9.2 Statistical Methods
9.2.1 Justification of sample size
126.96.36.199 Objective response rate
The primary endpoint of the trial is the objective tumor
response rate. Patients will be
250 mg and 500 mg daily dose levels ofZDI839 and stratified by ethnicity as
Japanese versus non-apanese.
The trial is
Within each strata, the goal is to have 90% power for a
2-sided 5% significance level test that
the response rate is greater than 5% when the true response rate is 20%. This
requires a total of 45 patients evaluable for response per
It will be concluded that the response rate within a strata is greater than 5% if there are at
least 6 responses in 45 patients (13.3% observed rate, 95% exact confidence
interval 5.1% to 26.8%).
Assuming 10% of patients are not evaluable for response, a
total of 100 Japanese patients and 100 non-Japanese patients
win be randomized
to obtain 45 patients evaluable for response in each of the 4 strata.
With the 2 ethnicity strata combined, the trial will have 90
patients evaluable for response per ZDI839 dose level. Assuming an overall
response rate of20%
for each dose level, a 95% exact confidence interval for the overall response
rate can be calculated for each dose level independently with a width of +/-
9.2 Statistical methods
9.2.1 Justification of sample size
188.8.131.52 Objective response rate and symptom improvement rate
Patients will be randomized equally between 250 and 500 mg
ZD1839. The two co-primary endpoints are the objective tumor response rate and
symptom improvement rate
9.2.2 Primary endpoints
· Objective tumor response (complete + partial response} using Southwest Oncology Group (SWOG) modified UICCIWHO criteria
· Symptom improvement rate as measured by the Lung Cancer Subscale (LCS) of the FACT-L
9.2.3 Secondary endpoints
· Disease control rate (complete + partial response + stable disease}
· Progression-free survival, overall survival
· Frequency and severity of adverse events (AEs)
· Changes in QOL using the FACT -L including time to worsening
· Trough concentrations of ZDI839
9.2.4 Exploratory endpoint
· .EGFR expression
9.2.5 Definitions of trial populations used in the analysis
Two populations, intent-to-treat, per-protocol, are defined in Table 4 below:
9.2.6 Assessment of efficacy
The primary analysis of the overall best objective tumor response rate will be based on the investigator's assessment. Data from the REC's assessment will be used to corroborate the analysis of objective tumor response.
The primary analysis population for the overall best objective tumor response rate and symptom improvement rate per LCS will be the intent-to-treat population. To assess population sensitivity, the tumor response rate will also be analyzed in the per-protocol population, and the symptom improvement rate will also be analyzed in the per-protocol population.
For each dose ofZD1839, Hochberg's procedure will be used to
maintain an overall
.025 significance level for the two co-primary endpoints. The I-sided
significance level for each endpoint will be calculated as the probability of
the observed number or greater events (objective responses or symptom
improvements) given the sample size assuming a true event rate of 5%. If the
larger of the two significance levels is oS .025, then it
can be concluded that the event rate for both co-primary endpoints is > 5%.
Otherwise, if the smaller of the two significance levels is £ .0125,
then it can be concluded that the event rate for the corresponding endpoint
alone is > 5%. Given exactly 100 patients per dose, 11 events are required
to conclude that the event rate for a dose is > 5% at both a I-sided .025
and .0125 significance level (11.0% observed rate, 95% c.i. 5.6% to 18.8%,
97.5% c.i.s 5.1% to 20.0%).
The response rate and symptom improvement rate will be estimated separately by dose. Exact 95% confidence intervals (c.i.) will be calculated for each rate.
The two doses ofZDI839 will be compared with respect to the two co-primary endpoints with Fisher's exact test. Multivariate logistic regression models will be used to further explore a significant difference.
Overall survival, progression-free survival, and time to worsening of symptoms per LCS will be analyzed in the intent-to-treat and per-protocol populations.
Kaplan-Meier plots will be calculated by dose (Kaplan and Meier 1958) Non-parametric 95% c.i..s will be calculated for the median event times (Brookmeyer and Crowley 1982). .The two doses will be compared with respect to these endpoints with an unadjusted logrank test at a 1-sided .025 significance level.
Multivariate proportional hazard models will be used to further explore significant levels.
Disease control will be based objective tumor assessments and will include those patients responding complete response and partial response (CR and PR), plus those patients with stable disease, confirmed and sustained for at least 4 weeks.