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Erlotinib Hydrochloride

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Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

After 14 days and after 56 days of treatment with Erlotinib participants underwent FDG-PET and FLT-PET scans.

FDG prepared in sterile buffered solution for intravenous injection. Dosage was based on the participant's weight not to exceed 15 mCi (millicurie).

2-deoxy-2-[18F]fluoro-D-glucose (FDG)

FLT 7 mCi dose prepared in sterile buffered solution for intravenous injection.

3'-deoxy-3'-[18F]fluorothymidine (FLT)

erlotinib HCl

Bernard Fine, M.D.

This is a single-arm, open-label, multicenter, international pilot study to evaluate changes that occur in 2-deoxy-2-\[18F\]fluoro-D-glucose (FDG)- and 3'-deoxy-3'-\[18F\]fluorothymidine(FLT)-PET (Positron Emission Tomography) imaging as a result of treatment with erlotinib in patients with recurrent or refractory non-small cell lung cancer (NSCLC). The study will enroll approximately 30 patients at approximately 4 sites in Australia and 2 sites in the United States.

A Study of Changes in FDG- and FLT-PET Imaging in Patients With Non-Small Cell Lung Cancer Following Treatment With Erlotinib

Pilot Study of Changes in FDG- and FLT-PET Imaging in Patients With Non-Small Cell Lung Cancer Following Treatment With Erlotinib

PFS was defined as the time from the date of first erlotinib dose to disease progression or death, whichever occurs first.

PFS was compared between patients with FDG-PET response and patients without FDG-PET response, independent of CT response (per RECIST 1.0) at Day 56 of treatment with erlotinib.

Mean of the percent changes in maximal standard uptake values (mSUVmax) from FDG-PET scans was used to define FDG-PET response. Based on European Organization for Research on the Treatment of Cancer (EORTC) definitions, an objective FDG-PET response was defined an mSUVmax \<-25%.

PFS was defined as the time from the date of first erlotinib dose to disease progression or death, whichever occurs first.

PFS was compared between patients with FDG-PET response (Complete /Partial Responses) and patients with FDG-PET progression, within the subset of patients who demonstrated stable disease on CT (per RECIST 1.0) at Day 56 of treatment with erlotinib. FDG-PET response; defined as a mSUVmax from FDG-PET scans of \<-25% and FDG-PET disease progression; defined as a mSUVmax \>+25% or the development of a new lesion with a mSUVmax above background not explained by another cause.

PFS was defined as the time from the date of first erlotinib dose to disease progression or death, whichever occurs first.

PFS was compared between patients with FLT-PET response and patients without FLT-PET response, independent of CT response (per RECIST 1.0) at Day 56 of treatment with erlotinib.

FLT-PET response was defined as a mSUVmax from FLT-PET scans \<-25%.

PFS was defined as the time from the date of first erlotinib dose to disease progression or death, whichever occurs first.

PFS was compared between patients with FLT-PET response and patients without FLT-PET response, independent of computed tomography (CT) response (per RECIST 1.0) at Day 56 of treatment with erlotinib.

FLT-PET response was defined as a mSUVmax from FLT-PET scans \<-25% and FLT-PET disease progression was defined as a mSUVmax from FLT-PET scans \>+25% or the development of a new lesion with a mSUVmax above background not explained by another cause.

Overall survival (OS) was defined as the time from the date of first erlotinib dose to death.

Overall survival (OS) was compared between patients with FDG-PET response and patients without FDG-PET response, independent of Response Evaluation Criteria in Solid Tumors (RECIST 1.0) computed tomography (CT) response at Day 56 of treatment with erlotinib. FDG-PET response was defined as a mSUVmax from FDG-PET scans \<-25%.

Overall survival (OS) was defined as the time from the date of first erlotinib dose to death.

OS was compared between patients with FDG-PET response and patients with FDG-PET progression, within the subset of patients who demonstrated stable disease (SD) on CT (per RECIST 1.0) at Day 56 of treatment with erlotinib.

FDG-PET response was defined as a mSUVmax from FDG-PET scans \<-25% and FDG-PET disease progression was defined as a mSUVmax from FDG-PET scans \>+25% or the development of a new lesion with a mSUVmax above background not explained by another cause.

Overall survival (OS) was defined as the time from the date of first erlotinib dose to death.

OS was compared between patients with FLT-PET response and patients without FLT-PET response, independent of CT response (per RECIST 1.0) at Day 56 of treatment with erlotinib.

FLT-PET response was defined as a mSUVmax from FLT-PET scans \<-25%.

Overall survival (OS) was defined as the time from the date of first erlotinib dose to death.

OS was compared between patients with FLT-PET response and patients with FLT-PET progression, within the subset of patients who demonstrated SD on CT (per RECIST 1.0) at Day 56 of treatment with erlotinib.

FLT-PET response was defined as a mSUVmax from FLT-PET scans of \<-25% and FLT-PET disease progression was defined as a mSUVmax from FLT-PET scans \>+25% or the development of a new lesion with a mSUVmax above background not explained by another cause.

In patients with computed tomography (CT)-stable disease (according to RECIST 1.0) at 56 days of erlotinib treatment, the percentage of patients who demonstrated FDG-PET responses after the initial 14 days and 56 days of erlotinib treatment.

FDG-PET response was defined as a mSUVmax from FDG-PET scans \<-25%.

CT SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since the treatment started.

In patients with CT-stable disease (according to RECIST 1.0) at 56 days of erlotinib treatment, the percentage of patients who demonstrated FLT-PET responses after the initial 14 days and 56 days of erlotinib treatment.

FLT-PET response was defined as a mSUVmax from FLT-PET scans \<-25%. CT SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since the treatment started.

In patients with partial response or progressive disease on CT (per RECIST 1.0) after 56 days of erlotinib treatment, the percentage of patients who demonstrated FDG-PET responses on Day 56 defined as a mSUVmax from FDG-PET scans \<-25%.

CT Partial Response defined as a 30% decrease in the sum of the longest diameter (LD) of target lesion taking as reference the baseline sum of the LD.

CT Progressive disease defined as a 20% increase in the sum of the longest diameter of target lesions taking as reference the smallest sum LD since treatment started or appearance of 1 or more new lesions.

In patients with partial response or progressive disease on CT (per RECIST 1.0) after 56 days of erlotinib treatment, the percentage of patients who demonstrated FLT-PET responses on Day 56 defined as a mSUVmax from FLT-PET scans \<-25%.

CT Partial Response defined as a 30% decrease in the sum of the longest diameter (LD) of target lesion taking as reference the baseline sum of the LD.

CT Progressive disease defined as a 20% increase in the sum of the longest diameter of target lesions taking as reference the smallest sum LD since treatment started or appearance of 1 or more new lesions.

The number of participants who experienced an adverse event judged by the investigator to be related to FLT-PET.

Roche Pharma AG

Genentech, Inc.

Includes evaluation of all Safety-Evaluable Patients \[n = 85\].

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

After 14 days and after 56 days of treatment with Erlotinib, participants underwent FDG-PET and FLT-PET scans. FDG-PET intravenous injection-dosage based on participant's weight not to exceed 15 mCi and FLT-PET intravenous dose of 7 mCi.

Erlotinib

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

Patients who were treated with any dose of erlotinib were included in the summary of baseline measures.

Age, Continuous

Sex: Female, Male

Medical Communications

The null hypothesis is that there is no difference in PFS between FDG Responders and FDG Non-Responders. The alternative hypothesis is that FDG Responders would have prolonged PFS compared with FDG Non-Responders.

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

FDG-PET was scheduled on screening, Day 14 and Day 56. FDG intravenous injection-dosage based on participant's weight not to exceed 15 mCi. Patients who had CR/PR on FDG-PET scans at Day 56 were included in this group.

Erlotinib_FDG Responders

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

FDG-PET was scheduled on screening, Day 14 and Day 56. FDG intravenous injection-dosage based on participant's weight not to exceed 15 mCi. Patients who did not have CR/PR on FDG-PET scans at Day 56 were included in this group.

Erlotinib_ FDG Non-Responders

FDG-Evaluable Patients. Participants who were treated with erlotinib and underwent all FDG-PET scans through Day 56 were included in the analysis. Censoring occurred at the date of the last tumor assessment.

Progression Free Survival (PFS) of Groups by FDG Response at Day 56

Day 14 response

Day 56 response

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

FDG-PET was scheduled on screening, Day 14 and Day 56. FDG intravenous injection-dosage based on participant's weight not to exceed 15 mCi.

FDG-Evaluable patients. Participants who were treated with erlotinib, underwent all FDG-PET scans through Day 56 and had stable disease by CT at Day 56 were included in the analysis.

Percentage of Patients With FDG-PET Responses

The null hypothesis is that there is no difference in PFS between FDG Responders and FDG Progressive Disease. The alternative hypothesis is that FDG Responders would have a prolonged PFS compared to FDG Progressive Disease.

Erlotinib_FDG Responders With CT SD at Day 56

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

FDG-PET was scheduled on screening, Day 14 and Day 56. FDG intravenous injection-dosage based on participant's weight not to exceed 15 mCi. Patients who had Progressive disease on FDG-PET scans at Day 56 were included in this group.

Erlotinib_FDG Progressive Disease With CT SD at Day 56

FDG-Evaluable patients were treated with erlotinib, underwent all FDG-PET scans through Day 56 and had SD by CT at Day 56. Censoring at last tumor assessment.

CT SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since treatment start.

PFS of Patients With FDG-PET Complete Response (CR)/Partial Response (PR) Versus FDG-PET Progressive Disease (PD) in Patients With Computed Tomography (CT) Stable Disease (SD) at Day 56

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

FLT-PET was scheduled on screening, Day 14 and Day 56. FLT intravenous injection dose was 7 mCi.

FLT-Evaluable Patients. Participants who were treated with erlotinib, underwent all FLT-PET scans through Day 56 and had stable disease by CT at Day 56 were included in the analysis.

Percentage of Patients With FLT-PET Responses

The null hypothesis is that there is no difference in PFS between FLT Responders and FLT Non-Responders. The alternative hypothesis is that FLT Responders would have prolonged PFS compared with FLT Non-Responders.

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

FLT-PET was scheduled on screening, Day 14 and Day 56. FLT intravenous injection dose was 7 mCi. Patients who had CR/PR on FLT-PET scans at Day 56 were included in this group.

Erlotinib_FLT Responders

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

FLT-PET was scheduled on screening, Day 14 and Day 56. FLT intravenous injection dose was 7 mCi. Patients who did not have CR/PR on FLT-PET scans at Day 56 were included in this group.

Erlotinib_ FLT Non-Responders

FLT-Evaluable Patients. Participants who were treated with erlotinib and underwent all FLT-PET scans through Day 56 were included in the analysis. Censoring occurred at the date of the last tumor assessment.

Progression Free Survival of Groups by FLT Response at Day 56

The null hypothesis is that there is no difference between FLT Responders and FLT Progressive Disease. Alternative hypothesis is that FLT responders would have prolonged PFS compared to FLT Progressive Disease.

Erlotinib_FLT Responders With CT SD at Day 56

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

FLT-PET was scheduled on screening, Day 14 and Day 56. FLT intravenous injection dose was 7 mCi. Patients who had Progressive disease on FLT-PET scans at Day 56 were included in this group.

Erlotinib_FLT Progressive Disease With CT SD at Day 56

FLT-Evaluable patients were treated with erlotinib, underwent all FLT-PET scans through Day 56 and had SD by CT at Day 56. Censoring at last tumor assessment.

CT SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since treatment start.

Progression Free Survival of Patients With FLT CR/PR Versus FLT PD in Patients With CT SD at Day 56

The null hypothesis is that there is no difference in OS between FDG Responders and FDG Non-Responders. The alternative hypothesis is that FDG responders would have prolonged OS compared with FDG Non-Responders.

Erlotinib_ FDG Non-Responder

FDG-Evaluable Patients. Participants who were treated with erlotinib and underwent all FDG-PET scans through Day 56 were included in the analysis. Censoring occurred at the last date patients known to be alive.

Overall Survival of Groups by FDG Response at Day 56

CT Partial response (n=4)

CT Progressive Disease (n=21)

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

FDG-PET was scheduled on screening, Day 14 and Day 56. FDG intravenous injection-dosage based on participant's weight no to exceed 15 mCi.

FDG-Evaluable Patients. Participants who were treated with erlotinib and underwent all FDG-PET scans through Day 56 were included in the analysis.

FDG Response in Subgroups by CT Response at Day 56

CT Progressive Disease (n=20)

FLT-Evaluable Patients. Participants who were treated with erlotinib and underwent all FLT-PET scans through Day 56 were included in the analysis.

FLT Response in Subgroups by CT Response at Day 56

The null hypothesis is that there is no difference in Overall Survival between FDG Responders and FDG Progressive Disease. The alternative hypothesis is that FDG Responders would have prolonged OS compared with FDG Progressive Disease.

Patients who were treated with erlotinib, underwent all FDG-PET scans thru Day 56 and had SD by CT at Day 56. Censoring at last date patients known to be alive.

CT SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since treatment start.

Overall Survival of Patients With FDG CR/PR Versus FDG PD in Patients With CT SD at Day 56

The null hypothesis is that there is no difference in OS between FLT Responders and FLT Non-Responders. The alternative hypothesis is that FLT Responders would have prolonged OS compared with FLT Non-Responders.

FLT-Evaluable Patients. Participants who were treated with erlotinib and underwent all FLT-PET scans through Day 56 were included in the analysis. Censoring occurred at the last date patients known to be alive.

Overall Survival of Groups by FLT Response at Day 56

The null hypothesis is that there is no difference in OS between FLT Responders and FLT Progressive Disease. The alternative hypothesis is that FLT Responders would have prolonged OS compared with FLT Progressive Disease.

Patients who were treated with erlotinib,underwent all FLT-PET scans thru Day 56 and had SD by CT at Day 56. Censoring at last date patients known to be alive.

CT SD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter since the treatment started.

Overall Survival of Patients With FLT CR/PR Versus FLT PD in Patients With CT SD at Day 56

All Participants who underwent any FLT-PET scan during the study (including screening) were included in the analysis.

FLT-PET was scheduled on screening, Day 14 and Day 56. FLT intravenous injection dose was 7 mCi.

Overall Study Participants

Patients with non-small cell lung cancer (NSCLC) who underwent FLT-PET scans.

Number of Participants With Adverse Events Due to FLT-PET Imaging

Erlotinib 150 mg/day taken orally at approximately the same time of day with 200 mL (6-8 Ounces) of water on an empty stomach. Participants received Erlotinib for 1 year or until they developed progressive disease or intolerable toxicity.

After 14 days and after 56 days of treatment with Erlotinib participants underwent FDG-PET (2-deoxy-2-\[18F\]fluoro-D-glucose-Positron Emission Tomogrpahy)and FLT-PET (3'-deoxy-3'-\[18F\]fluorothymidine-Positron Emission Tomogrpahy) scans.

FDG-PET intravenous injection dosage was based on participant's weight not to exceed 15 mCi and FLT-PET intravenous dose was 7 mCi.

Overall Study

Sang-We Kim, M.D.

Chang-Min Choi, Prof

Erlotinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Higher response rates were observed in a subset of patients with female gender, Asian ethnicity, no smoking history, mutations in EGFR tyrosine kinase, high EGFR gene copy number and adenocarcinoma histology. However, the therapeutic effect of Erlotinib is not confined to patients whose tumors harbor EGFR mutations and other predictors of efficacy of this agent. And these tests require time and sufficiently large specimens for processing, whereas many patients with advanced NSCLC are diagnosed based on cytology alone.

This study was designed to evaluate FLT-PET or FDG-PET usefulness in the early assessment of treatment response and in predicting patient outcome after erlotinib monotherapy for patients with non-small cell lung cancer prospectively. Changes in tumor FLT or FDG uptake 7 days after the initiation of treatment will be compared between responders and nonresponders based on subsequent CT scans.

1. Primary objectives:

   To see whether the % change in SUVmax of a tumor with FLT-PET or FDG-PET at 7 days after initiating erlotinib treatment compared with baseline SUVmax (ΔSUVmax) would predict the tumor's responsiveness. And the responsiveness will be decided with the CT scan after 6 weeks of erlotinib treatment.
2. Secondary objectives:

To compare ΔSUVmax and the degree of tumor shrinkage in longest diameter during erlotinib treatment.

To see ΔSUVmax in the tumors with stable disease. To see the time to progression and overall survival according to ΔSUVmax. To compare the result of FDG-PET and FLT-PET.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Changes in FDG- and FLT-PET Imaging in Patients With Non-Small Cell Lung Cancer Following Treatment With Erlotinib	NCT00453362	Non-Small Cell ...	2-deoxy-2-[18F]... 3'-deoxy-3'-[18... erlotinib HCl	18 Years -	Genentech, Inc.
The Role of Positron Emission Tomography (PET) During Erlotinib Treatment for Non-small Cell Lung Cancer	NCT01000428	Erlotinib Lung Cancer		18 Years - 85 Years	Asan Medical Center
A Study of Changes in FDG- and FLT-PET Imaging in Patients With Non-Small Cell Lung Cancer Following Treatment With Erlotinib	NCT00453362	Non-Small Cell ...	2-deoxy-2-[18F]... 3'-deoxy-3'-[18... erlotinib HCl	18 Years -	Genentech, Inc.
The Role of Positron Emission Tomography (PET) During Erlotinib Treatment for Non-small Cell Lung Cancer	NCT01000428	Erlotinib Lung Cancer		18 Years - 85 Years	Asan Medical Center

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