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A Study of Enzastaurin and Erlotinib in Participants With Solid Tumors and Lung Cancer

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT00452413
Collaborator
(none)
65
Enrollment
10
Locations
1
Arm
78.1
Duration (Months)
6.5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase I: A study to see what doses of Enzastaurin and Erlotinib are best tolerated by participants with solid tumor cancer.

Phase II: A study to see how long participants with non-small cell lung cancer (NSCLC) treated with Enzastaurin and Erlotinib live.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
65 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2 Trial of Enzastaurin and Erlotinib in Patients With Advanced Solid Tumors and Non-Small Cell Lung Cancer (NSCLC) After Prior Chemotherapy
Study Start Date :
May 1, 2007
Actual Primary Completion Date :
Jul 1, 2009
Actual Study Completion Date :
Nov 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Enzastaurin and erlotinib combination therapy

Enzastaurin: Phase 1, Dose Level 1: 500 milligram (mg) oral loading dose Day 1, 250 mg oral, daily Day 2-28, 28-day cycle until disease progression Phase 1, Dose Level 2: 1125 mg oral loading dose Day 1, 500 mg oral, daily until disease progression Phase 2: Dose determined from Phase 1, oral, daily, 28-day cycles until disease progression Erlotinib: • 150 mg, oral, daily, 28-day cycles until disease progression

Drug: enzastaurin
Administered orally
Other Names:
  • LY317615

    • Drug: erlotinib
    Administered orally

    Outcome Measures

    Primary Outcome Measures

    1. Recommended Phase 2 Dose for Enzastaurin Plus Erlotinib Combination Therapy (Assess the Tolerated Dose of the Combination Erlotinib and Enzastaurin) [Phase 1: Predose through end of Cycle 1 (28 days/cycle)]

      The recommended Phase 2 daily dose level was to be either 1 dose level below that in which 2 of 6 participants experienced dose-limiting toxicities (DLTs) in Phase 1 or the full doses of both enzastaurin and erlotinib (Phase 1, Dose Level 2) in the event that no more than 1 DLT occurred at the highest dose level (Dose Level 2). DLTs were defined as any of the following events during Phase 1, Cycle 1 that were considered by the investigator to be attributable to enzastaurin or the combination of enzastaurin with erlotinib: Grade 4 hematologic events; Grade 3 or 4 nonhematologic events except toxicities explained by a coexisting condition such as glucose disturbances in a diabetic or electrolyte imbalances from diarrhea or vomiting, and toxicities of nausea, vomiting, diarrhea, or skin rash that were tolerable with appropriate treatment.

    2. Phase 2: Progression-Free Survival (PFS) With the Enzastaurin Plus Erlotinib Combination Regimen [Phase 2: Baseline to measured PD (up to 20 months)]

      PFS was defined as the time from the date of study enrollment (baseline) to the first date of progressive disease (PD) (either objectively determined or clinical progression) or death from any cause. PD was defined by Response Evaluation Criteria in Solid Tumors [RECIST, version (v) 1.0] as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. For participants not known to have died as of the data cut-off date and who did not have PD, PFS was censored at the date of the last visit with adequate assessment. For participants who received subsequent anticancer therapy (after discontinuation from study treatment) prior to disease progression or death, PFS was censored at the date of last visit with adequate assessment prior to the initiation of post discontinuation anticancer therapy.

    Secondary Outcome Measures

    1. Phase I: Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) (Safety and AE Profile for Enzastaurin/Erlotinib Combination) [Phase 1: First dose through 30 days post last dose (up to 14 Cycles, 28 days/cycle)]

      A TEAE is any untoward medical occurrence that either occurred or worsened any time after treatment baseline, which did not necessarily have a causal relationship with this treatment. A summary of serious and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.

    2. Phase I: Pharmacokinetic (PK) Interactions Between Enzastaurin and Erlotinib: Apparent Oral Clearance of Erlotinib Under Steady State Conditions During Multiple Dosing (CLss/F) [Phase 1: Cycle 1, Day 22 [predose, 2 hours (h), 4 h, 6 h, 10 h postdose]]

      Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL obtained after an oral dose (apparent oral CL) is influenced by the fraction of the dose absorbed (F). Drug CL is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent oral CL of erlotinib over 10 hours at steady state (ss) on Day 22 was calculated.

    3. Phase I: PK Interactions Between Enzastaurin and Erlotinib: Maximum Observed Plasma Concentration at Steady State (Cmax,ss) [Phase 1: Cycle 1, Day 22 (predose, 2 h, 4 h, 6 h, 8 h postdose)]

      Maximum observed plasma concentration at steady state (Cmax,ss) of enzastaurin, its active metabolite (LSN326020) and total analyte were reported.

    4. Phase I: PK Interactions Between Enzastaurin and Erlotinib: Area Under the Plasma Concentration Time Curve at Steady State [AUC(Tau,ss)] [Phase 1, Cycle 1, Day 22 (predose, 2 h, 4 h, 6 h, and 8 h postdose)]

      Area under the plasma concentration time curve AUC(Tau,ss) of enzastaurin, its active metabolite (LSN326020) and total analyte were reported.

    5. Phase 2: Overall Survival (OS) [Phase 2: Baseline to date of death from any cause (up to 23 months)]

      OS was defined as the time from the date of study enrollment (baseline) to the date of death from any cause. For participants not known to have died as of the data cutoff date, OS was censored at the last contact date (last contact for participants in post discontinuation was equal to the last known alive date in mortality status).

    6. Phase 2: Duration of Response [Phase 2: Date of first response to date of PD (up to 18 months)]

      Duration of response: time from first objective assessment of complete response (CR) or partial response (PR) to first observation of PD. Using RECIST v1.0 criteria, CR was the disappearance of all target lesions; PR was either a ≥30% decrease in sum of LD of target lesions or a complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesion; PD was a ≥20% increase in sum of LD of target lesions, taking as references the smallest sum LD recorded since treatment started or the appearance of ≥1 new lesion. For responding participants not known to have died and who did not have PD, duration of response was censored at date of the last visit with adequate assessment. For responding participants who received subsequent anticancer therapy (after discontinuation from study treatment) prior to PD, duration of response was censored at the date of last visit with adequate assessment prior to the initiation of post discontinuation anticancer therapy.

    7. Phase 2: Percentage of Participants With Tumor Response [Phase 2: Baseline to date of PD (up to 18 months)]

      Tumor response was defined using RECIST, v1.0 criteria. CR was the disappearance of all target lesions; PR was either a ≥30% decrease in sum of LD of target lesions or a complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesion. PD was a ≥20% increase in sum of LD of target lesions, taking as references the smallest sum LD recorded since treatment started or the appearance of ≥1 new lesion. Stable Disease (SD) was defined as small changes that did not meet the above criteria. Percentage of participants with tumor response=[(number of participants with a CR, PR, SD, PD, and unknown response)/(total number of participants assessed)]*100.

    8. Phase 2: Number of Participants Who Experienced TEAEs (Safety and AE Profile) [Phase 2: Baseline through 30 days post last dose (up to 24 Cycles, 28 days/cycle)]

      A TEAE is any untoward medical occurrence that either occurred or worsened any time after treatment baseline, which did not necessarily have a causal relationship with this treatment. A summary of serious and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Phase 1: Any incurable solid malignancy, with no more than 3 prior systemic treatment regimens.

    Phase 2: Histologic diagnosis of advanced NSCLC, Stage IIIB with malignant pleural effusion or Stage IV per American Joint Committee on Cancer Staging Criteria for NSCLC. Participants must have failed 1 or 2 prior systemic treatment regimen(s).

    1. Performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) Scale

    2. Prior chemotherapy must be completed at least 2 weeks prior to study enrollment, and the participant must have recovered from acute toxic effects (except alopecia) prior to enrollment.

    3. Prior radiotherapy is allowed to <25% of the bone marrow. Prior radiotherapy must be completed at least 2 weeks before study enrollment, and the participant must have recovered from acute toxic effects (except alopecia) prior to enrollment.

    4. Non-measurable or measurable disease as defined by Response Evaluation Criteria in Solid Tumors [RECIST, version (v) 1.0].

    Exclusion Criteria:

    Participants who

    1. Are unable to swallow tablets.

    2. Unable to discontinue use of carbamazepine, phenobarbital, and phenytoin.

    3. Have previously been treated with an epidermal growth factor receptor (EGFR) inhibitor, including erlotinib.

    4. Are receiving concurrent administration of any other antitumor therapy.

    5. Have received treatment within the last 30 days with a drug (not including study drug) that has not received regulatory approval for any indication at the time of study entry.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Los Angeles California United States 90048
    2 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Palo Alto California United States 94305
    3 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. San Francisco California United States 94143
    4 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Louisville Kentucky United States 40207
    5 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Baltimore Maryland United States 21237
    6 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Minneapolis Minnesota United States 55455
    7 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Omaha Nebraska United States 68131
    8 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Portland Oregon United States 97213
    9 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Memphis Tennessee United States 38104
    10 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Lubbock Texas United States 79410

    Sponsors and Collaborators

    • Eli Lilly and Company

    Investigators

    • Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5PM Eastern time (UTC/GMT- 5 hours, EST), Eli Lilly and Company

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT00452413
    Other Study ID Numbers:
    • 11183
    • H6Q-MC-S030
    First Posted:
    Mar 27, 2007
    Last Update Posted:
    May 13, 2021
    Last Verified:
    Apr 1, 2021
    Additional relevant MeSH terms:
    Lung Neoplasms
    Carcinoma, Non-Small-Cell Lung
    Erlotinib Hydrochloride

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail This study included 2 phases: Phase 1, a dose-escalation phase (employing a standard "3 + 3" design with dose escalation to Dose Level 2 based upon observed toxicity) and Phase 2, a dose-confirmation phase.
    Arm/Group Title Phase 1, Dose 1 (Enzastaurin 250 mg, Erlotinib 150 mg) Phase 1, Dose 2 (Enzastaurin 500 mg, Erlotinib 150 mg) Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 500 milligram (mg) enzastaurin loading dose [250 mg twice daily (BID)] administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 250 mg dose administered once daily (QD). Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Enzastaurin: 1125 mg enzastaurin loading dose [375 mg 3 times daily (TID)] administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg total daily dose administered orally using either a BID or QD schedule. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Period Title: Overall Study
    STARTED 4 12 49
    Received at Least 1 Dose of Study Drug 4 12 49
    COMPLETED 0 0 0
    NOT COMPLETED 4 12 49

    Baseline Characteristics

    Arm/Group Title Phase 1, Dose 1 (Enzastaurin 250 mg, Erlotinib 150 mg) Phase 1, Dose 2 (Enzastaurin 500 mg, Erlotinib 150 mg) Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg) Total
    Arm/Group Description Enzastaurin: 500 mg enzastaurin loading dose (250 mg BID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 250 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg total daily dose administered orally using either a BID or QD schedule. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Total of all reporting groups
    Overall Participants 4 12 49 65
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    74.0
    (10.5)
    62.5
    (8.45)
    67.0
    (9.19)
    66.0
    (NA)
    Sex: Female, Male (Count of Participants)
    Female
    4
    100%
    9
    75%
    20
    40.8%
    33
    50.8%
    Male
    0
    0%
    3
    25%
    29
    59.2%
    32
    49.2%
    Race/Ethnicity, Customized (Count of Participants)
    Caucasian
    3
    75%
    8
    66.7%
    38
    77.6%
    49
    75.4%
    Hispanic
    0
    0%
    1
    8.3%
    1
    2%
    2
    3.1%
    East Asian
    1
    25%
    3
    25%
    7
    14.3%
    11
    16.9%
    African
    0
    0%
    0
    0%
    3
    6.1%
    3
    4.6%
    Region of Enrollment (Count of Participants)
    United States
    4
    100%
    12
    100%
    49
    100%
    65
    100%
    Stage of Disease at Initial Diagnosis (Count of Participants)
    Stage IIIB
    0
    0%
    1
    8.3%
    6
    12.2%
    7
    10.8%
    Stage IV
    4
    100%
    11
    91.7%
    43
    87.8%
    58
    89.2%

    Outcome Measures

    1. Primary Outcome
    Title Recommended Phase 2 Dose for Enzastaurin Plus Erlotinib Combination Therapy (Assess the Tolerated Dose of the Combination Erlotinib and Enzastaurin)
    Description The recommended Phase 2 daily dose level was to be either 1 dose level below that in which 2 of 6 participants experienced dose-limiting toxicities (DLTs) in Phase 1 or the full doses of both enzastaurin and erlotinib (Phase 1, Dose Level 2) in the event that no more than 1 DLT occurred at the highest dose level (Dose Level 2). DLTs were defined as any of the following events during Phase 1, Cycle 1 that were considered by the investigator to be attributable to enzastaurin or the combination of enzastaurin with erlotinib: Grade 4 hematologic events; Grade 3 or 4 nonhematologic events except toxicities explained by a coexisting condition such as glucose disturbances in a diabetic or electrolyte imbalances from diarrhea or vomiting, and toxicities of nausea, vomiting, diarrhea, or skin rash that were tolerable with appropriate treatment.
    Time Frame Phase 1: Predose through end of Cycle 1 (28 days/cycle)

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 1 who received at least 1 dose of study drug (either enzastaurin or erlotinib).
    Arm/Group Title Phase 1, Dose 1 and 2 (Enzastaurin and Erlotinib)
    Arm/Group Description Enzastaurin: Either 500 mg or 1125 mg enzastaurin loading dose administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, either 250 mg or 500 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Measure Participants 16
    Enzastaurin
    500
    Erlotinib
    150
    2. Primary Outcome
    Title Phase 2: Progression-Free Survival (PFS) With the Enzastaurin Plus Erlotinib Combination Regimen
    Description PFS was defined as the time from the date of study enrollment (baseline) to the first date of progressive disease (PD) (either objectively determined or clinical progression) or death from any cause. PD was defined by Response Evaluation Criteria in Solid Tumors [RECIST, version (v) 1.0] as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. For participants not known to have died as of the data cut-off date and who did not have PD, PFS was censored at the date of the last visit with adequate assessment. For participants who received subsequent anticancer therapy (after discontinuation from study treatment) prior to disease progression or death, PFS was censored at the date of last visit with adequate assessment prior to the initiation of post discontinuation anticancer therapy.
    Time Frame Phase 2: Baseline to measured PD (up to 20 months)

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 2 who received at least 1 dose of study drug (either enzastaurin or erlotinib). Eight participants were censored.
    Arm/Group Title Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg total daily dose administered orally using either a BID or QD schedule. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Measure Participants 41
    Median (90% Confidence Interval) [months]
    1.7
    3. Secondary Outcome
    Title Phase I: Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) (Safety and AE Profile for Enzastaurin/Erlotinib Combination)
    Description A TEAE is any untoward medical occurrence that either occurred or worsened any time after treatment baseline, which did not necessarily have a causal relationship with this treatment. A summary of serious and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
    Time Frame Phase 1: First dose through 30 days post last dose (up to 14 Cycles, 28 days/cycle)

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 1 who received at least 1 dose of study drug (either enzastaurin or erlotinib).
    Arm/Group Title Phase 1, Dose 1 (Enzastaurin 250 mg, Erlotinib 150 mg) Phase 1, Dose 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 500 mg enzastaurin loading dose (250 mg BID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 250 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Measure Participants 4 12
    Number [Participants]
    4
    100%
    12
    100%
    4. Secondary Outcome
    Title Phase I: Pharmacokinetic (PK) Interactions Between Enzastaurin and Erlotinib: Apparent Oral Clearance of Erlotinib Under Steady State Conditions During Multiple Dosing (CLss/F)
    Description Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL obtained after an oral dose (apparent oral CL) is influenced by the fraction of the dose absorbed (F). Drug CL is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent oral CL of erlotinib over 10 hours at steady state (ss) on Day 22 was calculated.
    Time Frame Phase 1: Cycle 1, Day 22 [predose, 2 hours (h), 4 h, 6 h, 10 h postdose]

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 1 who received at least 1 dose of study drug (enzastaurin or erlotinib) and had adequate sample data to estimate CLss/F of erlotinib.
    Arm/Group Title Phase 1, Dose 1 (Enzastaurin 250 mg, Erlotinib 150 mg) Phase 1, Dose 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 500 mg enzastaurin loading dose (250 mg BID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 250 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Measure Participants 3 11
    Geometric Mean (Geometric Coefficient of Variation) [Liters per hour (L/h)]
    6.07
    (19)
    5.75
    (45)
    5. Secondary Outcome
    Title Phase I: PK Interactions Between Enzastaurin and Erlotinib: Maximum Observed Plasma Concentration at Steady State (Cmax,ss)
    Description Maximum observed plasma concentration at steady state (Cmax,ss) of enzastaurin, its active metabolite (LSN326020) and total analyte were reported.
    Time Frame Phase 1: Cycle 1, Day 22 (predose, 2 h, 4 h, 6 h, 8 h postdose)

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 1 who received at least 1 dose of study drug (enzastaurin or erlotinib) and had adequate sample data to estimate Cmax,ss of enzastaurin, its active metabolite and total analyte.
    Arm/Group Title Phase 1, Dose 1 (Enzastaurin 250 mg, Erlotinib 150 mg) Phase 1, Dose 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 500 mg enzastaurin loading dose (250 mg BID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 250 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Measure Participants 3 12
    Enzastaurin
    618
    (709)
    1600
    (57)
    LSN326020
    431
    (806)
    980
    (41)
    Total Analyte
    978
    (797)
    2620
    (44)
    6. Secondary Outcome
    Title Phase I: PK Interactions Between Enzastaurin and Erlotinib: Area Under the Plasma Concentration Time Curve at Steady State [AUC(Tau,ss)]
    Description Area under the plasma concentration time curve AUC(Tau,ss) of enzastaurin, its active metabolite (LSN326020) and total analyte were reported.
    Time Frame Phase 1, Cycle 1, Day 22 (predose, 2 h, 4 h, 6 h, and 8 h postdose)

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 1 who received at least 1 dose of study drug (enzastaurin or erlotinib) and had adequate sample data to estimate AUC(Tau,ss) of enzastaurin, its active metabolite, and total analyte.
    Arm/Group Title Phase 1, Dose 1 (Enzastaurin 250 mg, Erlotinib 150 mg) Phase 1, Dose 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 500 mg enzastaurin loading dose (250 mg BID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 250 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Measure Participants 3 12
    Enzastaurin
    6590
    (412)
    18000
    (71)
    LSN326020
    7100
    (890)
    18000
    (44)
    Total Analyte
    14000
    (598)
    37100
    (51)
    7. Secondary Outcome
    Title Phase 2: Overall Survival (OS)
    Description OS was defined as the time from the date of study enrollment (baseline) to the date of death from any cause. For participants not known to have died as of the data cutoff date, OS was censored at the last contact date (last contact for participants in post discontinuation was equal to the last known alive date in mortality status).
    Time Frame Phase 2: Baseline to date of death from any cause (up to 23 months)

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 2 who received at least 1 dose of study drug (either enzastaurin or erlotinib). Eighteen participants were censored.
    Arm/Group Title Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg total daily dose administered orally using either a BID or QD schedule. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Measure Participants 31
    Median (95% Confidence Interval) [months]
    8.3
    8. Secondary Outcome
    Title Phase 2: Duration of Response
    Description Duration of response: time from first objective assessment of complete response (CR) or partial response (PR) to first observation of PD. Using RECIST v1.0 criteria, CR was the disappearance of all target lesions; PR was either a ≥30% decrease in sum of LD of target lesions or a complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesion; PD was a ≥20% increase in sum of LD of target lesions, taking as references the smallest sum LD recorded since treatment started or the appearance of ≥1 new lesion. For responding participants not known to have died and who did not have PD, duration of response was censored at date of the last visit with adequate assessment. For responding participants who received subsequent anticancer therapy (after discontinuation from study treatment) prior to PD, duration of response was censored at the date of last visit with adequate assessment prior to the initiation of post discontinuation anticancer therapy.
    Time Frame Phase 2: Date of first response to date of PD (up to 18 months)

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 2 who received at least 1 dose of study drug (either enzastaurin or erlotinib) and had a CR or PR response. Two participants were censored.
    Arm/Group Title Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg total daily dose administered orally using either a BID or QD schedule. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Measure Participants 3
    Median (95% Confidence Interval) [months]
    8.7
    9. Secondary Outcome
    Title Phase 2: Percentage of Participants With Tumor Response
    Description Tumor response was defined using RECIST, v1.0 criteria. CR was the disappearance of all target lesions; PR was either a ≥30% decrease in sum of LD of target lesions or a complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesion. PD was a ≥20% increase in sum of LD of target lesions, taking as references the smallest sum LD recorded since treatment started or the appearance of ≥1 new lesion. Stable Disease (SD) was defined as small changes that did not meet the above criteria. Percentage of participants with tumor response=[(number of participants with a CR, PR, SD, PD, and unknown response)/(total number of participants assessed)]*100.
    Time Frame Phase 2: Baseline to date of PD (up to 18 months)

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 2 who received at least 1 dose of study drug (either enzastaurin or erlotinib).
    Arm/Group Title Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg total daily dose administered orally using either a BID or QD schedule. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Measure Participants 49
    CR
    0
    0%
    PR
    10.2
    255%
    SD
    20.4
    510%
    PD
    42.9
    1072.5%
    Unknown
    26.5
    662.5%
    10. Secondary Outcome
    Title Phase 2: Number of Participants Who Experienced TEAEs (Safety and AE Profile)
    Description A TEAE is any untoward medical occurrence that either occurred or worsened any time after treatment baseline, which did not necessarily have a causal relationship with this treatment. A summary of serious and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
    Time Frame Phase 2: Baseline through 30 days post last dose (up to 24 Cycles, 28 days/cycle)

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 2 who received at least 1 dose of study drug (either enzastaurin or erlotinib).
    Arm/Group Title Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg total daily dose administered orally using either a BID or QD schedule. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    Measure Participants 49
    Number [participants]
    48
    1200%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Phase 1, Dose 1 (Enzastaurin 250 mg, Erlotinib 150 mg) Phase 1, Dose 2 (Enzastaurin 500 mg, Erlotinib 150 mg) Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Arm/Group Description Enzastaurin: 500 milligram (mg) enzastaurin loading dose [250 mg twice daily (BID)] administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 250 mg dose administered once daily (QD). Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Enzastaurin: 1125 mg enzastaurin loading dose [375 mg 3 times daily (TID)] administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg dose administered QD. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met. Enzastaurin: 1125 mg enzastaurin loading dose (375 mg TID) administered orally on Day 1 of a 28-day cycle. Day 2 through Day 28, 500 mg total daily dose administered orally using either a BID or QD schedule. Erlotinib: 150 mg dose of erlotinib administered orally QD. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal criteria were met.
    All Cause Mortality
    Phase 1, Dose 1 (Enzastaurin 250 mg, Erlotinib 150 mg) Phase 1, Dose 2 (Enzastaurin 500 mg, Erlotinib 150 mg) Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Phase 1, Dose 1 (Enzastaurin 250 mg, Erlotinib 150 mg) Phase 1, Dose 2 (Enzastaurin 500 mg, Erlotinib 150 mg) Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/4 (25%) 3/12 (25%) 18/49 (36.7%)
    Blood and lymphatic system disorders
    Anaemia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Cardiac disorders
    Cardio-respiratory arrest 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Cardiopulmonary failure 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Coronary artery occlusion 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Sinus tachycardia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Eye disorders
    Diplopia 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Constipation 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Upper gastrointestinal haemorrhage 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    General disorders
    Drug interaction 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Pyrexia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Infections and infestations
    Bronchitis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Paronychia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Pneumonia 0/4 (0%) 0 0/12 (0%) 0 4/49 (8.2%) 4
    Injury, poisoning and procedural complications
    Fall 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Radiation pneumonitis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Musculoskeletal and connective tissue disorders
    Back pain 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Nervous system disorders
    Ataxia 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Balance disorder 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Cerebrovascular accident 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Spinal cord compression 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Syncope 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Bronchostenosis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Cough 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Dyspnoea 1/4 (25%) 1 1/12 (8.3%) 1 2/49 (4.1%) 2
    Interstitial lung disease 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Pleural effusion 1/4 (25%) 1 1/12 (8.3%) 1 1/49 (2%) 1
    Pulmonary embolism 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Respiratory distress 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Vascular disorders
    Deep vein thrombosis 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Superior vena cava syndrome 1/4 (25%) 1 0/12 (0%) 0 1/49 (2%) 1
    Thrombosis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Other (Not Including Serious) Adverse Events
    Phase 1, Dose 1 (Enzastaurin 250 mg, Erlotinib 150 mg) Phase 1, Dose 2 (Enzastaurin 500 mg, Erlotinib 150 mg) Phase 2 (Enzastaurin 500 mg, Erlotinib 150 mg)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/4 (100%) 12/12 (100%) 47/49 (95.9%)
    Blood and lymphatic system disorders
    Anaemia 0/4 (0%) 0 0/12 (0%) 0 7/49 (14.3%) 9
    Iron deficiency anaemia 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Leukocytosis 1/4 (25%) 1 0/12 (0%) 0 1/49 (2%) 1
    Lymphopenia 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 2
    Neutropenia 0/4 (0%) 0 1/12 (8.3%) 2 0/49 (0%) 0
    Nucleated red cells 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Thrombocytopenia 0/4 (0%) 0 0/12 (0%) 0 5/49 (10.2%) 5
    Cardiac disorders
    Atrial fibrillation 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Bradycardia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Bundle branch block left 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Extrasystoles 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Palpitations 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Sinus tachycardia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Tachycardia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Ventricular extrasystoles 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Ear and labyrinth disorders
    Otorrhoea 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 2
    Endocrine disorders
    Hypothyroidism 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Eye disorders
    Blepharitis 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Conjunctivitis 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 5
    Diplopia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Dry eye 1/4 (25%) 1 2/12 (16.7%) 2 4/49 (8.2%) 4
    Erythema of eyelid 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Eye irritation 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Eyelash thickening 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Eyelid disorder 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Eyelid ptosis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Growth of eyelashes 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Lacrimation increased 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Macular oedema 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Ocular hyperaemia 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Periorbital oedema 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Retinal haemorrhage 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Vision blurred 0/4 (0%) 0 0/12 (0%) 0 3/49 (6.1%) 3
    Visual acuity reduced 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Visual impairment 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Gastrointestinal disorders
    Abdominal discomfort 0/4 (0%) 0 1/12 (8.3%) 2 0/49 (0%) 0
    Abdominal distension 1/4 (25%) 1 2/12 (16.7%) 2 2/49 (4.1%) 2
    Abdominal pain 2/4 (50%) 2 3/12 (25%) 3 2/49 (4.1%) 2
    Abdominal pain lower 0/4 (0%) 0 2/12 (16.7%) 2 0/49 (0%) 0
    Abdominal pain upper 0/4 (0%) 0 1/12 (8.3%) 1 3/49 (6.1%) 4
    Anorectal discomfort 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Aphthous stomatitis 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Chapped lips 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Cheilitis 0/4 (0%) 0 1/12 (8.3%) 2 0/49 (0%) 0
    Constipation 0/4 (0%) 0 2/12 (16.7%) 2 8/49 (16.3%) 8
    Diarrhoea 4/4 (100%) 4 11/12 (91.7%) 13 36/49 (73.5%) 54
    Dry mouth 0/4 (0%) 0 2/12 (16.7%) 2 2/49 (4.1%) 2
    Dyspepsia 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Dysphagia 0/4 (0%) 0 1/12 (8.3%) 2 1/49 (2%) 1
    Epigastric discomfort 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Faeces discoloured 1/4 (25%) 1 7/12 (58.3%) 8 3/49 (6.1%) 3
    Gastric ulcer 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Gastritis 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Gastrointestinal haemorrhage 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Gastrooesophageal reflux disease 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Gingival bleeding 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Haemorrhoids 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Melaena 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Nausea 0/4 (0%) 0 8/12 (66.7%) 9 21/49 (42.9%) 23
    Oral discomfort 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Oral mucosal discolouration 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Oral pain 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Oral papule 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Post-tussive vomiting 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Rectal haemorrhage 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Stomatitis 0/4 (0%) 0 0/12 (0%) 0 3/49 (6.1%) 3
    Tongue ulceration 1/4 (25%) 1 0/12 (0%) 0 0/49 (0%) 0
    Toothache 1/4 (25%) 1 0/12 (0%) 0 0/49 (0%) 0
    Vomiting 0/4 (0%) 0 5/12 (41.7%) 7 12/49 (24.5%) 12
    General disorders
    Asthenia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Chest discomfort 1/4 (25%) 1 0/12 (0%) 0 3/49 (6.1%) 3
    Chills 0/4 (0%) 0 3/12 (25%) 3 1/49 (2%) 1
    Early satiety 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Facial pain 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Fatigue 2/4 (50%) 2 9/12 (75%) 10 21/49 (42.9%) 26
    Feeling cold 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Feeling hot 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Feeling jittery 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Gait disturbance 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Influenza like illness 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Injection site bruising 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Local swelling 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Localised oedema 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Non-cardiac chest pain 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Oedema 0/4 (0%) 0 2/12 (16.7%) 2 0/49 (0%) 0
    Oedema peripheral 0/4 (0%) 0 2/12 (16.7%) 3 3/49 (6.1%) 3
    Pain 0/4 (0%) 0 3/12 (25%) 3 2/49 (4.1%) 2
    Pyrexia 2/4 (50%) 3 1/12 (8.3%) 1 4/49 (8.2%) 4
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 6
    Immune system disorders
    Contrast media allergy 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Infections and infestations
    Bronchitis 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Candida infection 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Cellulitis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Cystitis 1/4 (25%) 1 1/12 (8.3%) 1 0/49 (0%) 0
    Gastroenteritis viral 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Herpes zoster 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Infection 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Influenza 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Nail infection 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Nasopharyngitis 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 2
    Oral candidiasis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Paronychia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 4
    Pneumonia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Rash pustular 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Sepsis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Sinusitis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Tinea infection 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Upper respiratory tract infection 0/4 (0%) 0 2/12 (16.7%) 2 5/49 (10.2%) 5
    Vaginal abscess 0/4 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Viral infection 1/4 (25%) 1 0/12 (0%) 0 0/49 (0%) 0
    Viral upper respiratory tract infection 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Injury, poisoning and procedural complications
    Arthropod sting 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Contusion 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Humerus fracture 0/4 (0%) 0 1/12 (8.3%) 2 0/49 (0%) 0
    Laceration 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Ligament sprain 1/4 (25%) 1 0/12 (0%) 0 0/49 (0%) 0
    Muscle strain 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Procedural pain 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Subdural haematoma 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Sunburn 1/4 (25%) 1 0/12 (0%) 0 0/49 (0%) 0
    Investigations
    Alanine aminotransferase increased 0/4 (0%) 0 0/12 (0%) 0 3/49 (6.1%) 3
    Aspartate aminotransferase decreased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Aspartate aminotransferase increased 0/4 (0%) 0 0/12 (0%) 0 4/49 (8.2%) 4
    Band neutrophil count increased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Blood albumin decreased 0/4 (0%) 0 2/12 (16.7%) 2 2/49 (4.1%) 2
    Blood alkaline phosphatase 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Blood alkaline phosphatase increased 0/4 (0%) 0 2/12 (16.7%) 2 5/49 (10.2%) 5
    Blood bilirubin increased 0/4 (0%) 0 0/12 (0%) 0 4/49 (8.2%) 6
    Blood chloride decreased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Blood cholesterol increased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Blood creatinine increased 0/4 (0%) 0 0/12 (0%) 0 3/49 (6.1%) 3
    Blood lactate dehydrogenase decreased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Blood lactate dehydrogenase increased 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Blood lactic acid increased 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Blood methaemoglobin present 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Blood urea increased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Blood urine present 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    C-reactive protein increased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Cardiac murmur 1/4 (25%) 1 1/12 (8.3%) 1 0/49 (0%) 0
    Electrocardiogram abnormal 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Fibrin d dimer increased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Haematocrit decreased 0/4 (0%) 0 0/12 (0%) 0 3/49 (6.1%) 3
    Haemoglobin decreased 0/4 (0%) 0 0/12 (0%) 0 4/49 (8.2%) 5
    Heart rate decreased 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Lymphocyte count decreased 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Mean cell haemoglobin decreased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Mean cell volume decreased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Monocyte count decreased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Neutrophil count decreased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Neutrophil count increased 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Neutrophil percentage decreased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Neutrophil percentage increased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 2
    Platelet count decreased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Platelet count increased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Prealbumin decreased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Protein total decreased 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Red blood cell count decreased 0/4 (0%) 0 0/12 (0%) 0 4/49 (8.2%) 5
    Romberg test positive 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Transaminases increased 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Weight decreased 0/4 (0%) 0 0/12 (0%) 0 9/49 (18.4%) 10
    Weight increased 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    White blood cell count increased 0/4 (0%) 0 0/12 (0%) 0 3/49 (6.1%) 3
    Metabolism and nutrition disorders
    Decreased appetite 1/4 (25%) 1 7/12 (58.3%) 8 19/49 (38.8%) 24
    Dehydration 1/4 (25%) 1 0/12 (0%) 0 6/49 (12.2%) 7
    Diabetes mellitus 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Electrolyte imbalance 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Hypercalcaemia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 2
    Hyperglycaemia 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Hypernatraemia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Hypoalbuminaemia 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 2
    Hypoglycaemia 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 4
    Hypokalaemia 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Hyponatraemia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/4 (0%) 0 2/12 (16.7%) 2 5/49 (10.2%) 5
    Back pain 0/4 (0%) 0 5/12 (41.7%) 6 9/49 (18.4%) 11
    Bone pain 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Bursitis 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Clubbing 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Flank pain 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Muscle spasms 1/4 (25%) 1 0/12 (0%) 0 4/49 (8.2%) 6
    Muscular weakness 0/4 (0%) 0 1/12 (8.3%) 2 1/49 (2%) 1
    Musculoskeletal chest pain 1/4 (25%) 1 0/12 (0%) 0 2/49 (4.1%) 2
    Musculoskeletal pain 1/4 (25%) 1 4/12 (33.3%) 4 2/49 (4.1%) 2
    Myalgia 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Osteoarthritis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Osteoporosis 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Pain in extremity 0/4 (0%) 0 3/12 (25%) 4 3/49 (6.1%) 3
    Pain in jaw 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Pathological fracture 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Sjogren's syndrome 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma 1/4 (25%) 1 0/12 (0%) 0 0/49 (0%) 0
    Tumour pain 0/4 (0%) 0 0/12 (0%) 0 3/49 (6.1%) 4
    Nervous system disorders
    Ataxia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Brachial plexopathy 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Brain oedema 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Dizziness 2/4 (50%) 2 2/12 (16.7%) 2 6/49 (12.2%) 6
    Dysgeusia 1/4 (25%) 1 5/12 (41.7%) 5 3/49 (6.1%) 3
    Headache 0/4 (0%) 0 2/12 (16.7%) 2 6/49 (12.2%) 6
    Hypersomnia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Hypoaesthesia 1/4 (25%) 1 0/12 (0%) 0 0/49 (0%) 0
    Myoclonus 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Neurological decompensation 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Neuropathy peripheral 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Peripheral sensory neuropathy 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Sensory loss 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 2
    Somnolence 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Syncope 0/4 (0%) 0 0/12 (0%) 0 5/49 (10.2%) 5
    Psychiatric disorders
    Anxiety 0/4 (0%) 0 0/12 (0%) 0 3/49 (6.1%) 3
    Bruxism 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Confusional state 0/4 (0%) 0 0/12 (0%) 0 4/49 (8.2%) 4
    Depression 0/4 (0%) 0 2/12 (16.7%) 2 2/49 (4.1%) 2
    Hallucination 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Insomnia 1/4 (25%) 1 1/12 (8.3%) 1 7/49 (14.3%) 7
    Mental status changes 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Renal and urinary disorders
    Chromaturia 3/4 (75%) 3 9/12 (75%) 9 4/49 (8.2%) 4
    Dysuria 0/4 (0%) 0 2/12 (16.7%) 2 0/49 (0%) 0
    Haematuria 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Hydronephrosis 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Micturition urgency 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 2
    Nocturia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Pollakiuria 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Proteinuria 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Renal failure 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Renal impairment 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Ureteric obstruction 1/4 (25%) 1 0/12 (0%) 0 0/49 (0%) 0
    Urinary retention 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Reproductive system and breast disorders
    Erectile dysfunction 0/4 (0%) 0 1/3 (33.3%) 1 0/29 (0%) 0
    Gynaecomastia 0/4 (0%) 0 1/3 (33.3%) 1 0/29 (0%) 0
    Menopausal symptoms 0/4 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Vulvovaginal dryness 0/4 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Cough 0/4 (0%) 0 4/12 (33.3%) 4 14/49 (28.6%) 18
    Dry throat 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Dysphonia 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 2
    Dyspnoea 2/4 (50%) 2 6/12 (50%) 7 12/49 (24.5%) 12
    Dyspnoea exertional 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Epistaxis 1/4 (25%) 1 3/12 (25%) 3 4/49 (8.2%) 7
    Haemoptysis 1/4 (25%) 1 1/12 (8.3%) 1 2/49 (4.1%) 3
    Hypoxia 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Oropharyngeal pain 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 2
    Pharyngeal oedema 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Pleural effusion 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Pleuritic pain 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Pneumothorax 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Productive cough 1/4 (25%) 1 0/12 (0%) 0 2/49 (4.1%) 2
    Pulmonary embolism 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Rhinorrhoea 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Rhonchi 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Sinus congestion 1/4 (25%) 1 0/12 (0%) 0 2/49 (4.1%) 2
    Upper-airway cough syndrome 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Wheezing 1/4 (25%) 1 2/12 (16.7%) 2 4/49 (8.2%) 7
    Skin and subcutaneous tissue disorders
    Alopecia 1/4 (25%) 1 3/12 (25%) 4 5/49 (10.2%) 6
    Blister 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Decubitus ulcer 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Dermatitis acneiform 1/4 (25%) 1 2/12 (16.7%) 2 6/49 (12.2%) 6
    Dermatitis contact 1/4 (25%) 1 1/12 (8.3%) 1 0/49 (0%) 0
    Dry skin 1/4 (25%) 2 4/12 (33.3%) 4 10/49 (20.4%) 11
    Ecchymosis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 2
    Erythema 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Exfoliative rash 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Hyperhidrosis 0/4 (0%) 0 1/12 (8.3%) 1 1/49 (2%) 1
    Nail disorder 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Onychoclasis 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Palmar-plantar erythrodysaesthesia syndrome 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Petechiae 0/4 (0%) 0 2/12 (16.7%) 2 0/49 (0%) 0
    Photosensitivity reaction 1/4 (25%) 1 0/12 (0%) 0 0/49 (0%) 0
    Pruritus 2/4 (50%) 2 5/12 (41.7%) 8 7/49 (14.3%) 8
    Rash 3/4 (75%) 3 9/12 (75%) 13 29/49 (59.2%) 36
    Rash erythematous 0/4 (0%) 0 1/12 (8.3%) 1 3/49 (6.1%) 3
    Rash follicular 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0
    Rash macular 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 3
    Rash maculo-papular 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Rash papular 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 2
    Rash pruritic 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Scab 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Skin disorder 0/4 (0%) 0 2/12 (16.7%) 2 0/49 (0%) 0
    Skin fissures 0/4 (0%) 0 1/12 (8.3%) 1 2/49 (4.1%) 3
    Skin ulcer 0/4 (0%) 0 1/12 (8.3%) 2 0/49 (0%) 0
    Vascular disorders
    Deep vein thrombosis 0/4 (0%) 0 0/12 (0%) 0 1/49 (2%) 1
    Hypertension 0/4 (0%) 0 0/12 (0%) 0 2/49 (4.1%) 2
    Hypotension 0/4 (0%) 0 0/12 (0%) 0 4/49 (8.2%) 4
    Thrombosis 0/4 (0%) 0 1/12 (8.3%) 1 0/49 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Chief Medical Officer
    Organization Eli Lilly and Company
    Phone 800-545-5979
    Email ClinicalTrials.gov@lilly.com
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT00452413
    Other Study ID Numbers:
    • 11183
    • H6Q-MC-S030
    First Posted:
    Mar 27, 2007
    Last Update Posted:
    May 13, 2021
    Last Verified:
    Apr 1, 2021