6 February 2003



Karen M. Templeton-Somers, Ph.D.

Supervisory Health Science Administrator

Advisors and Consultants Staff


HFD-21, Room 1093

5630 Fishers Lane

Rockville, MD 20852-1734

RE: NDA 21-041 DepoCyt® Phase IV Commitments

Dear Dr. Somers:

As requested in your letter dated January 23, 2003, enclosed are 40 copies (and 2 electronic copies in Microsoft Word) of the background package for the Oncologic Drugs Advisory Committee meeting scheduled March 12-13, 2003. SkyePharma will be presenting and update on its Phase IV commitments of NDA 21-041, DepoCyt (cytarabine liposome injection) for the intrathecal treatment of lymphomatous meningitis.

As requested, both the paper and electronic copies have been marked "AVAILABLE FOR PUBLIC DISCLOSURE IWTHOUT REDACTION" as described in the Guidance for Industry "Disclosing Information Provided to Advisory Committees in Connection with Open Advisory Committee Meetings Related to the Testing or Approval of New Drugs and Convened by the Center for Drug Evaluation and Research, Beginning on January 1, 2000."

Speakers and presenters from SkyePharma are as follows:

Gordon L. Schooley, Ph.D. Stephen B. Howell, M.D.

Senior Vice President Professor of Medicine

Global Clinical and Regulatory Affairs Director, Cancer Pharmacology Program

SkyePharma Inc. University of California, San Diego

Please let me know if you require any further information in preparation for the ODAC meeting.




Gordon L. Schooley, Ph.D.

Sr. Vice President

Global Clinical and Regulatory Affairs





  1. General Information
    1. Drug Name: DepoCyt® (cytarabine liposome injection)
    2. Indication: DepoCyt is indicated for the intrathecal treatment of lymphomatous meningitis. Neoplastic meningitis is an orphan indication with an estimated incidence of 1,200 cases/year.
    3. Accelerated Approval Date: April 1, 1999. DepoCyt was approved on the basis of a pivotal trial in 28 patients with lymphomatous meningitis supported by data from a Phase 1 trial (19 patients), two additional pharmacokinetic trials (11 and 13 patients), and a randomized prospective controlled trial (61 patients) and subsequent open-label trial (89 patients) in patients with solid tumor neoplastic meningitis.
  2. Description of Commitment including titles of individual studies

SkyePharma committed to conducting a Phase IV Post-Marketing study (Protocol C0101-010) and a pharmacokinetic sub-study titled "A randomized clinical study to determine the patient benefit and safety of DepoCyt (Cytarabine Liposomal Injection) for the treatment of solid tumor neoplastic and lymphomatous meningitis." These studies were to be initiated within six (6) months. The original estimated dates for the study timeline are as follows:


Start date: September 1999

Interim Analysis: 4th Quarter 2001 (after 50% of events)

Enrollment Completion: September 2003

SkyPharma also estimated 6 months for final data analysis and 3 months for study report completion.

The following amendments were made to the Protocol:

    1. The Pharmacokenetic study was in incorporated into the Phase IV Post-Marketing study (Protocol C0101-010).
    2. Protocol was subsequently categorized as a Phase III/IV study, so as to simultaneously pursue an indication in patients with solid tumor neoplastic meningitis. The title of the amended study is "A randomized phase III/IV clinical study to determine the patient benefit and safety of DepoCyt (cytarabine liposome injection) for the treatment of neoplastic meningitis".

    4. Sample size was changed from approximately 100 patients total to enroll patients until 75 patients with solid tumor neoplastic meningitis achieved the clinical endpoint of neurological progression or death. This is estimated to be a total of 110 patients.
    5. The interim analysis was eliminated.
    6. Addition of European clinical study sites.
    7. Stratified randomization for North America vs. Europe.
  1. Study Details
    1. Essentials of Study Design

1. Summary of Study Sites

Forty-three (43) study sites are currently participating in the Phase III/IV trial. A summary of participating sites is in Appendix 1:

    1. 18 study sites are currently participating in the U.S.
    2. 2 study sites are currently participating in Canada
    3. 24 study sites are currently participating in Europe

2. Patient Population

The trial is open to adult patients with lymphomatous or solid tumor neoplastic meningitis documented within 21 days of randomization by either:

    1. positive CSF cytology for lymphoma or solid tumor neoplasm OR
    2. characteristic signs and symptoms of neoplastic meningitis PLUS an MRI or CT scan indicating the presence of meningeal tumor.

3. Endpoints

The primary endpoint is progression-free survival defined as the time to neurological progression or death.

4. Treatment Schema

Lymphoma patients are randomized (1:1) to DepoCyt or cytarabine. Solid tumor patients are randomized (1:1) to DepoCyt or methotrexate. Randomization is further stratified by region (U.S. vs. Europe). Treatment consists of two phases: 6 Induction cycles (2 weeks per cycle) and 4 Maintenance cycles (4 weeks per cycle). DepoCyt patients are treated once at the beginning of each Induction cycle and once at the beginning of each Maintenance cycle. Cytarabine and methotrexate patients are treated twice per week during Induction and once per week during Maintenance. At the completion of treatment, all patients are followed monthly through 1 year after study entry and bi-monthly for the following 12 months for neurological assessments.

5. Efficacy and Safety Monitoring

CSF cytology, laboratory assessments, and neurological assessments prior to each treatment cycle. In addition, adverse events are monitored through 30 days following the start of the patient’s final treatment cycle.

6. Statistical Design

The study is designed to have an 80% power of detecting a 50% reduction in the rate at which solid tumor patients suffer neurological progression. The estimated number of necessary events is 75. Accrual of both solid tumor and lymphomatous meningitis patients will continue until 75 solid tumor patients have suffered neurologic progression or have died. Anticipated total accrual of patients with either lymphomatous or solid tumor neoplastic meningitis is 110 based on the observation that approximately two-thirds of the patients accrued to the trial thus far have solid tumor neoplastic meningitis and one third lymphomatous meningitis. An intent-to-treat (ITT) analysis will consider all patients randomized and analyzed according to the drug of randomization irrespective of whether or not they actually received the drug to which they were assigned. Kaplan-Meier distributions will be analyzed using the log-rank test for progression-free survival (time to neurological progression or death).

    1. Date of Initiation
    2. Identification of investigators began immediately after DepoCyt approval in April of 1999. The study was ready for patient accrual in October 1999. However, available supplies of DepoCyt were recalled in October 1999, and no drug was available for 18 months until FDA approved reintroduction to the market in March 2001. Trial preparation was reactivated immediately thereafter and the first patient was enrolled on 03 July 2001.

    3. Accrual
    4. As of 31 January 2003, 49 patients have been enrolled, 12 of which were enrolled with lymphomatous neoplastic meningitis.


      Enrollment status:

      2001: 16 patients

      2002: 27 patients

      2003: 40 patients to be enrolled (6 patients were enrolled by 31 Jan 2003)

      2004: 27 patients to be enrolled

      Total: 110 patients

    5. Estimated Timeline for Study Completion
    6. The current enrollment rate is sufficient to meet SkyePharma’s enrollment commitment by August 2004.

      Start date: March 2001

      Interim analysis: Eliminated as per agreement with FDA

      Enrollment Complete: August 2004

      Last patient visit: Approximately March 2005

      Report Completion: August 2005 – approximately 6 months

      Following the last patient visit

      Total elapsed time: Approximately 4-1/2 years (identical to the

      original commitment)

    7. Estimated Timeline for Submission of Study Results

The study calls for a two-year follow-up period following randomization. However, due to the severity of the disease under study, the likelihood of a patient failing to reach neurological progression or death within 6 months after receiving initial treatment is low. It is anticipated that the clinical database could be closed Q2 2005 should all participating patients reach the primary endpoint by March 2005. Should this occur, the study results would be available by the third quarter of 2005. This is approximately 4-1/2 years of elapsed time from the study start, which is same elapsed time as the original Phase IV commitment of March 1999. The final clinical study report could be submitted to FDA within one month following report completion. However, should one or more of the patients enrolled after the first quarter of 2003 have progression-free survival for two years following randomization, there could be a respective delay in the analysis of the data. For this reason, the proposed timeline to provide study results is between approximately Q3 2005 and Q1 2007.


  1. Other Issues
    1. Difficulties encountered in conduct/accrual/completion of trials
    2. 1. Changes in medical practice

      With the initial approval and commercial availability of DepoCyt for the treatment of lymphomatous neoplastic meningitis in the United States and Canada, there appears to have been a shift in the standard treatment of patients inflicted with this disease. There is certainly interest among clinicians to initiate DepoCyt treatment in patients with lymphomatous neoplastic meningitis without enrolling them in this controlled, randomized clinical trial. Considering that a lymphoma patient could be randomized to ara-C in this trial, which requires 4 times more clinic visits than if treated with DepoCyt, many of the U.S. investigators queried to participate in this trial chose not to.

      Similarly, as part of the consent process, patients are informed of the treatment options that are available to them other than participating in this controlled study. These options include off-study treatment with commercially available DepoCyt without the patient having to worry about being randomized to ara-C or methotrexate, both of which are administered twice weekly.

      Although both of these issues are potentially hindrances to study enrollment, 18 U.S. institutions have been recruited and the rate of enrollment in the U.S. appears to be in-line with enrollment in the prior Phase III controlled studies. In addition, European sites were recently added to the study, which should aid in completing the study within the currently specified timelines since DepoCyt, although approved in Europe for lymphomatous meningitis patients, is not yet distributed by SkyePharma’s. European licensee.

      2. Safety considerations

      The safety of the trial is continuously monitored and there have been no reasons to believe that safety would adversely effect the study completion timelines.

      3. Other: Product unavailable

      A recall of both lots distributed between April and October 1999 was initiated when the free cytarabine content was found to be out of specification during stability studies. These results were unexpected and atypical of prior history with the product. SkyePharma conducted a lengthy and rigorous investigation of possible sources of product instability and discovered that the problem was caused by a slight change in the composition of one of the lipids due to a minor change in a single step of the manufacturing process used by the lipid supplier. A comprehensive investigation report was submitted to FDA in July 2000 documenting the single cause for the recall and corrective and preventive actions taken by the Sponsor. SkyePharma met with FDA in September 2000 and when additional stability data became available, FDA approved resumption of commercial distribution in March 2001. Thus, DepoCyt was not available for conduct of the post-marketing trial for a period of 18 months.

    3. Other Applicant Concerns











Appendix 1: Active Centers Protocol SKY0101-010

Investigator Center No. Institution City Country

William Shapiro MD 2 Barrow Neurological Phoenix USA


Pamela New MD 3 University of Texas San Antonio USA

Health Science Center

Pamela Khosla MD 5 Rush Cancer Institute Chicago USA

Surasak Phuphanich MD 6 H. Lee Moffitt Cancer Tampa USA

Center and Research Inst.

Eric Wong MD 9 Beth Israel Deaconess Boston USA

Medical Center

Benjamin Lawler MD 10 Marshfield Clinic Marshfield USA

Paul Moots MD 19 Vanderbuilt University Nashville USA

Medical Center

Kurt Jaeckle MD 23 Mayo Clinic Jacksonville USA

Deborah Blumenthal MD 27 Huntsman Cancer Institute Salt Lake City USA

Marc Chamberlain MD 28 USC Los Angeles USA

Subramanian Hariharan MD 29 JFK Neuroscience Institute Edison USA

Lynne Taylor MD 30 Virginia Mason Medical Seattle USA


Lynn Ashby MD 36 Straub Clinic and Hospital Honolulu USA

Jeffrey Olson MD 37 Windship Cancer Institute Atlanta USA

David Irwin MD 38 Alta Bates Comprehensive Berkeley USA

Cancer Center

Thomas Coyle MD 39 SUNY Upstate Medical Syracuse USA


Investigator Center No. Institution City Country

George Marcoullis MD 40 Comprehensive Cancer Bronx USA


David Linch MD 56 UCL London WC1E 6HX United Kingdon

A.Y. Rostom MD 50 The Royal Marsden Surrey, SM2 5PT United Kingdom


Thomas A. Lister MD 51 St. Bartholomew's Hospital London EC1A 7BE United Kingdom

Peter Johnson MD 53 Southampton General Southampton S016 6YD United Kingdom


David Spooner MD 57 Queen Elizabeth Hospital Birmingham B15 2TH United Kingdom

Ann Hunter MD 63 Leicester Royal Infirmary Leicester LE1 5WW United Kingdom


Simon M.G.J. Daenen MD 49 University Hospital 9713 GZ Groningen The Netherlands

Albert Twijnstra MD 54 University Hospital of 6202 AZ Maastricht The Netherlands


Christiana Sessa MD 45 Ospedale San Giovanni Bellinzona Switzerland

John Crown MD 58 St. Vincent's Hospital Dublin 4 Ireland

Simus O'Reilly MD 64 Cork University Hosptial Wilton, Cork Ireland

Maccon Keane MD 65 University College Galway Ireland


Brian Moulton MD 68 Irish Clinical Oncology Dublin 2 Ireland

Research Group

Dieter Hoelzer MD 52 Klinilum der J.W. 60590 Frankfurt Germany


Mathias Schmid MD 59 Unilkinilum Ulm D-89070 Ulm Germany


Investigator Center No. Institution City Country

Dirk Behringer MD 60 Universitatsklinikum-Freiburg D-79106 Freiburg Germany

K. Hossfeld MD 61 Medizinische Universitatsklinik D-20246 Hamburg Germany

Kurt Possinger MD 62 Charite University Hospital Mitte D-Berlin Germany

Jean-Louis Misset MD 43 Hopital Saint-Louis 75010 Paris France

Jean-Pierre Droz MD 44 Center Leon Berard Lyon France

Sopie Taillibert MD 46 Chu Pitie-Salpetriere Hospital Paris Cedex F-75651 France

Jean-Luc Harousseau MD 47 Centre Hospitalier Universitaire 44093 Nantes Cedex 1France

Bertrand Coiffier MD 48 Centre Hospitaliere F-69495 Pierre-Benite France

Rena Buckstein MD 22 Toronto Sunnybrook Toronto Canada

Regional Cancer Centre

David Eisenstat MD 34 CancerCare Manitoba Winnipeg Canada

Dominique Lossignol MD 41 Institut Jules Bordet Bruxelles B-1000 Belgium