# Presentation: 109581

## Presented at the 

**March 13, 2003**
**Oncologic Drugs Advisory Committee**
**meeting**
**By**
**Stephen Howell, M.D.**
**Skyepharma, Inc.**

## DepoCyte® (cytarabine liposome injection):  NDA 21-041

**Sustained release formulation of cytarabine (ara-C) developed in 1987**
**Ara-C is encapsulated in the chambers of 20 ********m particles made up of phospholipids and cholesterol**
**After intrathecal injection the particles spread throughout the neuraxis and slowly release ara-C over 2 – 3 weeks**
**Indication: lymphomatous meningitis**
**Accelerated approval date: April 1, 1999**
**Total drug development time: 11 years**

***DepoCyte******®****** (cytarabine liposome injection):  NDA 21-041***

## Basis of approval: High response rate in patients with lymphomatous meningitis

## Clinical trials in NDA

**Solid Tumor Neoplastic**
** ****Meningitis**
**61 Patients**

**Lymphomatous Meningitis**
**33 Patients**

**Leukemia Meningitis**
**5 Patients**

**Phase I**
**19 Patients**

**European PK Study**
**13 Patients **

**Phase IV**
** ****89 Patients**

**Confirmatory PK Study**
**11 Patients **

## Post-marketing commitment

**A controlled, randomized trial ****to determine the patient benefit and safety of DepoCyt for the treatment of solid tumor neoplastic and lymphomatous meningitis**
**Trial to include a pharmacokinetic substudy**
**Trial to be initiated within 6 months**
**Total elapsed time: ******** 4.5 years**

**4.5 yrs**

## SKY0101-010 controlled trial – Objective

**Purpose:**
**Confirm the “clinical benefit” of DepoCyt treatment for patients with lymphomatous and solid tumor neoplastic meningitis**
**Provide additional evidence to support approval for solid tumor neoplastic meningitis**
**Design: prospective, randomized controlled**
**Primary endpoint: time to neurological progression**
**Secondary endpoints:**
**Survival**
**Improvement in neurological symptoms**
**Quality of life**
**Cytologic response rate**
**Safety**
**Interim assessment dropped**

## SKY0101-010 controlled trial – Eligibility criteria

**Biopsy proven lymphoma or malignant solid tumor**
**Neoplastic meningitis diagnosed on basis of:**
**A positive CSF cytology within 21 days  prior to randomization, OR  **
**Characteristic signs and symptoms and an MRI or CT scan showing meningeal tumor**
**Age ********18 years**

## SKY0101-010 controlled trial – Schematic

## SKY0101-010 controlled trial – Schematic for patients with solid tumor neoplastic meningitis 

## SKY0101-010 controlled trial – Schematic for patients with lymphomatous meningitis

## SKY0101-010 controlled trial – Evaluation

**Neurological evaluation prior to treatment and at the beginning of each treatment cycle plus at each follow up visit**
**Detailed documentation of the basis for concluding that neurological progression has occurred**
**CSF cytology and chemistries at start of and end of each cycle**
**Adverse events occurring from 21 days prior to start of treatment through 28 days after last dose**

## Primary statistical analyses planned

**Analysis #1**

**All patients randomized to DepoCyt (solid tumor & lymphoma)**

**All patients randomized to compator drug (either MTX or ara-C) (solid tumor & lymphoma)**

**Analysis #2**

**Solid tumor patients randomized to DepoCyt**

**Solid tumor patients randomized to  MTX**

**Powered to detect a 50% reduction in the hazard function for time to neurologic progression in patients with solid tumor neoplastic meningitis. Estimated number of events necessary = 75**
****** ****= 0.8,  ******** = 0.038 (adjusted for multiple comparisons)**

## Post-marketing trial execution

**Trial set up began immediately after approval**
**Investigator selection, IRB approvals, and contracts completed and trial opened 10/99**
**All DepoCyt recalled from market 10/99:**
**No product available for clinical trials for 17 mo**
**FDA approved re-introduction 3/01**
**Trial re-initiation began immediately in 3/01**
**Investigator selection/site qualification**
**IRB approval**
**Contract negotiation**
**First patient entered 7/3/01**

## Original and revised timelines are the same

**Start**
**7/01**

**Enrollment complete 8/04**

**Report complete 8/05**

**2001**

**2002**

**2003**

**2004**

**2005**

**2006**

**Drug availabale 3/01**

**4.5 yr**

**17 mo**

**4.1 yr**

## Product recall

**Oct 1999: some lots of DepoCyt found to release excess cytarabine on stability testing**
**Raw material supplier made unannounced change in manufacturing process of one lipid that eliminated small amount of EDTA**
**EDTA replaced, product again available March 2001**
**New assays to assure quality of raw materials established**

## SKY0101-010 – Current patient accrual

**Total study sites: 37**
**USA - 16 **
**EU - 19**
**Canada - 2 **
**Total patients entered: 57**
**Solid tumor - 43**
**Lymphoma - 14**
**Accrual rate  to date ******** 2.4 patients/mo**
**Accrual rate last 6 months ******** 4.7 patients/mo**
**Accrual rate of prior pivotal trial 2.9 patients/mo**

## SKY0101-010 – Current patient accrual

**Total patients entered: 57**
**USA/Canada - 38**
**Solid tumor - 26**
**Lymphoma –12**
**Europe - 19**
**Solid tumor - 17**
**Lymphoma - 2**

## Challenges to study completion

**Very limited number of cases/yr**
**Only a small fraction available for trial participation**
**Trial participation vs off-study treatment**
**Randomization reluctance:**
**Patient concern about possibility of having to receive 4 intrathecal injections (standard therapy) vs just 1 injection every 2 weeks (DepoCyt)**
**Competition for patients**
**Other drugs under development for this indication**

## THANK YOU