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

• Definition of TTPR

• TTPR in gastro-intestinal stromal tumors

• TTPR to design a trial in advanced colorectal cancer

• TTPR for trials of personalized medicine

• Tentative conclusions

Outline

The TTP ratio (TTPR)

TTP1

First

progression

Second

progression

DeathStart of Rx

for advanced

disease

TTP2

TTPR = TTP2 / TTP1

Rx1 Rx2 Rx3 …

TTP3

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 asTTPR = 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.

TTPR-based designs : second-line treatment only

TTP1

First

progression,

entry on trial

Second

progression

Start of Rx

for advanced

disease

TTP2

Rx1 Rx2

TTP1

First

progression

Second

progression

Start of Rx

for advanced

disease,

entry on trial

TTP2

Rx1 Rx2

TTPR-based designs : two lines of treatment

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

Partial response 2/3 (67%)

Stable disease 13/36 (36%)

Progressive disease 12/72 (17%)

All patients 27/110 (25%)

Ref: Zalcberg et al, Eur J Cancer 41:1751-7, 2005.

TTPR when doubling dose of imatinib for progressing gastro-intestinal stromal tumors

Ref: Debiec-Rychter et al, Eur J Cancer 42:1093-1103, 2006.

R

196 *181 *

800 mg imatinib daily400 mg imatinib daily

* Nr of patients with adequate DNA for KIT genotype analysis

Trial comparing two imatinib doses in patients with gastro-intestinal stromal tumors

Ref: Debiec-Rychter et al, Eur J Cancer 42:1093-1103, 2006.

Cumulative incidence of response by KIT mutation

Proportion of patients with TTPR > 1.25 after cross-over from 400 mg to 800 mg

Exon 11 mutation (N=248) 83%

Exon 9 mutation (N=58) 57%

Wild type (N=52) 7%

Ref: Debiec-Rychter et al, Eur J Cancer 42:1093-1103, 2006.

P= 0.0017P= 0.0012

TTPR after cross-over by KIT mutation

Ref: Tournigand et al, J Clin Oncol 22:229-37, 2004.

R

111109

FOLFOX – FOLFIRIFOLFIRI – FOLFOX

Trial comparing two chemotherapy sequences in patients with advanced colorectal tumors

Primary endpoint = Time to second progression (TTP1 + TTP2)

Secondary endpoints = TTP1, TTP2, survival

Distribution of TTPR in advanced colorectal cancer

TTP Ratio

Pro

babili

ty

TTP Ratio

0.0

0.2

0.4

0.6

0.8

1.0

0 0.4 0.8 2 3 4 5 6

Patients Events

147 137

TTP Ratio

Pro

babili

ty

TTP Ratio

0.0

0.2

0.4

0.6

0.8

1.0

0 0.4 0.8 2 3 4 5 6

Patients Events

147 137

50%

0.5

Distribution of TTPR in advanced colorectal cancer

of the patients had a TTPR > 0.5

TTP Ratio

Pro

babili

ty

TTP Ratio

0.0

0.2

0.4

0.6

0.8

1.0

0 0.4 0.8 2 3 4 5 6

Patients Events

147 137

33%

Distribution of TTPR in advanced colorectal cancer

of the patients had a TTPR > 0.8

0.8

TTP Ratio

Pro

babili

ty

TTP Ratio

0.0

0.2

0.4

0.6

0.8

1.0

0 0.4 0.8 2 3 4 5 6

Patients Events

147 137

25%

1

Distribution of TTPR in advanced colorectal cancer

of the patients had a TTPR > 1

TTP Ratio

Pro

babili

ty

TTP Ratio

0.0

0.2

0.4

0.6

0.8

1.0

0 0.4 0.8 2 3 4 5 6

Patients Events

147 137

20%

1.25

Distribution of TTPR in advanced colorectal cancer

of the patients had a TTPR > 1.25

TTPR – test of hypothesis

A possible null hypothesis is:

H0: TTPR = TTP2 / TTP1 HR0

versus the alternative hypothesis:

HA: TTPR = TTP2 / TTP1 > HR0

TTP Ratio

Pro

babili

ty

TTP Ratio

0.0

0.2

0.4

0.6

0.8

1.0

0 0.4 0.8 2 3 4 5 6

Patients Events

147 137

50%

0.75

Test of hypothesis in advanced colorectal cancer

H0 : TTPR ≤ 0.75

A sign test statistic

For the ith patient, let ri be 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)X = (² i ri) / ² i ri²has a ² distribution with 1 d.f.

Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000.

A sign test statistic

Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000.

80%

85%

90%

HR0 = 0.7 = 0.05Correlation = 0.7

A sign test statistic

Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000.

HR0 = 0.7 = 0.05Correlation = 0.5

A sign test statistic

Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000.

HR0 = 0.7 = 0.05Correlation = 0.3

TTP1 vs. TTP2 in advanced colorectal cancer

R² = 0.03

TTP1 vs. TTP2 in advanced colorectal cancer

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.

TTPR – another test of hypothesis

Let p be the proportion of patients for whom TTPR > HR0.

A possible null hypothesis is:

H0: p p0

versus the alternative hypothesis:

HA: p > p0

which leads to Flemings’ one-stage or Simon’ two-stage designs.

TTP Ratio

Pro

babili

ty

TTP Ratio

0.0

0.2

0.4

0.6

0.8

1.0

0 0.4 0.8 2 3 4 5 6

Patients Events

147 137

22%

1.33

Tests of hypothesis in advanced colorectal cancer

H0 : p0 ≤ 22%

Trial of molecular profiling

TTP1

Last

progression,

entry on trial

Progression

on targeted

therapy

TTP2

At least two prior therapies for

advanced disease, no further therapy

available

Molecular profiling of tumor biopsy by IHC, FISH or micro-

array to identify target

Ref: Von Hoff, AACR 100th Annual Meeting, Denver, CO, April 18-22, 2009.

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%)

Trial of molecular profiling

Ref: Von Hoff, AACR 100th Annual Meeting, Denver, CO, April 18-22, 2009.

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

Trial of molecular profiling

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