6 February 2003
Karen M. Templeton-Somers, Ph.D.
Supervisory Health Science Administrator
Advisors and Consultants Staff
FDA, CDER, ORM
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
INFORMATION REGARDING ACCELERATED APPROVAL
CLINICAL PHASE 4 COMMITMENTS
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. 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:
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:
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).
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.
As of 31 January 2003, 49 patients have been enrolled, 12 of which were enrolled with lymphomatous neoplastic meningitis.
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
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
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. 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.
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
Benjamin Lawler MD 10 Marshfield Clinic Marshfield USA
Paul Moots MD 19 Vanderbuilt University Nashville USA
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
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
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