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DepoCyt®: Enrollment Completed
Oncology Drugs Advisory Committee
November 8, 2005
Gordon L. Schooley, Ph.D.Chief Scientific Officer
SkyePharma Inc.
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• Sustained release formulation of cytarabine (ara-C)
• Ara-C is encapsulated in the chambers of 20 m particles made up of phospholipids and cholesterol
• After intrathecal injection, the particles spread throughout neuraxis & slowly release ara-C over 2 – 3 weeks
• Indication: lymphomatous meningitis
• Accelerated approval date: April 1, 1999
DepoCyte™ (cytarabine liposome injection): NDA 21-041
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DepoCyte ventricular CSF pharmacokinetics Free ara-C concentration (Ph I trial)
Time (Days)0 7 14 21
Fre
e ar
a-C
Co
nce
ntr
atio
n (g
/mL
)
0.01
0.1
1
10
10050 mg, DepoCyt
30 mg, Free Ara-C
T1/23.4 h
T1/2141 h
AssumedMinimumCytotoxic
Level
Ventricular injection/ventricular sampling
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Basis of approval: High Cytological response rate in
lymphomatous meningitis patients
No. randomized and receiving drug
No. responders
Response rate
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7
41%
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1
6%
ara-CDepoCyt
(P ≤ 0.04)
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Phase IV Commitments
• A controlled randomized trial to determine patient benefit (clinical endpoint) and safety of DepoCyt® for the treatment of lymphomatous meningitis
• A pharmacokinetic study
• Trial to be initiated in 6 months (by 9/99)
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DepoCyt SKY0101- 010Phase IV Study
Objective:• Confirm clinical benefits of DepoCyt® vs. standard therapy in
adult patients with lymphomatous or solid tumor neoplastic meningitis
Design: Prospective, open-label, randomized, controlled
Primary endpoint: Progression-free survival• Neurological evaluation prior to treatment & start of each Tx cycle• investigators decision that progression has occurred
• Documented with specific signs and symptoms
Secondary endpoints:• Survival, • cytological response rate & chemistries (start & end of cycles)• Improvements in neurological symptoms, quality of life, safety
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DepoCyt SKY0101- 010Phase IV Study
Key Eligibility Criteria:
• Biopsy proven lymphoma or malignant solid tumor
• Neoplastic meningitis diagnosed on basis of:• Positive CSF cytology, or• Characteristic signs and symptoms plus an MRI or CT
scan indicating presence of meningeal tumor
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SKY0101-010 controlled trial – Schematic
All patients received dexamethasone 4 mg BID Days 1 – 5; 2 mg BID day 6; 1 mg BID day 7 of each cycle.
Follow up Visits
IT DepoCyt(50 mg)
RANDOMIZATION
IT 50mg ara-Cor 10mg MTX
Induction 6 cycles
Every 2 wksX 12 Weeks
Twice a wkX 12 wks
Month
Every 4 wksX 16 Weeks
Once a wk X 16 wks
Treatment
Maintenance 4 cycles
Every MonthX 6 Months
Every other month x 12
months
0 3 7 12 24
Every MonthX 6 Months
Every other month x 12 months
Positive CSF
cytology or CNS
imaging
Solid tumor or
lymphoma
Stratification: lymphoma vs. solid tumor, USA vs. EC
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SKY0101-011 PK Study
Objective:• To evaluate CSF PK of free and total ara-C following
intraventricular administration of DepoCyt®
Study Sites:• 2 sites in Europe
Accrual:• 12 subjects were treated & provided PK samples
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DepoCyt NDA 21-041 Status: Phase IV Commitment
Study SKY0101-010 • Initiated: 9/99
• Enrollment completed: 11/04
Study SKY0101-011• Initiated: 9/04• Enrollment completed: 4/05
Submit final study reports Dec. 2005
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DepoCyt Phase IV Status: Timelines
Study Initiated: 9/99
Sponsor-initiated product recall: 10/99
Product re-introduced: 3/01
Study Re-initiated: 7/01
Enrollment completed: 11/04
Study Report: 12/05
2001 2002 2003 2004 2005 2006
17 mo
4.5 yr
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DepoCyt Phase IVStatus: Patient Accrual
Total study sites: 45 (25 sites recruited patients)North America 26 (12 sites recruited patients)EU 19 (13 sites recruited patients)
Total patients recruited 124 USA/Can EuropeSolid tumor 100 51 49Lymphoma 24 14 10
Accrual ratesU.S. / Canada / EU: ~3.0 patients/mo U.S. / Canada ~1.5 patients/mo (~2.9/mo in phase III)
Ave. enrollment of ~1 patient per site per year Ave. enrollment of ~1 LM patient per site per 4 yrs.
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Schematic of DepoCyte trials
Solid Tumor Neoplastic Meningitis (STNM)
61 PatientsDepoCyte vs. MTX
Lymphomatous Meningitis (LM) 33 pts.
Lymphoma 5 pts.DepoCyte vs. ara-C
Phase I19 Patients
Phase IV 110 Patients
Phase I Pediatric19 Patients
European PK Study13 Patients
USA PK Study11 Patients
SKYE0101-010 & -011 LM: 24 PatientsSTNM: 100 Patients PK: 12 PatientsDepoCyt N=296
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Study Design Challenges
It was anticipated –• Enrollment of ≥ 75 LM pts. within 5 years was not possible• NOTE: Only 24 LM patients were enrolled in 4 years
In response – Solid tumor neoplastic meningitis patients were included in the study population
Consequence• Study population different than DepoCyt NDA population • Increase in study variability due to multiple populations • Sample size for LM sub-group analysis too small
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Study Design ChallengesOne Example
Availability of higher-resolution imaging equipment-Imaging widely used for diagnosis of neoplastic meningitis
In Response – Investigator demands - phase IV inclusion criteria expanded - Beyond positive cytology used in phase III to include patients with positive MRI/CT scan
Consequence – <50% of patients have cytology available for assessment
Progression free survival (PFS) ~½ compared to phase IIIDid reliance upon CNS imaging (or other factors) have an impact upon type of LM patients enrolled?
Ability to detect meaningful PFS differences compromised
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Challenges to study completion
Few number of lymphomatous meningitis cases–Only a small fraction available for trial participation
Trial participation vs. off-study treatment–DepoCyt commercially available – no interest in participation –Fear of randomization to cytarabine group
4 intrathecal injections (IT) per cycle vs. one per cycle of DepoCyt Quality of life issue with only months of survival remaining
Competition for patients–Competiting clinical studies for lymphomatous meningitis patients
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Challenges to study completion
North America recruitment rate too slow to meet Phase IV commitment in a timely manner
In response - - 19 European study sites were recruited Standards of care & patient management
Differences: Europe vs. US & Canada – increase in variabilityStudy site-to-site variability – increase from 26 to 45 study sites
Consequence - - Data from European sites complicated data interpretation
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Summary Questions
Has the Post marketing study commitment been fulfilled?
Draft report sent to FDA although analysis continues
Next step: SkyePharma - FDA discussion
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Summary Questions
Does this study provide useful information?
Safety – yes.
Efficacy – To be determined as confounding factors on a small sample of lymphomatous meningitis treated patients is problematic and subject to additional analysis
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Summary Questions
Is it feasible to conduct a confirmatory trial of a clinical endpoint in lymphomatous meningitis (LM)
To conduct of a study in lymphomatous meningitis within a reasonable time frame (~5 yrs) some compromises must be (were) made that may confound the interpretation of the data
To enroll sufficient number of patients based on most clinical endpoints in a controlled study may take 10-15 years.
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