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Eric Pujade-Lauraine on behalf of all GCIG collaborators

CALYPSO trial. Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer. Eric Pujade-Lauraine on behalf of all GCIG collaborators. Background.

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Eric Pujade-Lauraine on behalf of all GCIG collaborators

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  1. CALYPSO trial Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxelin Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine on behalf of all GCIG collaborators

  2. Background • Despite response to 1st-line treatment, relapse is eventual for most patients with advanced ovarian cancer (AOC) • Choice of relapsed disease treatment is dependent on interval since prior platinum-based therapy • Relapse within 6 months: platinum-resistant disease • Relapse over 6 months: platinum-sensitive disease • Carboplatin-paclitaxel is standard in platinum-sensitive disease

  3. Rationale for PLD-Carboplatin Doublet • Due to risk of cumulative neuropathy and of hair loss, other carboplatin combinations have been explored • Pegylated liposomal doxorubicin (PLD) is a rational choice for combined therapy • PLD outperformed topotecan in platinum-sensitive population in large randomized trial (significant benefit in PFS and OS)1,2 • Phase II trial of PLD-carboplatin verified safety and efficacy3 1Gordon et al. J Clin Oncol. 2001;19:3312-3322; 2Gordon et al. ECCO 12. September 2003 (poster); 3Ferrero et al. Ann Oncol. 2007;18:263-268.

  4. CALYPSO Study Schema International, Intergroup, Open-label, Randomized Phase III Study Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line platinum-based therapy (previous taxane required) R A N D O M I Z E Experimental arm: CD PLD 30 mg/m2 IV d 1 Carboplatin AUC 5 d 1 Q 28 days x 6 courses* Control arm: CP Paclitaxel 175 mg/m2 IV d 1 Carboplatin AUC 5 d 1 • Stratification: • Therapy-free interval (6-12 mo vs > 12 mo) • Measurable disease (yes vs no) • Center Q 21 days x 6 courses* *or progression in patients with SD or PR

  5. Key Eligibility Criteria • Age ≥ 18 years • ECOG performance status ≤ 2 • Histologically proven diagnosis of cancer of the ovary, fallopian tube, or extra-ovarian papillary serous tumors • Disease progression > 6 months after 1st- or 2nd-line platinum-based therapy • Previous taxane exposure • Measureable disease (RECIST criteria) or CA 125 assessable disease (GCIG criteria) or histologically proven diagnosis of relapse

  6. Endpoints. Statistical discussions Primary endpoint • Progression-free survival (PFS) Statistical considerations • Two-arm, parallel, NON-INFERIORITY study design • Statistical assumptions based on PFS from ICON4/AGO-OVAR 2.2 trial1 • Declare non-inferior if HR one-side 95% CI <1.23 (CD:CP) for PFS • Power of 90% and one-sided confidence level of 95% • Number of events required : 745 1Parmar et al. Lancet. 2003;361:2099-2106.

  7. Endpoints Secondary endpoints • Qualitative and quantitative toxicities • Quality of life (EORTC QLQ-C-30 version 3.0 and OV-28 questionnaire version 1.0) • Overall survival (OS)

  8. Accrual N=976

  9. CALYPSO Worldwide Collaboration Austria, Australia, Belgium, Canada, Denmark, Finland, France, Germany, Italy, New Zealand, Saudi Arabia, Spain, Sweden, Switzerland, Turkey

  10. Accrual by Groups 317 227 137 76 71 60 49 22 17

  11. Baseline Characteristics (1) * Missing values to attain 100%.

  12. Baseline Characteristics (2)

  13. Treatment Exposure * P< 0.001; ** Patients receiving at least one cycle

  14. Hematologic Toxicity NS=not significant.

  15. Selected Non-Hematologic Toxicities During Treatment *P< 0.001

  16. Selected Non-Hematologic Toxicities During Treatment Alopecia *P< 0.001

  17. Long-Lasting Toxicity *P< 0.001 EORTC OV28 – QoL Peripheral Neuropathy Neuropathy score over time

  18. Early Treatment Discontinuation * P< 0.001

  19. Carboplatin Hypersensitivity Reactions *P< 0.001 Protocol included EORTC guidelines for re-challenge after a hypersensitivity reaction to carboplatin

  20. Follow-up and Number of Events Median follow-up 22 months Number of events Progressions or deaths 824 (85%) Deaths 322 (33%)

  21. Progression-Free Survival (ITT)

  22. Symmetry of Tumor Assessments

  23. Sensitivity PFS analysis

  24. Multivariate Analysis of Baseline Predictive Factors on PFS Significant predictors of PFS included

  25. Key findings • In patients with platinum-sensitive relapsing ovarian cancer, the combination of PLD-carboplatin was not inferior in term of PFS to paclitaxel-carboplatin, and even was found significantly superior • 18% reduction in risk of recurrence (HR 0.82; P=0.005) • Overall survival data immature, with only 322 deaths to date • Paclitaxel-carboplatin associated with more severe toxicity (carboplatin hypersensitivity), alopecia, and long-lasting toxicity (neuropathy) • Moderate reversible HFS, mucositis, and nausea/vomiting more frequent with PLD

  26. Conclusions • Carboplatin-PLD demonstrated a superior therapeutic index (benefit/risk ratio) versus current standard, carboplatin-paclitaxel • PLD- carboplatin offers an evidence-based option for patients with platinum-sensitive recurrent ovarian cancer

  27. Acknowledgement Patients and theirfamilies, and … GINECO AGO-OVAR NSGO NCIC-CTG ANZGOG AGO-Austria EORTC MITO MANGO Study Office B. Votan G. Elser G. Andersen M. Bacon J. Martin B. Volger A. Demeester J. Bryce R. Fossati N. Le Fur P. Schantl C. Jeppesen C. Goudreau K. Carlton J. Ulmer Investigators E. Pujade -Lauraine A. Lortholary F. Joly B.Weber L. Gladieff A. Floquet R. Largillier M. Fabbro A. Goupil R. Delva E. Guardiola F. Priou G.DeRauglaudre D. Coeffic … J. Pfisterer J. Sehouli A. Du Bois P. Wimberger B. Schmalfeldt J. Huober S. Mahner M. Gropp M. Thill K. Baumann A. Burges A. Staehle R. Kreienberg A. Belau M. Beckmann S. Loibl A. Hasenburg G. Emons W. Aulitzky L. Spaetling … G. Kristensen J. Kaern R. Sandvei J. Herrstedt E. Aavall -Lundqvist T. Hogberg B. Lund K. Boman H. Havsteen M. Hansen J. Maenpaa … E. Eisenhauer L. Elit P. Sauthier J. Bentley A. Oza H. Chalchal A. Sugimoto M. Heywood P. Bessette D. Popkin L. Kaizer W. Gotlieb P. Walde … P. Vasey B. Fitzharris M. Buck T. Bonaventura M. Vaughan M. Davy A. O’Donnell C. Steer M. Quinn M. Friedlander A. Goldrick F. Kirsten … C. Marth A. Zeimet A. Reinthaller L. Angleitner -Boubenizek H. Schauer P. Sevelda E. Petru… I. Vergote N. Reed K. Van Eygen P. Ottevanger M. Van der Burg A. Casado Herraez S. Pignata G. Scambia R. Sorio E. Breda A. De Matteis A. Ferrero N. Colombo N. Donadello D. Gueli Alletti A. Lissoni S. Siena DSMB M. Gore M. Brady M. Seiden Statistics V. Gebski C. Brown Data Management H. Karsenty L. Bertel, B. Voulaz S. Perrin Web site D. Pihan Safety Office S. AzouzT. Tran Coordinating Centre A. Bonvoisin E. Plançon F. Pinot N. Chiannilkulchai Supported by Shering Plough International S. Stopatschinskaja C. Doherty B. Winograd B. Hartley K. Djazouli K. Rehman M. Fehr G. Tulunay

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