Non-small Cell Lung Cancer
Conditions
Keywords
NSCLC, Eribulin Mesylate, Erlotinib
Brief summary
This is a Phase 2, multicenter, randomized study of two different dose regimens of eribulin mesylate in combination with intermittent erlotinib in patients with previously treated, advanced non-small cell lung cancer.
Interventions
DRUGeribulin mesylate + erlotinib
21-day Regimen: Eribulin mesylate given at a dose of 2 mg/m2 as a 2-5 min intravenous (IV) bolus on Day 1 and 150 mg of erlotinib given orally once daily, one hour before or two hours after the ingestion of food, on Days 2-16 of a 21-day cycle.
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed non-small cell lung cancer (NSCLC) * At least one prior platinum-based doublet anti-cancer treatment for recurrent or advanced NSCLC * Disease progression during or after the last anti-cancer therapy * Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 * Serum creatinine less than or equal to 2.0 mg/dL or creatinine clearance 40 mL/min according to Cockcroft and Gault formula: * Absolute neutrophil count greater than or equal to 1.5 x 10\^9/L, hemoglobin greater than or equal to 10 g/dL (can be corrected by growth factor or transfusion), and platelet count greater than or equal to 100 x 10\^9/L * Total bilirubin less than or equal to 1.5 times the upper limit of normal (ULN) and alkaline phosphatase (AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times ULN (in the case of liver metastases less than or equal to 5 times ULN). In case AP is greater than 3 times ULN (in absence of liver metastases) or greater than 5 times ULN (in presence of liver metastases) AND subject also is known to have bone metastases, the liver specific AP must be separated from the total and used to assess the liver function instead of the total AP. * At least one lesion of greater than or equal to 1.5 cm in longest diameter for non-lymph nodes or greater than or equal to 1.5 cm in shortest diameter for lymph nodes which is serially measurable according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.17 * Males and females, age greater than or equal to 18 years * Provide written informed consent * Are willing and able to comply with all aspects of the protocol * Females of childbearing potential must have a negative serum beta-human chorionic gonadotropin (Beta-hCG) at Visit 1 (Screening) and a negative urine pregnancy test prior to starting study drug (Visit 2). Female subjects of childbearing potential must agree to be abstinent or to use highly effective methods of contraception (eg, condom + spermicide, condom + diaphragm with spermicide, intrauterine device (IUD), or have a vasectomised partner) having starting for at least one menstrual cycle prior to starting study drugs and throughout the entire study period and for 30 days (longer if appropriate) after the last dose of study drug. Those women using hormonal contraceptives must also be using an additional approved method of contraception (as described previously). Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. * Male subjects who are not abstinent or have not undergone a successful vasectomy, who are partners of women of childbearing potential must use, or their partners must use a highly effective method of contraception (eg, condom + spermicide, condom + diaphragm with spermicide, IUD) starting for at least one menstrual cycle prior to starting study drugs and throughout the entire study period and for 30 days (longer if appropriate) after the last dose of study drug. Those with partners using hormonal contraceptives must also be using an additional approved method of contraception (as described previously).
Exclusion criteria
* Prior therapy with eribulin or an tyrosine kinase inhibitor of the epidermal growth factor receptor * Subjects with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued steroids for this indication for greater than or equal to 4 weeks before starting study treatment. Symptoms attributed to brain metastases must be stable for greater than or equal to 4 weeks before starting study treatment; radiographic stability should be determined by comparing contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) brain scan performed during screening to a prior scan performed 4 weeks earlier. * Existing anti-cancer therapy-related toxicities of grade greater than or equal to 2, other than any grade of alopecia or grade less than or equal to 2 neuropathy, which are acceptable * Current smokers who will not stop smoking one week prior to treatment and during the study * History of congestive heart failure with New York Heart Association (NYHA) Grade greater than II, unstable angina, myocardial infarction within the past 6 months, serious cardiac arrhythmia * Electrocardiogram with QTc interval greater than or equal to 500 msec based upon Bazett's formula (QTcB) * Females who are pregnant (positive Beta-hCG test) or breastfeeding * Subject with hypersensitivity to eribulin and /or erlotinib or any of the excipients * Presence of a progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors * Subjects who are known to be human immunodeficiency virus (HIV) positive, because the neutropenia caused by the study treatments may make such subjects particularly susceptible to infection * Subjects with active viral hepatitis (A, B, or C) as demonstrated by positive serology * Radiotherapy, chemotherapy, biological therapy or investigational agents within 2 weeks prior to start of study treatment * Meningeal carcinomatosis * History of drug or alcohol dependency or abuse within approximately the last 2 years * Medically unfit to receive the study drug or unsuitable for any other reason according to investigator judgment * Any history of or concomitant medical condition that, in the opinion of the Investigator, would compromise the subject's ability to safely complete the study * Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From date of first dose of study drug until, or up to the date of data cutoff (07 Apr 2011) | ORR was defined as the percentage of participants whose best overall response (BOR) was either a confirmed complete response (CR) or a partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria for target lesions assessed by computed tomography (CT) or magnetic resonance imaging (MRI) and based on investigator assessment. CRs and PRs had to be confirmed by a repeat assessment of response (CR or PR) separated by at least 4 weeks (28 days). CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than 10 millimeters. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR and the corresponding 95% two-sided confidence intervals (CI) were estimated for each treatment regimen using the Clopper-Pearson method for calculating the exact binomial CI. (CR + PR) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | From date of first document CR or PR (whichever was recorded first) until first documentation of disease progression or death due to any cause, or up to data cutoff (31 May 2013) up to 3.25 years | DOR was assessed for participants with a BOR of CR or PR, and was defined as the time from first documented evidence of CR or PR (whichever status was recorded first) until the first documented sign of disease progression or death (due to any cause), whichever was first. DOR was defined for participants with a confirmed CR or PR. For participants in the subset of responders who did not progress or die, duration of response was censored. DOR was analyzed using the Kaplan-Meier method. |
| Progression-Free Survival (PFS) | From date of first dose of study drug until documentation of disease progression or death from any cause (whichever occurred first), or up to data cutoff (31 May 2013) up to 3.25 years | PFS was measured as the time from the date of first administration of study treatment until the first documentation of disease progression or death (due to any cause), whichever occurred first, as determined by investigator assessment based on RECIST v1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. For participants who did not have an event (i.e. those who had not progressed, and were alive at the date of data cut-off or lost to Follow-up), progression-free survival was censored. Participants who did not progress in their disease were censored on the date of their last tumor assessment preceding the start of any additional anticancer therapy. PFS was analyzed using the Kaplan-Meier method. |
| Disease Control Rate (DCR) | From date of first dose of study drug until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (31 May 2013), up to approximately 3.25 years | DCR was defined as the percentage of participants who had a BOR of CR or PR, or stable disease (SD; duration of SD lasted for at least 7 weeks). To be assigned a BOR of SD, the time from the first administration of study drug until the date of documented SD was to be greater than or equal to 7 weeks (49 days). A participant's tumor assessment had to be at least 7 weeks following the randomization date to be consider SD. DCR and the corresponding exact Clopper-Pearson 95% CI were computed by treatment regimen. (CR + PR + SD) |
| Overall Survival (OS) | From date of first dose of study drug until date of death from any cause or up to data cutoff (31 May 2013), up to approximately 3.25 years | OS was defined as the length of time in months from the date of first administration of study drug until the date of death from any cause, and was based on the data cutoff date. In the absence of confirmation of death, participants were censored either at the date that the participant was last known to be alive or the date of study cutoff, whichever came first. OS and the corresponding 2-sided 95% CI was analyzed using the Kaplan-Meier method. |
Countries
Hong Kong, Malaysia, Singapore, South Korea, Taiwan, Thailand, United States
Participant flow
Pre-assignment details
164 participants were screened. Of these 164 participants, 41 were screening failures, and 123 were randomized into the study. Of the 41 screen failures, 31 participants failed to meet inclusion or exclusion criteria and 10 were excluded due to adverse events, withdrew consent, and other reasons.
Participants by arm
| Arm | Count |
|---|---|
| Eribulin Mesylate Plus Erlotinib, 21 Day Regimen Eribulin mesylate was given at a dose of 2 mg/m\^2 as a 2 to 5 min intravenous (IV) bolus on Day 1 and 150 mg of erlotinib was given orally once daily, one hour before or two hours after the ingestion of food, on Days 2 to 16 of a 21-day cycle. | 63 |
| Eribulin Mesylate Plus Erlotinib, 28 Day Regimen Eribulin mesylate was given at a dose of 1.4 mg/m\^2 as a 2 to 5 min IV bolus on Days 1 and 8, and 150 mg of erlotinib given orally once daily, one hour before or two hours after the ingestion of food, on Days 15 to 28 of a 28-day cycle. | 60 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 15 | 8 |
| Overall Study | Other | 3 | 4 |
| Overall Study | Participant choice | 6 | 5 |
| Overall Study | Withdrawal of consent | 1 | 1 |
Baseline characteristics
| Characteristic | Eribulin Mesylate Plus Erlotinib, 21 Day Regimen | Eribulin Mesylate Plus Erlotinib, 28 Day Regimen | Total |
|---|---|---|---|
| Age, Continuous | 61.7 Years STANDARD_DEVIATION 11.08 | 63.1 Years STANDARD_DEVIATION 10.05 | 62.4 Years STANDARD_DEVIATION 10.57 |
| Sex/Gender, Customized Gender Female | 30 Participants | 27 Participants | 57 Participants |
| Sex/Gender, Customized Gender Male | 33 Participants | 33 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 59 / 63 | 51 / 60 |
| other Total, other adverse events | 61 / 63 | 60 / 60 |
| serious Total, serious adverse events | 38 / 63 | 27 / 60 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants whose best overall response (BOR) was either a confirmed complete response (CR) or a partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria for target lesions assessed by computed tomography (CT) or magnetic resonance imaging (MRI) and based on investigator assessment. CRs and PRs had to be confirmed by a repeat assessment of response (CR or PR) separated by at least 4 weeks (28 days). CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than 10 millimeters. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR and the corresponding 95% two-sided confidence intervals (CI) were estimated for each treatment regimen using the Clopper-Pearson method for calculating the exact binomial CI. (CR + PR)
Time frame: From date of first dose of study drug until, or up to the date of data cutoff (07 Apr 2011)
Population: Full analysis set (FAS) (Intent-to-treat population) included all participants who took at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eribulin Mesylate Plus Erlotinib, 21 Day Regimen | Objective Response Rate (ORR) | 12.7 Percentage of participants |
| Eribulin Mesylate Plus Erlotinib, 28 Day Regimen | Objective Response Rate (ORR) | 16.7 Percentage of participants |
p-value: 0.2041-sided exact binomial
p-value: 0.0411-sided exact binomial
Secondary
Disease Control Rate (DCR)
DCR was defined as the percentage of participants who had a BOR of CR or PR, or stable disease (SD; duration of SD lasted for at least 7 weeks). To be assigned a BOR of SD, the time from the first administration of study drug until the date of documented SD was to be greater than or equal to 7 weeks (49 days). A participant's tumor assessment had to be at least 7 weeks following the randomization date to be consider SD. DCR and the corresponding exact Clopper-Pearson 95% CI were computed by treatment regimen. (CR + PR + SD)
Time frame: From date of first dose of study drug until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (31 May 2013), up to approximately 3.25 years
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eribulin Mesylate Plus Erlotinib, 21 Day Regimen | Disease Control Rate (DCR) | 47.6 Percentage of participants |
| Eribulin Mesylate Plus Erlotinib, 28 Day Regimen | Disease Control Rate (DCR) | 63.3 Percentage of participants |
Secondary
Duration of Response (DOR)
DOR was assessed for participants with a BOR of CR or PR, and was defined as the time from first documented evidence of CR or PR (whichever status was recorded first) until the first documented sign of disease progression or death (due to any cause), whichever was first. DOR was defined for participants with a confirmed CR or PR. For participants in the subset of responders who did not progress or die, duration of response was censored. DOR was analyzed using the Kaplan-Meier method.
Time frame: From date of first document CR or PR (whichever was recorded first) until first documentation of disease progression or death due to any cause, or up to data cutoff (31 May 2013) up to 3.25 years
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eribulin Mesylate Plus Erlotinib, 21 Day Regimen | Duration of Response (DOR) | 9.4 Months |
| Eribulin Mesylate Plus Erlotinib, 28 Day Regimen | Duration of Response (DOR) | 9.7 Months |
Secondary
Overall Survival (OS)
OS was defined as the length of time in months from the date of first administration of study drug until the date of death from any cause, and was based on the data cutoff date. In the absence of confirmation of death, participants were censored either at the date that the participant was last known to be alive or the date of study cutoff, whichever came first. OS and the corresponding 2-sided 95% CI was analyzed using the Kaplan-Meier method.
Time frame: From date of first dose of study drug until date of death from any cause or up to data cutoff (31 May 2013), up to approximately 3.25 years
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eribulin Mesylate Plus Erlotinib, 21 Day Regimen | Overall Survival (OS) | 7.6 Months |
| Eribulin Mesylate Plus Erlotinib, 28 Day Regimen | Overall Survival (OS) | 8.5 Months |
Secondary
Progression-Free Survival (PFS)
PFS was measured as the time from the date of first administration of study treatment until the first documentation of disease progression or death (due to any cause), whichever occurred first, as determined by investigator assessment based on RECIST v1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. For participants who did not have an event (i.e. those who had not progressed, and were alive at the date of data cut-off or lost to Follow-up), progression-free survival was censored. Participants who did not progress in their disease were censored on the date of their last tumor assessment preceding the start of any additional anticancer therapy. PFS was analyzed using the Kaplan-Meier method.
Time frame: From date of first dose of study drug until documentation of disease progression or death from any cause (whichever occurred first), or up to data cutoff (31 May 2013) up to 3.25 years
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eribulin Mesylate Plus Erlotinib, 21 Day Regimen | Progression-Free Survival (PFS) | 3.5 Months |
| Eribulin Mesylate Plus Erlotinib, 28 Day Regimen | Progression-Free Survival (PFS) | 3.8 Months |