## DESCRIPTION OF THE PRODUCT

## Tositumomab & iodine I 131 tositumomab RadioImmunoTherapy 

Iodine I 131 tositumomab is a radioimmunotherapeutic agent developed for
the treatment of patients with multiply relapsed/refractory,
CD20‑positive B‑cell, low‑grade non-Hodgkin's lymphoma (NHL), with or
without transformation.

The product consists of unlabeled and radiolabeled murine monoclonal
antibodies, referred to as anti‑B1 antibody and iodine I 131 anti‑B1
antibody, respectively. The approved USAN names are:

-   tositumomab for the unlabeled anti-B1antibody

-   iodine I 131 tositumomab for the labeled antibody.

Tositumomab (anti-B1 antibody) is an IgG~2a,~ murine monoclonal antibody
that binds to the CD20 antigen on the surface of normal and malignant
human B cells. Iodine I 131 tositumomab therapy is believed to produce
its cytotoxic effect through through the effects of ionizing radiation;
the extent to which immune-mediated cytotoxic activity contributes to
this effect is unknown.

## Composition of Tositumomab & iodine I 131 tositumomab RadioImmunoTherapy

Bexxar therapy is theCorixa's proposed trade name for a treatment
regimen that includes the combination of the unlabeled IgG2a anti‑CD20
murine monoclonal antibody (tositumomab), and the same IgG2a anti‑CD20
antibody radiolabeled with iodine 131 (iodine I 131 tositumomab).

## 

## Dosing Regimen

Description of Dosing Regimen

In clinical studies, the selection of the iodine I 131 tositumomab dose
was individualized; each patient's dose was based upon a
patient-specific biodistribution profile and the dose needed to deliver
65-76 cGy to known tumor sites.

The stated goal of this dosing method was to achieve an improved
therapeutic index by maximizing the radiation dose to the lymphoma and
controlling toxicity.

Figure 1 is a schematic presentation of the dosing methodology for
iodine I 131 tositumomab therapy.

Figure 1: Iodine I 131 Tositumomab Therapy

![](media/image1.wmf){width="5.979861111111111in"
height="1.7201388888888889in"}

### Figure 2: Calculation of Patient-Specific Dose for Iodine I 131 Tositumomab Therapy 

A patient‑specific activity of iodine I 131 tositumomab therapy is
calculated for each patient using the following equation.

  ---------------------- ------------------- ------- ----------------------
  Dose (mCi) =           Activity Hours (mCi X       Prescribed Total Body
                         h)                          Dose (cGy)

                         Residence Time (h)          75 cGy
  ---------------------- ------------------- ------- ----------------------

The methodology for determining the activity of iodine I 131 tositumomab
in millicuries (mCi) to be administered to the patient involves the
following steps:

1.  Administration of the dosimetric dose of iodine  131 tositumomab
    therapy.

2.  Acquisition of total body radiation counts on three separate days
    (Day 0,\
    Day 2--4, and Day 6--7) with a gamma camera and using the
    information to determine individual patient clearance rate of
    iodine 131.

3.  Determination of the Area-under-the-Curve using tables provided by
    Corixa.

4.  Determination of the Residence Time using worksheets provided by
    Corixa.

5.  Determination of the patient-specific activity (total mCi dose)
    using the formula.

**Rationale for Dosing Regimen**

The use of iodine I 131 tositumomab and the dosing regimen were based on
preclinical and clinical data summarized below.

Preclinical Information

Preclinical studies demonstrated that

-   Localization of iodine I 131 tositumomab was B‑cell specific, based
    upon data from preclinical toxicology studies (repeat dose study in
    \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--) and the open literature.

-   Iodine 131 was excreted primarily in the urine based upon from
    general knowledge and published literature. No specific study
    conducted by the sponsor.

-   B cells were decreased after treatment with iodine I 131 tositumomab
    based upon data from preclinical toxicology studies (repeat dose
    study in \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--).

-   There were no significant drug-related effects on the number of
    T cells based upon data from preclinical toxicology studies (repeat
    dose study in \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--).

-   Tumor uptake of iodine I 131 tositumomab was increased after
    predosing with unlabeled tositumomab based upon data published in
    from reference 29 (Cancer Research \'92) used anti-B1 antibody.

## 

Clinical Data in Support of proposed dosing regimen

Maximum tolerated, non-myeloablative, total-body dose (TBD)

The **maximum tolerated, non-myeloablative, total-body dose (TBD)** was
established in the Phase 1 Study RIT‑I‑000 using a standard
dose-escalation schedule evaluating doses beginning at 25 cGy and
increasing by 10‑cGy increments until the dose‑limiting toxicity (DLT)
was reached. Two of three patients had DLT at 85 cGy TBD. Thus, the
maximum tolerated total body dose was determined to be 75 cGy. This dose
(75 cGy) was further attenuated for obese patients and patients with
lower pre‑therapy platelet counts.

[Dose Adjustment for obese patients]{.underline}

[Summary]{.underline}: The **dose for obese patients** was adjusted to
137% of their calculated lean body mass. The adjustment was introduced
to account for the fact that obese patients can be modeled as an outer
shell of fat with little radioantibody accumulation in the region
surrounding the lean body mass.64 Clinical data were consistent with
this model in that 2 of 3 obese patients who received an unattenuated
dose of 75 cGy developed Grade IV thrombocytopenia and Grade IV
neutropenia. By comparison, of 14 obese patients who received an
attenuated dose of 75 cGy to the lean body mass, only 2 (14%) developed
Grade IV thrombocytopenia and 3 (21%) developed Grade IV neutropenia.

> [TBD Reduction for Obesity]{.underline}
>
> Identification of a higher incidence of hematologic toxicity in obese
> patients and patients with baseline thrombocytopenia led to dose (TBD)
> reduction for these two groups of subjects. These two TBD reductions
> were introduced in Amendment 3 of study RIT-II-001 in
> \-\-\-\-\-\-\-\-\-\--.
>
> To examine the effect of these dose reductions, hematologic data were
> analyzed from subjects in studies RIT-I-000, RIT-II-001, RIT-II-002
> (Arm A and crossover), and RIT-II-004 who received the relevant TBD.
> It is noted that subjects from RIT-II-003 were excluded from analyses
> because they had not received chemotherapy and, therefore, would not
> be expected to have a comparable incidence of hematologic toxicity.
>
> The following table summarizes the hematologic toxicity observed (by
> NCI CTC grade) for obese patients who received a 75 cGy TBD as an
> adjusted or unadjusted dose. Obesity was defined as exceeding 137% of
> the lean body mass (Ref. 2). The weight limit by height was defined by
> the following equations:
>
> **Gender Definition**
>
> **Males** Obese if weight (kg) \>65.76 + 1.452 (height in cm -- 152)
>
> **Females** Obese if weight (kg) \>62.34 + 1.247 (height in cm -- 152)
>
> Seventeen subjects dosed at 75 cGy TBD were classified as obese.
> Fourteen subjects received an attenuated dose based on 137% of their
> calculated lean body mass and 3 subjects did not receive an attenuated
> dose but were dosed based on the total body mass.
>
> A reduction in the incidence of Grade IV hematologic toxicity was
> noted with the dose attenuation. Of the subjects not receiving an
> attenuated dose, 2 of 3 (67%) subjects developed Grade IV
> thrombocytopenia, 2 of 3 (67%) subjects developed Grade IV
> neutropenia, and 2 of 3 (67%) subjects developed Grade IV anemia. Of
> the subjects receiving an attenuated dose, 2 of 14 (14%) subjects
> developed Grade IV thrombocytopenia, 3 of 14 (21%) subjects developed
> Grade IV neutropenia, and 0 of 14 (0%) subjects developed Grade IV
> anemia.

+---------------------------------------+---------------+---------------+
| **Hematologic toxicity in obese       |               |               |
| patients according**                  |               |               |
|                                       |               |               |
| **to dose (adjusted or unadjusted     |               |               |
| dose)**                               |               |               |
+---------------------------------------+---------------+---------------+
| **NCI CTC Grade**                     | **TBD         | **No TBD**    |
|                                       | Reduced**     |               |
|                                       |               | **Reduction** |
|                                       | **(n=14)**    |               |
|                                       |               | **(n=3)**     |
+---------------------------------------+---------------+---------------+
| **WBC ( x 1000 cells/mm^3^)**         |               |               |
+---------------------------------------+---------------+---------------+
| 0 (nadir ≥4.0)                        | 1 (7%)        | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 1 (nadir 3.0 to \<4.0)                | 3 (21%)       | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 2 (nadir 2.0 to \<3.0)                | 8 (57%)       | 1 (33%)       |
+---------------------------------------+---------------+---------------+
| 3 (nadir 1.0 to \<2.0)                | 1 (7%)        | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 4 (nadir \<1.0)                       | 1 (7%)        | 2 (67%)       |
+---------------------------------------+---------------+---------------+
| **Platelets ( x 1000 cells/mm^3^)**   |               |               |
+---------------------------------------+---------------+---------------+
| 0 (nadir ≥150)                        | 1(7%)         | 1 (33%)       |
+---------------------------------------+---------------+---------------+
| 1 (nadir 75 to \<150)                 | 5 (36%)       | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 2 (nadir 50 to \<75)                  | 6 (43%)       | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 3 (nadir 25 to \<50)                  | 0 (0%)        | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 4 (nadir 10 to \<25)                  | 1 (7%)        | 1 (33%)       |
+---------------------------------------+---------------+---------------+
| 4+ (nadir \<10)                       | 1 (7%)        | 1 (33%)       |
+---------------------------------------+---------------+---------------+
| **Hemoglobin (g/dL)**                 |               |               |
+---------------------------------------+---------------+---------------+
| 0 (nadir ≥12.0)                       | 6 (43%)       | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 1 (nadir 10.0 to \<12.0)              | 5 (36%)       | 1 (33%)       |
+---------------------------------------+---------------+---------------+
| 2 (nadir 8.0 to \<10.0)               | 2 (14%)       | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 3 (nadir 6.5 to \<8.0)                | 1 (7%)        | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 4 (nadir \<6.5)                       | 0 (0%)        | 2 (67%)       |
+---------------------------------------+---------------+---------------+
| **ANC (x 1000 cells/mm^3^)**          |               |               |
+---------------------------------------+---------------+---------------+
| 0 (nadir ≥2.0)                        | 2 (14%)       | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 1 (nadir 1.5 to \<2.0)                | 1 (7%)        | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 2 (nadir 1.0 to \<1.5)                | 7 (50%)       | 1 (33%)       |
+---------------------------------------+---------------+---------------+
| 3 (nadir 0.5 to \<1.0)                | 1 (7%)        | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 4 (nadir 0.1--0.5)                    | 3 (21%)       | 0 (0%)        |
+---------------------------------------+---------------+---------------+
| 4+ (nadir \<0.1)                      | 0 (0%)        | 2 (67%)       |
+---------------------------------------+---------------+---------------+

Dose Adjustment in the prescribed TBD for patients with baseline
platelet counts between 100,000 cells/mm^3^ and 149,999 cells/mm^3^

[Summary:]{.underline} The **adjustment in the prescribed TBD for
patients with baseline platelet counts between 100,000 cells/mm^3^ and
149,999 cells/mm^3^** was based on data that suggested that these
patients sustained a higher incidence of Grade III/IV hematological
toxicity when treated with 75 cGy. Of 20 patients who received an
unattenuated dose of 75 cGy, 8 (40%) developed Grade IV thrombocytopenia
and 6 (30%) developed Grade IV neutropenia. Of the 38 patients who
received an attenuated dose of 65 cGy, 11 (29%) developed Grade IV
thrombocytopenia and 10 (26%) Grade IV neutropenia.

> [TBD Reduction for Thrombocytopenia]{.underline}
>
> Dose reduction to 65 cGy TBD was selected by the sponsor for subjects
> with baseline thrombocytopenia, defined as platelet count between
> 100,000 cells/mm^3^ and 149,999 cells/mm^3^.
>
> Fifty-eight subjects were enrolled with baseline platelets between
> 100,000 cells/mm^3^ and 150,000 cells/mm^3^ and received either a 65
> or 75 cGy TBD. Thirty-eight subjects received a 65 cGy TBD, the
> proposed reduction in TBD for this subgroup, and 20 subjects received
> a standard 75 cGy TBD. A reduction in the incidence of Grade IV
> hematologic toxicity was noted with the dose reduction.
>
> The following table summarizes the maximum hematologic toxicity grade
> for all subjects who entered with platelet counts between 100,000
> cells/mm^3^ and 150,000 cells/mm^3^ according to dose (attenuated
> \[65cGy\] or unadjusted dose.

+------------------------+----------------------+---------------------+
| **Hematologic toxicity |                      |                     |
| in thrombocytopenic    |                      |                     |
| patients according**   |                      |                     |
|                        |                      |                     |
| **to dose (adjusted    |                      |                     |
| vs. unadjusted dose)** |                      |                     |
+------------------------+----------------------+---------------------+
| **NCI CTC Grade**      | **Attenuated Dose    | **Non-Attenuated    |
|                        | \[65 cGy\]**         | \[75cGy\]**         |
|                        |                      |                     |
|                        | **n=38**             | **n=20**            |
+------------------------+----------------------+---------------------+
| **WBC** (1000          |                      |                     |
| cells/mm^3^)           |                      |                     |
+------------------------+----------------------+---------------------+
| 0 (nadir ≥4.0)         | 2 (5%)               | 0 (0%)              |
+------------------------+----------------------+---------------------+
| 1 (nadir 3.0 to \<4.0) | 9 (24%)              | 2 (10%)             |
+------------------------+----------------------+---------------------+
| 2 (nadir 2.0 to \<3.0) | 7 (18%)              | 5 (25%)             |
+------------------------+----------------------+---------------------+
| 3 (nadir 1.0 to \<2.0) | 16 (42%)             | 9 (45%)             |
+------------------------+----------------------+---------------------+
| 4 (nadir \<1.0)        | 4 (11%)              | 4 (20%)             |
+------------------------+----------------------+---------------------+
| **Platelets (x 1000    |                      |                     |
| cells/mm^3^)**         |                      |                     |
+------------------------+----------------------+---------------------+
| 0 (nadir ≥150)         | 0 (0%)               | 0 (0%)              |
+------------------------+----------------------+---------------------+
| 1 (nadir 75 to \<150)  | 6 (16%)              | 3 (15%)             |
+------------------------+----------------------+---------------------+
| 2 (nadir 50 to \<75)   | 10 (26%)             | 4 (20%)             |
+------------------------+----------------------+---------------------+
| 3 (nadir 25 to \<50)   | 11 (29%)             | 5 (25%)             |
+------------------------+----------------------+---------------------+
| 4 (nadir 10 to \<25)   | 8 (21%)              | 6 (30%)             |
+------------------------+----------------------+---------------------+
| 4+ (nadir \<10)        | 3 (8%)               | 2 (10%)             |
+------------------------+----------------------+---------------------+
| **Hemoglobin (g/dL)**  |                      |                     |
+------------------------+----------------------+---------------------+
| 0 (nadir ≥12.0)        | 10 (26%)             | 3 (15%)             |
+------------------------+----------------------+---------------------+
| 1 (nadir 10.0 to       | 11 (29%)             | 10 (50%)            |
| \<12.0)                |                      |                     |
+------------------------+----------------------+---------------------+
| 2 (nadir 8.0 to        | 7 (18%)              | 3 (15%)             |
| \<10.0)                |                      |                     |
+------------------------+----------------------+---------------------+
| 3 (nadir 6.5 to \<8.0) | 9 (24%)              | 3 (15%)             |
+------------------------+----------------------+---------------------+
| 4 (nadir \<6.5)        | 1 (3%)               | 1 (5%)              |
+------------------------+----------------------+---------------------+
| **ANC (x 1000          |                      |                     |
| cells/mm^3^)**         |                      |                     |
+------------------------+----------------------+---------------------+
| 0 (nadir ≥2.0)         | 6 (16%)              | 1 (5%)              |
+------------------------+----------------------+---------------------+
| 1 (nadir 1.5 to \<2.0) | 5 (13%)              | 1 (5%)              |
+------------------------+----------------------+---------------------+
| 2 (nadir 1.0 to \<1.5) | 8 (21%)              | 4 (20%)             |
+------------------------+----------------------+---------------------+
| 3 (nadir 0.5 to \<1.0) | 9 (24%)              | 8 (40%)             |
+------------------------+----------------------+---------------------+
| 4 (nadir 0.1--0.5)     | 9 (24%)              | 4 (20%)             |
+------------------------+----------------------+---------------------+
| 4+ (nadir \<0.1)       | 1 (3%)               | 2 (10%)             |
+------------------------+----------------------+---------------------+

#### 

Effect of administering unlabeled tositumomab

The **effect of administering unlabeled tositumomab** prior to the
administration of labeled antibody was evaluated in the first
25 patients in Study RIT‑I‑000. Patients received either 0, 95 or 475 mg
of unlabeled antibody as a pre-dose with a 10‑mg dose of labeled
antibody. Total body residence times (TBRTs) (i.e., rate of clearance of
iodine I 131 tositumomab) of radioactivity were longer in those patients
who received the larger pre‑dose so that a lower administered activity
(mCi) of iodine I 131 tositumomab was needed to deliver the prescribed
total body dose of radiation. In addition, there was a trend toward
improved tumor targeting with iodine I 131 tositumomab in patients with
splenomegaly or high tumor burden who received the larger pre‑dose.
Based on these results, all subsequent patients received a total protein
dose of 485 mg (Note: the dose of the labeled antibody in the dosimetric
dose was increased to 35 mg because up to a 35‑mg dose of labeled
antibody was required for the therapeutic dose. The majority of the
patients studied received a predose of 450‑mg of unlabeled antibody
prior to the dosimetric dose.).

Administration of a patient-specific administered activity

**Administration of a patient-specific administered** **activity** was
chosen by the sponsor because the clearance of radioimmunoconjugates has
been observed to be highly variable from patient to patient. The
variability in TBRT correlates with known and measurable parameters,
such as body weight, tumor cell mass and spleen mass. Therefore, in the
sponsor's opinion, the radiation dose can only be determined from
individualized, total-body dosimetry.

Figure 3. demonstrates the range in the mCi dose required to deliver a
target total body dose (TBD) of 75 cGy.

#### Figure 3: mCi Required to Deliver 75 cGy (N = 608)

![](media/image2.wmf){width="4.498611111111111in"
height="3.1868055555555554in"}