# Presentation: 677920

## FDA Presentation

**to the **
**Oncologic Drugs Advisory**
**Committee**
- Tositumomab Therapeutic Regimen
- Corixa Corporation
**BLA 125011**
- December 17, 2002

## Tositumomab Therapeutic Regimen Review Team

- Product/Chairperson:	Terrye G. Zaremba, Ph.D.
- Clinical Reviewers:	Stephen Litwin, M.D.
- 					George Mills, M.D.
- 					Harvey Luksenburg, M.D.
- 					Kaushikkumar Shastri, M.D.
- Biostatistician:		Satish Misra, Ph.D.
- Pharm/Tox:		Martin D. Green, Ph.D.
- Radiochemistry:		Leon Epps, Ph.D.
- BioResearch Monitor:	Mary Andrich, M.D.
- Facilities Specialist:	Deborah Trout, B.S.
- Project Managers:	Karen Jones, B.S.
- 					Craig Doty, Pharm. D
- 					Michael A. Noska, M.S** **

## Submission Time-Line

**Sept 14, 2000-  BLA 125011 submitted**
**RIT-II-004- 5/31/2000 study report**
**RIT-II-000 and 001- final study reports**
**RIT-II-002 and 003-interim study reports**
**ISS - 286 subjects**
**Dec 14, 2000**
**CP98-020 interim study report**
**ISS - 308 subjects**

## Timeline (2)

**March 16, 2001 – **_**FDA Action letter #1**_
**Multiple requests for info on product characterization and manufacture**
**Inadequate efficacy database -single pivotal trial with substantially different efficacy in transformed vs. non-transformed, some supportive data submitted as interim reports**
**Inadequate safety database - substantial missing data for acute heme toxicity and delayed hematologic, thyroid and HAMA events**

## Timeline (3)

**August 27, 2001**
**RIT-II-003 second interim report through 12/20/2000**
**ISS update – 309 patients**
**Sept 7, 2001**
**Final study report CP97-012**
**Amended study report RIT-II-002 - MIRROR panel review, data cut-off Jan. 2001**

## Timeline (4)

**Sept 10, 2001- Corixa response to FDA letter **
**Dec 11, 2001**
**RIT-II-004- amended final study report, data cutoff Jan 2001, MIRROR panel review Sept 2001**
**ISS update – 620 patients (includes 387 from expanded access)**
**Long-term responders- various studies- MIRROR panel review**
**Additional info for CP98-020**

## Timeline (5)

**March 5, 2002**
**ISS update: corrected errors &  gave additional hematology data collected from audit at clinical study sites in 620 pts**
**March 12, 2002- **_**FDA action letter #2**_
**Need to demonstrate a meaningful therapeutic advance over existing treatment (Zevalin approved Feb. 2002)**
**Additional safety data needed**

## Timeline (6)

**July 2, 2002**
**Case report forms and report tabulations for long-term responder subpopulation**
**July 11, 2002**
**Revised  proposed indication**
**Requested accelerated approval for chemo-refractory and standard approval for Rituximab-refractory pts**
**Amendment 1 to final study report for CP97-012**

## Timeline (7)

**October 4, 2002**
**Amendment 2 to final study report for CP97-012**
**October 30, 2002**
**Independent review for additional patients with transformed histology in CP 97-012 **
**October 31, 2002 – Corixa completes response to FDA 3/12/2002 letter**

## Timeline (8)

**December 10, 2002 –Responses to Bi Mo inspectional findings**
**Outstanding issues on clinical trial **
**identification of dose delivered vs. dose prescribed for patients in efficacy studies**
**FDA will need to confirm safety profile of proposed dose**

## Tositumomab Therapeutic Regimen (TTR)Monoclonal Antibody Characteristics

**Tositumomab and I-131-Tositumomab**
**Tositumomab also called “Anti-B1”**
**Murine IgG****2a****, l**
**Recognizes CD20**

## Characteristics of CD20

**Transmembrane phosphoprotein with a molecular weight of 33-37 kDa**
**Present on the surface of pre-B and mature B cells**
**Expressed on >90% of B-cell lymphomas**
**Not present on stem cells, mature plasma cells, or other nonlymphoid normal tissues**
**Is not shed or internalized upon antibody binding**

## Monoclonal Antibody Characteristics (2) 

** ****Manufactured by standard tissue culture and purification techniquees**
** ****I-131- Tositumomab radiolabeled by the IODO-GEN****®**** method**

## Slide 14

## TTR  Components

**Unlabeled:**
- 	-**Tositumomab 3 mL vial: 35 mg @ 14 mg/mL**
- 	**-Tositumomab 20 mL vial: 225** **mg @ 14 mg/mL**

## TTR Components (2)

**Labeleld (I-131-Tositumomab**
**Dosimetric vial: not less than 20 mL in a 30 mL vial.  Protein concentration between 0.10 and 0.25 mg/mL.  Calibrated activity of 12-18 mCi.**
**Therapeutic vial: not less than 20 mL in a 30 mL vial.  Protein concentration between 1.1 and 2.5 mg/mL.  Calibrated activity of 112-168**

## TTR  Procedure

**Step 1 – Imaging**
**Tositumomab 450 mg in 0.9% NaCl injection in total volume of 50 mL IV over 60 minutes**
**I-131 Tositumomab (dosimetric) 5 mCi + 35 mg Tositumomab in 0.9% NaCl injection in total volume of 30 mL IV over 20 minutes**

## TTR  Procedure

**Step 2 - Therapy (7-14 days post imaging)**
**Tositumomab 450 mg in 0.9% NaCl injection in total volume of 50 mL IV over 60 minutes**
**I-131-Tositumomab (therapeutic) 35 mg containing the patient-specific dose (mCi) IV over 20 minutes**

## TTR  Procedure

**Thyroid protective agent is given beginning at least 24 hours ****prior to the first infusion of I-131 Tositumomab (dosimetric dose) and continues for 14 days following the last infusion of I-131 Tositumomab (therapeutic dose).**

## Remaining CMC Issues

**A number of manufacturing issues remain to be resolved**
**One contract facility remains to be inspected**