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03_OZA.ppt

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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/m2 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 regimens1,2 • MTD: 2.5 mg/m2 qwk for 3 wk, followed by 1 wk off; 6.0 mg/m2 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 t1/2 ~4 d • Elimination largely nonrenal (<0.1% renal) • Linear pharmacokinetics across dose range studied (0.3-10.0 mg/m2 ) • 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/m2 )
  • 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 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 Benson AB et al. J Clin Oncol. 2004;22:2918-2926.
  • 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 Trial Cancer type Pts treated Current dose q3W Safety Response* Phase I/II (2203e) Epithelial ovarian, second-line 45 10.0 DLT: fatigue, diarrhea, gr 4 uric acid 1 CR, 10 PR, 8SD Phase I/II (2113) Mostly ovarian, second-line 37 Including 26 OvCa EPO 4.8 and Carbo AUC 6 DLT: fatigue, nausea, abdominal pain Ovarian responses 13 CR/PR, 3 SD, 5 PD, 5 UNK CA-125 : 70% RR
  • 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 Adverse events Dose range Dose intensity N= 108 6.5- 13 mg/m2 q.3 wks 2.1-4.3 mg/m2 wk N= 351 2.5mg/m2 wk 3/4 1.87 mg/m2 wk All grades n (%) g3/4 (%) All grades n (%) Diarrhea 70 (64.8) 17 (15.7) 270 (76.9) Nausea 33 (30.6) 0 189 (53.8) Fatigue 46 (42.6) 10 (9,3) 177 (50.4) Vomiting 30 (27.7) 5 (4.6) 116 (33.0) Peripheral neuropathy 28 (25.9) 3 (2.8) 100 (28.5) Constipation 16 (14.8) 0 79 (22.5) Abdominal pain 35 (32.4) 2 (1.9) 109 (31.1)
  • 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/m2 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/m2 /carboplatin AUC 6 • Fatigue and allergic reaction/severe abdominal cramping – MTD: patupilone 4.8 mg/m2 /carboplatin AUC 6 • Optimal dose is currently being further refined in phase I trials Overall Best Response, n (%) Total Population, N = 37 Ovarian/ Peritoneal, n = 31 Platinum Sensitive, n = 26 CR 1 (2.7) 1 (3.2) 1 (3.8) PR 12 (32.4) 12 (38.7) 10 (38.5) SD 4 (10.8) 3 (9.7) 2 (7.7) PD 10 (27.0) 5 (16.1) 4 (15.4) Unknown 10† (27.0) 10 (32.3) 9 (34.6)
  • 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 progressionRandomization 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.