | 14% (5/37)              | 13%(3/23)               |
+-----------------+-------------------------+-------------------------+
| CCR             | 11% (4/37)              | 0 (0/23)                |
+-----------------+-------------------------+-------------------------+
| PR              | 38% (14/37)             | 8% (2/23)               |
+-----------------+-------------------------+-------------------------+
| ORR             | 62% (23/37)             | 21% (5/23)              |
+-----------------+-------------------------+-------------------------+
| SD              | 8% (3/37)               | 4% (1/23)               |
+-----------------+-------------------------+-------------------------+
| PD              | 30% (11/37)             | 74% (17/23)             |
+-----------------+-------------------------+-------------------------+

1.  Analyses of response according to I-131 dose administered

> The dose of 131-Iodine administered was derived for each subject. This
> exploratory analyses were conducted to assess for relationships
> between response to Iodine I-131 tositumomab treatment and the total
> dose of 131-I administered or the dose adjusted for body mass or
> surface area administered. The results are presented in the table
> below.

2.  During the course of the study, the source of the tositumomab
    antibody was changed from \-\-\-\-\-\-- to Coulter. The antibodies
    from the different manufacturing sites were biochemically comparable
    and yielded a similar pharmacokinetic profile. A comparison of the
    response rates by antibody-source showed a slightly higher but not
    significantly different response rate for the
    \-\-\-\-\-\--manufactured antibody product than for the
    Coulter-manufactured product.

+------------------------+-------------------+------------------------+
| **I-131-B1 Therapy     |                   |                        |
| Response Assessment    |                   |                        |
| by**                   |                   |                        |
|                        |                   |                        |
| **Antibody             |                   |                        |
| Manufacturer**         |                   |                        |
+------------------------+-------------------+------------------------+
| **Antibody             | **Overall         | **Total number of      |
| Manufacturer**         | Response Rate**   | patients treated**     |
|                        |                   |                        |
|                        | **(No.            |                        |
|                        | re                |                        |
|                        | sponders/total)** |                        |
+------------------------+-------------------+------------------------+
| **Coulter-manufactured | 35% (7/20)        | 20                     |
| antibody**             |                   |                        |
+------------------------+-------------------+------------------------+
| **\-\-\-\-\            | 52% (21/40)       | 40                     |
| -\-\-\--manufactured** |                   |                        |
|                        |                   |                        |
| **antibody**           |                   |                        |
+------------------------+-------------------+------------------------+
| **Total**              | 46% (28/60)       | 60                     |
+------------------------+-------------------+------------------------+

The following figure illustrates the relative comparison of the duration
of response for each patient following treatment with their LQC and
following treatment with iodine I 131 tositumomab. On the left side of
the figure are data from 5 patients with a longer duration of response
for the LQC; in the center there are data from 29 patients with less
than 30 days difference in the duration of response; and on the right
side of the figure are data from 26 patients with a longer duration of
response after iodine I 131 tositumomab.

### Figure: Paired Comparison of Duration of Response

###  

![](media/image2.wmf){width="4.884027777777778in"
height="2.732638888888889in"}

Safety Assessment

The most common and the most severe adverse events were hematologic
toxicities. The following are the most common non-hematologic
toxicities: asthenia (57%), fever (38%), nausea (37%), increased cough
(30%), pain (25%), anorexia (25%), vomiting (22%), diarrhea (22%),
abdominal pain (20%), chills (18%), infection (17%), and dyspnea (15%).
The non-hematologic toxicities were predominantly mild to moderate in
severity. The hematologic toxicities were predominantly severe (grade 3
or 4 according to the NCI CTC) and prolonged in nature. The profile of
the hematologic toxicity is summarized in the following table.

**Per-Patient Incidence of**

**Grade 3-4 Hematologic Toxicity**

+----------------------------------------------------+-----------------+
| **Hematologic Toxicity**                           | **Efficacy      |
|                                                    | studies**       |
|                                                    |                 |
|                                                    | **n=229**       |
+----------------------------------------------------+-----------------+
| **Neutropenia**                                    |                 |
+----------------------------------------------------+-----------------+
| \% Documented Grade 3-4 toxicity                   | 59%             |
+----------------------------------------------------+-----------------+
| Median days to nadir (95% CI)                      | 42 (41, 45)     |
+----------------------------------------------------+-----------------+
| 25^th^ and 75^th^ percentiles for days to nadir    | 39 ; 47         |
+----------------------------------------------------+-----------------+
| Median duration of documented Grade 3-4 toxicity   | 30 (22, 43)     |
+----------------------------------------------------+-----------------+
| 25^th^ and 75^th^ percentiles for duration of      | 21; 49          |
| toxicity (days)                                    |                 |
+----------------------------------------------------+-----------------+
| ##                                                 |                 |
+----------------------------------------------------+-----------------+
| ##### Thrombocytopenia                             |                 |
+----------------------------------------------------+-----------------+
| \% Documented Grade 3-4 toxicity                   | 48%             |
+----------------------------------------------------+-----------------+
| Median days to nadir (95% CI)                      | 34 (32, 35)     |
+----------------------------------------------------+-----------------+
| 25^th^ and 75^th^ percentiles for days to nadir    | 28; 40          |
+----------------------------------------------------+-----------------+
| Median duration of documented Grade 3-4 toxicity   | 29 (23, 40)     |
+----------------------------------------------------+-----------------+
| 25^th^ and 75^th^ percentiles for duration of      | 22; 43          |
| toxicity (days)                                    |                 |
+----------------------------------------------------+-----------------+
| ##### Anemia                                       |                 |
+----------------------------------------------------+-----------------+
| \% Documented Grade 3-4 toxicity                   | 19%             |
+----------------------------------------------------+-----------------+
| Median days to nadir (95% CI)                      | 48 (42, 55)     |
+----------------------------------------------------+-----------------+
| 25^th^ and 75^th^ percentiles for days to nadir    | 39; 60          |
+----------------------------------------------------+-----------------+
| Median duration of documented Grade 3-4 toxicity   | 22 (6, 36)      |
+----------------------------------------------------+-----------------+
| 25^th^ and 75^th^ percentiles for duration of      | 16; 36          |
| toxicity (days)                                    |                 |
+----------------------------------------------------+-----------------+

Serious Adverse Events (SAE)

There were 23 SAE reported in 17 (28%) patients. An additional 4
patients (7% of the study population) developed MDS. A summary of these
events are provided below

-   004-013-001- 69 yo male who presented with dyspnea, right-sided
    pleuritic chest pain, dry cough and fatigue on study day 68. The
    patient was not febrile and ANC was 1.7. A VQ scan was
    indeterminate. The patient was treated with antibiotics and coumadin
    (for presumptive diagnoses of **pneumonia** and/or **pulmonary
    embolism**)

-   004-013-002- 62 yo female hospitalized on study day 75 with
    productive cough and wheezing. The patient was afebrile and ANC was
    normal. The patient was treated for **exacerbation of COPD** and
    **bronchitis**, with symptomatic improvement.

-   004-013-005- 63 yo male developed rapidly progressive disease,
    particularly a cervical mass with compression of local structures.
    The patient was removed from study on day 20. On study day 30, he
    was admitted with fever, non-productive cough, anemia and
    thrombocytopenia (ANC was grade 0). The presumptive diagnosis was
    **aspiration pneumonia**. The patient also required platelet and RBC
    transfusions. He did not respond to antibiotic therapy with
    persistent fevers and progressive disease. He died on study day 43.

-   004-015-005- 59 yo male who admitted for his therapeutic infusion on
    study day 8. The infusion was interrupted three times severe
    Infusional toxicity within 5 minutes of the initiation of infusion
    on each attempt. The infusion reactions consisted of severe rigors,
    tachycardia to 133 pbm, and on the last attempt, temperature of 39.4
    in conjunction with severe rigors. The patient was observed
    overnight and remained afebrile. A pre-infusion HAMA was negative; a
    post-infusion attempt HAMA was not obtained. Although not identified
    as an SAE, this would appear to represent a significant **allergic
    reaction** requiring in-patient observation. The patient never
    received the radiolabeled portion of the therapeutic dose. The
    patient was subsequently hospitalized on study day 20 for
    **pneumonia**. The patient was hospitalized on study day 91 for a
    second episode of **pneumonia** and anemia requiring 5 units pRBCs
    (discharged with hemoglobin on 8.5 gmn/dL). The patient had evidence
    of persistent anemia and received additional pRBC transfusions and a
    course of epoietin therapy (study days 111-181). The patient had
    several subsequent admissions for bronchitis and pneumonia prior to
    removal from study on day 168 for disease progression.

-   004-013-010: 53 yo male developed shaking chills and fever to 39.1 C
    the evening of the dosimetric dose infusion. The fever and chills
    resolved. The patient was admitted for the therapeutic dose and
    again experience fever and shaking chills that evening. The patient
    was subsequently diagnosed with **catheter-related sepsis** on study
    day 16 after continued fevers and development of tenderness at the
    port-a-cath site. The patient was admitted for catheter removal on
    study day 23 and was noted to be hypoxic. A diagnosis of **P.
    carinii pneumonia** was made and he was treated with antibiotics
    including high dose Bactrim. On study day 42, the patient developed
    pancytopenia, requiring transfusions, filgrastim, and dose-reduction
    of Bactrim; cytopenias recovered by study day 62.

-   004-013-013: 55 yo female who was diagnosed with superior vena cava
    syndrome secondary to thrombosis (attributed to catheter) on study
    day 28

-   004-013-017: 62 yo male admitted on study day 21 for **abdominal
    distention, constipation, and left sided chest pain**. The etiology
    of these complaints remains unclear. The patient was also admitted
    on study day 47 for **anemia** requiring transfusions
    (intermittently until patient left study on day 60) and on study day
    56 for thoracentesis. The patient was withdrawn from study on day 57
    for progression disease.

-   004-014-002: 58 yo female admitted on study day 13 and 22 for
    **severe pain, pitting edema of the extremities due to disease
    progression**. The patient **died** of progressive disease on day
    41.

-   004-014-007: 58 yo female who was removed from study on day 24 for
    disease progression and **died** on study day 79

-   004-015-003: 59 yo male was hospitalized for therapeutic dose
    administered on study day 9 and developed new onset **atrial
    flutter** on study day 12. Patient under successful conversion to
    normal sinus rhythm on study day

-   004-015-006: 71 yo female fell on study day 77 and **fractured her
    right hip**. Post-operative course complicated by persistent fevers
    and confusion. Patient was discharged from study on day 110 due to
    the intervening medical complications and died at home on study day
    136.

-   004-106-001: 62 yo male with normal platelet count of 160,000, ANC
    2.5 and hemoglobin on study day 0. On the day of therapeutic
    infusion, platelet count was 140,000. Patient was dosed at 75mCi TBD
    based on day 0 CBC. The patient experience transient cytopenias days
    34-42. On study day 131, patient was admitted with **febrile
    neutropenia** and **pancytopenia**. Subsequent course complicated
    by H. simplex infection. The patient was treated with filgrastim and
    transfusion support. Recovery of counts was documented on study day
    167.

-   004-016-003: 45 yo female with multiple chemotherapeutic regimens
    prior to entry, received 75cGy TBD in May 1997. The patient had an
    ongoing CR as of September 1999 with normal CBC, however
    cytogenetics were abnormal on bone marrow aspirate in Oct. 1999.
    Patient has had repeated abnormal cytogenetics with normal CBC as of
    August 2000. This patient has a diagnosis of evolving **MDS**.

-   004-016-004: 55 yo male admitted on study day 73 with **intractable
    nausea and vomiting, dehydration and renal failure.** The patient
    was removed from study on day 77. The etiology of the protracted
    vomiting was felt to be due to disease progression and the patient
    subsequently received additional chemotherapy.

-   004-016-007: 61 yo male with multiple prior chemotherapeutic
    regimens who received 75 cGy TBD in August 1997. The patient was
    platelet and RBC transfusions intermittently between September and
    December 1997. The patient had persistent thrombocytopenia
    (45,000-78,000) throughout 1998 and 1999. Although disease
    progression was documented in 1998, he received no additional
    treatment for NHL. A diagnosis of **MDS** was made in Jan. 2001.

-   004-016-008: 72 yo female presented with **worsening of pre-existing
    peripheral neuropathy** (burning leg pain bilaterally) on study
    day 20. Symptoms persisted and worsened despite outpatient medical
    management in a pain clinic. The patient was admitted on study day
    74 with intractable pain from arthralgias, myalgias, and neuropathy.
    Management during hospitalization not well described; the patient
    was discharged on study day 81 on gabapentin with improvement in
    pain. Pain was persistent at study day 188.

-   004-016-011: 75 yo female with a history of prior SVT (on
    therapeutic anticoagulation) and a history of dyspnea on exertion on
    study day --1. The patient continued to have dyspnea, which
    progressed over time and was attributed to disease progression
    (including chest wall mass and recurrent pleural effusion) following
    treatment. The patient was hospitalized on study day 52 for
    **increasing dyspnea** attributed the chest wall mass causing
    restriction, and to a lesser degree, recurrent pleural. Although
    "cardiomegaly" is reported by sponsor, narrative summary states that
    LVEF was normal and heart was normal size. The patient was
    discharged to hospice and died on study day 61.

-   004-018-001: This 39 yo female experienced rapidly progressive
    disease through prior therapy. Prior treatment included cytarabine 1
    gm/m^2^ and etoposide 100 mg/m^2^ IV on days 1-5, administered on
    October \-\--, (cycle 1) and November \-\-\--, 1996 (cycle 2). The
    second cycle was complicated by catheter-related sepsis (Staph
    aureus) treated with catheter removal. CBC, creatinine and liver
    functions were normal during that admission. The patient was
    re-admitted for the dosimetric dose on November \-\--,1996 (study
    day --2) with increasing pleural effusions. Following administration
    of the dosimetric dose on Nov. \-\--, 1996 (day 0), she underwent
    thoracentesis and chest tube placement. On study day 6, the patient
    was noted to have hyperbilirubinemia and increased LFTs. On Dec.
    \-\-- 1996 (study day 10), she was admitted for the therapeutic dose
    with a history of increasing lethargy and 2-3 day history of
    confusion described as "trouble finding the right words".
    Examination reports extensive expressive and receptive dysphasia
    with slight impairment of memory. The patient was mildly
    thrombocytopenic (77,000) with worsening LFTs, notably LDH of 11,
    640 IU/ml. A diagnosis of hepatic encephalopathy was made on study
    day 12, with progressive hepatic deterioration and death on study
    day 14.

-   004-020-007: 45 yo male with diagnosis of NHL in Dec. 1994 and
    multiple chemotherapeutic regimens prior to study entry, received
    therapeutic dose of 82 mCi (75 cGy TBD) on Jan \-\--, 1998. Baseline
    CBC (12/12/97) revealed ANC 5.6, hemoglobin 12 gm/dL, and platelets
    116,000. The patient responded to treatment (apparent CR) but
    suffered persistent thrombocytopenia through 1998 and 1999 with
    development of leukopenia in 1999 and a diagnosis of **MDS** in
    September 1999. The patient suffered subdural hematoma in June 2000
    (secondary to thrombocytopenia) and died with progressive hemorrhage
    and hemoptysis on \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--.

-   004-020-008: 62 yo male with a diagnosis of NHL in November 1995. He
    received multiple chemotherapeutic regimens prior to study entry in
    Jan. \--, 1998. The patient received the therapeutic dose of 96 mCi
    (65 cGy TBD) on Jan \--, 1998. Pretreatment CBC revealed ANC 1.8
    hemoglobin 10.8 and platelet count of 104,000. The most recent prior
    chemotherapy regimen was CHOP/CNPP which was discontinued on Dec.
    11,1996. The patient achieved a PR to 131-Iodine tositumomab but
    progressed on study day 392. Subsequent therapy included a single
    course (4 weekly doses) of Rituxan. The patient's CBC was reported
    to be "normal" in June 2000, but abnormal in November 2000. A
    diagnosis of **MDS** was made in Jan. 2001.

-   004-029-001: 72 yo male enrolled on Jan \-\--, 1998 with a ANC of
    2.8, hemoglobin of 16.0 gm/dL, and platelets 134, 000 (most recent
    chemotherapy completed August 1997). The patient received the
    dosimetric dose on Jan \-\--, 1998 and a therapeutic dose of 66 mCi
    (65 cGy TBD) on January \-\--, 1998. The patient was hospitalized
    for anuria on study day 85 due to **bilateral obstructive
    hydronephrosis**, treated with percutaneous nephrostomy. He
    simultaneously developed bilateral lower extremity edema; in the
    evaluation of this, a diagnosis of **bilateral DVT** was made. On
    study day 90, the patient underwent cystoscopy (reason not provided)
    and a diagnosis of lymphoma invading the bladder was made.