# Study IL 0016

9.2 Statistical Methods

9.2.1 Justification of sample size

9.2.1.1 Objective response rate

The primary endpoint of the trial is the objective tumor response rate.
Patients will be randomized between 250 mg and 500 mg daily dose levels
of ZDI839 and stratified by ethnicity as Japanese versus non-Japanese.
The trial is sized to independently evaluate the tumor response rate in
the four strata defined by ZDI839 dose and ethnicity.

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 strata 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 will 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 of 20% 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 +/- 10% (Fleiss,Joseph L 1981).

[Study IL0039]{.underline}

9.2 Statistical methods

9.2.1 Justification of sample size

9.2.1.1 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, which will be analyzed on an intent-to-treat
basis. The trial is sized to independently evaluate the two co-primary
endpoints for each ZD1839 dose. For both the objective tumor response
rate and symptom improvement rate, the goal is to have a power of .90
for a 1-sided .0125 significance level test that the rate is ≤5 % when
the true rate is 15%. This requires that 200 patients be randomized to
obtain 100 per dose of ZD 1839 (Fleiss 1981). This design achieves a
1-sided .0115 significance level and power of .901. The two doses of ZD
1839 will be compared with respect to the two co-primary endpoints with
Fisher\'s exact lest.

9.2.2 Primary endpoints

-   Objective tumor response (complete + partial response} using
    Southwest Oncology Group (SWOG) modified UICCIWHO criteria

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-   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}

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-   Progression-free survival, overall survival

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-   Frequency and severity of adverse events (AEs)

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-   Changes in QOL using the FACT -L including time to worsening

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-   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:

![](media/image1.png){width="5.440277777777778in"
height="1.8430555555555554in"}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 of ZD1839, Hochberg\'s procedure will be used to maintain
an overall 1sided .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 ???≤ .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 on 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.