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The time to progression ratio for phase II trials of personalized medicine

The time to progression ratio for phase II trials of personalized medicine. Marc Buyse, ScD IDDI, Louvain-la-Neuve, and I-BioStat, Hasselt University, Belgium marc.buyse@iddi.com. Outline. Definition of TTPR TTPR in gastro-intestinal stromal tumors

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The time to progression ratio for phase II trials of personalized medicine

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  1. The time to progression ratio for phase II trials of personalized medicine Marc Buyse, ScD IDDI, Louvain-la-Neuve, and I-BioStat, Hasselt University, Belgium marc.buyse@iddi.com

  2. Outline • Definition of TTPR • TTPR in gastro-intestinal stromaltumors • TTPR to design a trial in advanced colorectal cancer • TTPR for trials of personalizedmedicine • Tentative conclusions

  3. The TTP ratio (TTPR) TTP1 TTP2 TTP3 Rx1 Rx2 Rx3 … Death First progression Second progression Start of Rx for advanced disease TTPR = TTP2 / TTP1

  4. Use of TTPR Cytostatics are not expected to induce tumor shrinkage, but it is hoped that they can stabilize the tumor (delay progression). For second-line therapies, the « time to progression ratio » (or « growth modulation index »), is defined as TTPR = TTP2 / TTP1 Given the natural history of most tumors, TTPR generally does not exceed 1 (i.e. TTP2 tends to be shorter than TTP1). Von Hoff suggested that TTPR > 1.33 reflects activity of the second-line therapy. Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000.

  5. TTPR-based designs : second-line treatment only TTP1 TTP2 Rx1 Rx2 First progression, entry on trial Second progression Start of Rx for advanced disease

  6. TTPR-based designs : two lines of treatment TTP1 TTP2 Rx1 Rx2 First progression Second progression Start of Rx for advanced disease, entry on trial

  7. TTPR when doubling dose of imatinib for progressing gastro-intestinal stromal tumors Proportion of patients with TTPR > 1.33 after cross-over from 400 mg to 800 mg of imatinib daily, broken down by response to 400mg Ref: Zalcberg et al, Eur J Cancer 41:1751-7, 2005.

  8. Trial comparing two imatinib doses in patients with gastro-intestinal stromal tumors R 181 * 196 * 400 mg imatinib daily 800 mg imatinib daily • * Nr of patients with adequate DNA for KIT genotype analysis Ref: Debiec-Rychter et al, Eur J Cancer 42:1093-1103, 2006.

  9. Cumulative incidence of response by KIT mutation Ref: Debiec-Rychter et al, Eur J Cancer 42:1093-1103, 2006.

  10. TTPR after cross-over by KIT mutation Proportion of patients with TTPR > 1.25 after cross-over from 400 mg to 800 mg P= 0.0017 P= 0.0012 Ref: Debiec-Rychter et al, Eur J Cancer 42:1093-1103, 2006.

  11. Trial comparing two chemotherapy sequences in patients with advanced colorectal tumors R 109 111 FOLFIRI – FOLFOX FOLFOX – FOLFIRI • Primary endpoint = Time to second progression (TTP1 + TTP2) • Secondary endpoints = TTP1, TTP2, survival Ref: Tournigand et al, J Clin Oncol 22:229-37, 2004.

  12. Distribution of TTPR in advanced colorectal cancer

  13. Distribution of TTPR in advanced colorectal cancer  of the patients had a TTPR > 0.5 50% 0.5

  14. Distribution of TTPR in advanced colorectal cancer  of the patients had a TTPR > 0.8 33% 0.8

  15. Distribution of TTPR in advanced colorectal cancer  of the patients had a TTPR > 1 25% 1

  16. Distribution of TTPR in advanced colorectal cancer  of the patients had a TTPR > 1.25 20% 1.25

  17. TTPR – test of hypothesis A possible nullhypothesis is: H0: TTPR = TTP2 / TTP1 HR0 versus the alternative hypothesis: HA: TTPR = TTP2 / TTP1> HR0

  18. Test of hypothesis in advanced colorectal cancer H0 : TTPR ≤ 0.75 50% 0.75

  19. A sign test statistic For the ithpatient, let ribe equal to +1 if TTP2 > TTP1  HR0 –1 if TTP2 TTP1  HR0 and TTP2 is uncensored The test statistic (equivalent to a sign test statistic) X² = (i ri)² / i ri² has a ² distribution with 1 d.f. Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000.

  20. A sign test statistic • HR0 = 0.7 • = 0.05 • Correlation = 0.7 90% 85% 80% Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000.

  21. A sign test statistic • HR0 = 0.7 • = 0.05 • Correlation = 0.5 Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000.

  22. A sign test statistic • HR0 = 0.7 • = 0.05 • Correlation = 0.3 Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000.

  23. TTP1vs. TTP2 in advanced colorectal cancer R² = 0.03

  24. TTP1vs. TTP2 in advanced colorectal cancer

  25. Statistics for correlated survival times In the absence of censoring, TTP1 and TTP2 can be compared using a paired t-test or a non-parametric test for paired observations. If TTP2 is censored, TTP1 and TTP2 are paired survival times. The ordinary rank test statistics (e.g. logrank or Gehan-Wilcoxon) can be used with variance corrected to account for the correlation between TTP1 and TTP2. Ref: Jung, Lifetime Data Analysis 5:67-79, 1999.

  26. TTPR – another test of hypothesis Let p be the proportion of patients for whom TTPR > HR0. A possible nullhypothesis is: H0: p  p0 versus the alternative hypothesis: HA: p > p0 which leads to Flemings’ one-stage or Simon’ two-stage designs.

  27. Tests of hypothesis in advanced colorectal cancer H0 : p0 ≤ 22% 22% 1.33

  28. Trial of molecular profiling TTP1 TTP2 Molecular profiling of tumor biopsy by IHC, FISH or micro-array to identify target At least two prior therapies for advanced disease, no further therapy available Last progression, entry on trial Progression on targeted therapy Ref: Von Hoff, AACR 100th Annual Meeting, Denver, CO, April 18-22, 2009.

  29. Trial of molecular profiling Trial designed to test p0 (proportion of patients with TTPR > 1.3): H0: p  p0 = 15% Primary analysis: proportion of patients with TTPR > 1.3: 18 / 66 (27%, 95% C.I. 17% - 38%, P = 0.007) Breast 8 / 18 (44%) Colorectal 4 / 11 (36%) Ovarian 1 / 5 (20%) Others 5 / 32 (16%) Ref: Von Hoff, AACR 100th Annual Meeting, Denver, CO, April 18-22, 2009.

  30. Trial of molecular profiling Promising results, and amongst the 18 patients with TTPR > 1.3, none would have received same drug through plysician’s choice. However, • Is TTPR > 1.3 good enough? • Trial was not randomized, therefore no evidence that physician’s choice could have yielded similar results • Only 66 patients of 106 could have molecular profiling

  31. Trial designs using TTPR – pros and cons + Test time to progression rather than response; hence well suited to test cytostatic agents + Patients serve as their own control, a desirable feature to control between-patient variability + Efficient if substantial correlation between TTP1 and TTP2 • Choice of appropriate value for HR0 • TTP1 difficult to estimate retrospectively, and potentially biased downwards if standard first-line treatment included in design and new agent is promising • Inefficient if poor correlation between TTP1 and TTP2

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