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  • 1. Patupilone Ovarian Programme Amit M. Oza, MD Princess Margaret Hospital Toronto, Canada
  • 2. Early phase I program
    • Two phase I studies done using different schedules
    • Study objectives
      • Maximum tolerated dose (MTD)
      • Dose-limiting toxicity (DLT)
      • Safety
      • Pharmacokinetics
    • Study design:
      • Patupilone q3wk, 5–7-min infusion (n = 57)
      • Patupilone qwk (6 wk on/3 wk off, later 3 wks on 1 wk off) 5–7-min infusion (n = 86)
    • Initial dose: 0.3 mg/m 2
    Calvert AH et al. Ann Oncol. 2003;20:21-22. Abstract 760.
  • 3. Initial Patupilone phase I studies showed activity in multiple tumor types
    • Initial phase I studies examined qwk or q3wk regimens 1,2
    • MTD: 2.5 mg/m 2 qwk for 3 wk, followed by 1 wk off; 6.0 mg/m 2 q3wk
    • Diarrhea was DLT, and occurred predictably 9-11 days after initial dosing
      • Significant neuropathy uncommon; no episodes of grade 3/4 myelosuppression
    • Patupilone showed responses in multiple tumor types:
      • 7 PR (2 in CRC, 2 in breast, 1 in ovarian, 1 in unknown primary, 1 in carcinoid) and 5 minimal responses (2 in CRC, 2 in ovarian, 1 in NSCLC)
    1 Calvert PM et al. Proc Am Soc Clin Oncol. 2001;20:108a. Abstract 429. 2 Rubin EH et al. J Clin Oncol. 2005;23:9120-9129.
  • 4. Patupilone pharmacokinetics
    • Rapid and extensive tissue distribution
    • Terminal t 1/2 ~4 d
    • Elimination largely nonrenal (<0.1% renal)
    • Linear pharmacokinetics across dose range studied (0.3-10.0 mg/m 2 )
    • Protein binding 95% ± 2%
    • No evidence of drug accumulation with repeated cyclical q3wk dosing
    Calvert AH et al. Ann Oncol. 2003;20:21-22. Abstract 760. Novartis. Data on File. 2006.
  • 5. Dose-proportional relationship between AUC and Patupilone dose Novartis. Data on File. 2006. AUC = area under the curve. Dose (mg/m 2 )
  • 6. No evidence of Patupilone accumulation with repeated cyclical q3wk dosing Time (h) Novartis. Data on File. 2006.
  • 7. New phase I/II studies of Patupilone
    • New phase I/II clinical trials were initiated to improve safety and efficacy, incorporating:
      • q3wk schedule
        • Preclinical data indicated that higher single doses could be more efficacious
        • Avoids dosing immediately prior to onset of predicted diarrhea
      • Proactive antidiarrheal management
      • Improved dose intensity possible
    • Proactive Management of Diarrhea
      • Educating patients and caregivers
      • Providing patients with loperamide tablets
      • Proactively calling patients at home
      • Following ASCO guidelines for chemotherapy-induced diarrhea
  • 8. ASCO guidelines for treatment-induced diarrhea Benson AB et al. J Clin Oncol. 2004;22:2918-2926. Uncomplicated grade 1/2 Loperamide Progression to severe diarrhea Persistent grade 1/2 Admit to hospital Opiates/octreotide IV fluids Discontinue loperamide Start octreotide or opium tincture High-dose loperamide Persistent grade 1/2 Grade 3/4 or complicated grade 1/2
  • 9. Studies with new three weekly schedule
    • Three Ph I/II studies were begun to determine MTD and Ph II/III dose of IV patupilone in q3wk regimen
        • Relapsed/Refractory Ovarian Cancer (relapsed within 6 mths of first line platinum)
        • Second line NSCLC (relapse after initial platinum combination therapy)
        • Metastatic heavily pretreated colorectal cancer
      • Starting dose of Patupilone was 6.5mg/m2 (higher than previous MTD)
      • Dose escalation up to 11mg in ovarian and 13 mg in NSCLC
      • Recommended Ph II/III dose determined – 10 mg/m2 q 3wk
  • 10. Ongoing phase I/II studies: Every 3 weeks schedule Ovarian responses 13 CR/PR, 3 SD, 5 PD, 5 UNK CA-125 : 70% RR DLT: fatigue, nausea, abdominal pain EPO 4.8 and Carbo AUC 6 37 Including 26 OvCa Mostly ovarian, second-line Phase I/II (2113) 1 CR, 10 PR, 8SD DLT: fatigue, diarrhea, gr 4 uric acid 10.0 45 Epithelial ovarian, second-line Phase I/II (2203e) Response* Safety Current dose q3W Pts treated Cancer type Trial
  • 11. Patupilone adverse events
    • Diarrhea most frequent adverse event; predictable and manageable
    • Median time to diarrhea is 10 days (CI 9,13)
    • Median duration of > grade 1 diarrhea is 2 days (CI 1,4)
    • Minimal myelosuppression, alopecia, renal, hepatic, or cardiac dysfunction
    • Recommended Phase II / III dose is 10mg/m2 q 3 w
    100 (28.5) 3 (2.8) 28 (25.9) Peripheral neuropathy 79 (22.5) 0 16 (14.8) Constipation All grades n (%) g3/4 (%) All grades n (%) 109 (31.1) 2 (1.9) 35 (32.4) Abdominal pain 116 (33.0) 5 (4.6) 30 (27.7) Vomiting 177 (50.4) 10 (9,3) 46 (42.6) Fatigue 189 (53.8) 0 33 (30.6) Nausea 270 (76.9) 17 (15.7) 70 (64.8) Diarrhea N= 351 2.5mg/m 2 wk 3/4 1.87 mg/m 2 wk N= 108 6.5- 13 mg/m 2 q.3 wks 2.1-4.3 mg/m 2 wk Adverse events Dose range Dose intensity
  • 12. Phase Ib study of Carboplatin/Patupilone combination in advanced cancer
    • Objective:
      • To determine MTD of patupilone in combination with carboplatin in patients with advanced solid tumors
    • Population:
      • 37 patients with advanced cancer
        • 84% with ovarian/peritoneal cancer; 5 with platinum-resistant disease
      • Up to 2 prior chemotherapy regimens
    • Design:
      • Patupilone via 5- to 10-min IV infusion at doses of 3.6–6.0 mg/m 2 q3wk, immediately followed by carboplatin via 60-minute IV infusion at dose of AUC 5 or 6 mg/mL per min
    Gore M et al. Presented at: 41st Annual American Society of Clinical Oncology, 2005.
  • 13. Phase Ib study of Carboplatin/Patupilone combination in advanced cancer
    • Results:
      • DLTs in 2 patients with patupilone 6 mg/m 2 /carboplatin AUC 6
        • Fatigue and allergic reaction/severe abdominal cramping
      • MTD: patupilone 4.8 mg/m 2 /carboplatin AUC 6
        • Optimal dose is currently being further refined in phase I trials
    9 (34.6) 10 (32.3) 10 † (27.0) Unknown 4 (15.4) 5 (16.1) 10 (27.0) PD 2 (7.7) 3 (9.7) 4 (10.8) SD 10 (38.5) 12 (38.7) 12 (32.4) PR 1 (3.8) 1 (3.2) 1 (2.7) CR Platinum Sensitive, n = 26 Ovarian/ Peritoneal, n = 31 Total Population, N = 37 Overall Best Response, n (%)
  • 14. Registration program for Patupilone in ovarian cancer
    • Current first-line chemotherapy is combination of platinum drug and paclitaxel
    • Agents lacking cross-resistance to both paclitaxel and platinum compounds are needed for patients with recurrent or refractory disease
    • Overall survival (OS) in platinum-resistant disease is poor, and thus new therapies that improve outcomes are needed
    • Significant activity seen with patupilone as single agent in phase I/II platinum-refractory/resistant ovarian study (24% response rate); and in combination with carboplatin in platinum sensitive disease
    Smit WM et al Presented at: 13th European Cancer Conference; 2005, abstract # 909.
  • 15. EXTEND: Phase III study of Patupilone vs PLD in platinum refractory/resistant ovarian cancer Design
    • Inclusion criteria
    • Recurrent epithelial ovarian cancer
    • Failed initial platinum-based therapy or relapsed within 6 mo of completion
    Patupilone 10 mg/m2 q3wk PLD 50 mg/m2 q4wk
    • Primary endpoint: OS
    • Selected secondary endpoints: progression-free survival, overall response (RECIST and CA125), duration of response, and time to progression
    Randomization Smit WM et al Presented at: 13th European Cancer Conference; 2005, abstract # 909. n = 810
  • 16. EXTEND – Study oversight
    • FDA and EMEA advice sought and agreement obtained
    • Study Steering Committee (SSC) – Will provide guidance on conduct, accrual and publications
    • An independent Data Safety Monitoring Board (DSMB) will be constituted for periodic safety & efficacy review
    • Independent Review Committee (IRC) – Will review the efficacy data of all patients (CT scans, Ca-125 and clinical data)
  • 17. Conclusions
    • Patupilone has been tested in ovarian cancer patients, both as monotherapy and in combination with carboplatin, with encouraging results.
    • Current evidence demonstrates that patupilone has antitumor activity in patients with ovarian cancer who received prior platinum therapy.
    • The safety profile is acceptable.
    • The pharmacokinetic data are promising.