1 / 17

Patupilone Ovarian Programme

This article provides an overview of the Patupilone Ovarian Program, including the initial phase I studies, pharmacokinetics, and the development of a new three-weekly dosing schedule. The article also discusses ongoing phase I/II studies and the combination of Patupilone with carboplatin in advanced cancer patients.

lockard
Download Presentation

Patupilone Ovarian Programme

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. PatupiloneOvarian 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) 1Calvert PM et al. Proc Am Soc Clin Oncol. 2001;20:108a. Abstract 429. 2Rubin 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 Dose (mg/m2) AUC = area under the curve. Novartis. Data on File. 2006.

  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.

  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

  11. 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 Patupilone adverse events

  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

  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 Patupilone 10 mg/m2 q3wk • Inclusion criteria • Recurrent epithelial ovarian cancer • Failed initial platinum-based therapy or relapsed within 6 mo of completion • Primary endpoint: OS • Selected secondary endpoints:progression-free survival, overall response (RECIST and CA125), duration of response, and time to progression Randomization n = 810 PLD 50 mg/m2 q4wk Smit WM et al Presented at: 13th European Cancer Conference; 2005, abstract # 909.

  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.

More Related