Metastatic Breast Cancer
Conditions
Keywords
Locally, Recurrent, Breast, Cancer
Brief summary
The purpose of the study is to evaluate the anti-tumor activity of LY2523355 relative to ixabepilone for the treatment of metastatic or locally recurrent breast cancer using change in tumor size as a continuous measure of response.
Interventions
DRUGLY2523355
Administered intravenously as a one hour infusion
DRUGixabepilone
Administered intravenously
DRUGpegfilgrastim
Administered intravenously
DRUGfilgrastim
Administered intravenously
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have histologic or cytologic diagnosis of metastatic or locally recurrent breast cancer that is not amenable to therapy given with curative intent. * Have measurable disease defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 guidelines. * Have received 2 or more prior standard cytotoxic chemotherapy regimens for metastatic breast cancer and be, in the opinion of the investigator, an appropriate candidate for experimental therapy. Regimens received in the neoadjuvant or adjuvant setting are not counted as prior regimens. * Have received a prior taxane in the neoadjuvant, adjuvant, or metastatic setting. * Have recovered from the acute effects of prior chemotherapy, hormonal therapy, and radiation prior to study enrollment. * Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. * Have adequate organ function.
Exclusion criteria
* Have Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater (moderate or worse) peripheral neuropathy * Have a second primary malignancy. * Have symptomatic, untreated, or uncontrolled central nervous system metastases. * Have received autologous stem cell transplant following high-dose chemotherapy. * Have serious preexisting medical conditions that in the opinion of the investigator would preclude participation in this study. * Have active symptomatic fungal, bacterial, and/or known viral infection including active human immunodeficiency virus (HIV) or viral hepatitis. * Have previously received LY2523355 in another study investigating this agent or therapy with ixabepilone or an ixabepilone-containing regimen. * Have a history of radiation therapy involving more than 25 percent of the bone marrow. * Have a Fridericia corrected QT (QTcF) interval of \>470 milliseconds (msec) on screening electrocardiogram (ECG). * Have QRS widening of \>120 msec on screening ECG. * Cannot change or stop taking a strong Cytochrome P450 3A4 (CYP3A4) inhibitor or CYP3A4 inducer per the ixabepilone label. * Have hypersensitivity to drugs formulated with Cremophor® EL per the ixabepilone label.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Tumor Size (CTS) From Baseline to the End of Cycle 2 | Baseline up to end of Cycle 2 (Day 42) | The log ratio of tumor size at Cycle 2 to tumor size at baseline is calculated for each participant, where the tumor size is the sum of the target lesion measurements at each assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving an Overall Response (Overall Response Rate) | Baseline to measured progressive disease or date of death from any cause (up to 423 days) | Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guidelines. CR is a disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 millimeters (mm). PR is an at least 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with measurable disease, multiplied by 100. |
| Progression-free Survival (PFS) | Baseline to measured progressive disease or date of death from any cause (up to 423 days) | Progression-free survival (PFS) is the time from the date of randomization to the first date of progressive disease (PD) or death due to any cause, whichever occurs first. PD is as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guidelines, and is defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if that was the smallest on study). In addition, the sum must have demonstrated an absolute increase of at least 5 millimeter (mm) (the appearance of 1 or more new lesions was considered progression). Kaplan-Meier analysis was performed on the observed distribution of PFS. Participants were censored from analysis for the following reasons: lack of disease assessment, lost to follow-up, and further anticancer therapy started. Median PFS is presented. |
| Percentage of Participants Achieving a Clinical Benefit (Clinical Benefit Rate) | Baseline to measured progressive disease or date of death from any cause (up to 423 days) | Clinical benefit rate is the proportion of participants who achieve a best response of complete response (CR), partial response (PR), or stable disease (SD) as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guidelines. CR is a disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 millimeters (mm). PR is an at least 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. SD is neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as progressive disease, taking as reference the smallest sum diameter since treatment started. Clinical benefit rate is calculated as a total number of participants with CR, PR, or SD divided by the total number of participants with measurable disease, multiplied by 100. |
| Pharmacokinetics, Maximum Plasma Concentration (Cmax) of LSN2546307 | Cycle 1: Day 1 and Day 3 | Cmax is the maximum plasma concentration of LSN2546307 (metabolite) after a 1-hour intravenous infusion of LY2523355 on Day 1 and Day 3 of Cycle 1. |
| Pharmacokinetics, Intracycle Accumulation Ration (Ra) of LY2523355 | Cycle 1: Day 1 and Day 3 | The intracycle accumulation ratio (Ra) is defined as the LY2523355 Cmax on Day 3 of Cycle 1 to the LY2523355 Cmax on Day 1 of Cycle 1 after a 1-hour intravenous infusion of LY2523355 on Day 1 and Day 3 of Cycle 1. |
| Pharmacokinetics, Maximum Plasma Concentration (Cmax) of LY2523355 | Cycle 1: Day 1 and Day 3 | Cmax is the maximum plasma concentration of LY2523355 after a 1-hour intravenous infusion of LY2523355 on Day 1 and Day 3 of Cycle 1. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Deaths on Study Through the Follow-up Period | Baseline through end of treatment follow-up (up to 423 days) | The percentage of participants who died through the follow-up period of the study; the cause of death was not captured. A summary of serious and other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. |
Countries
United States
Participant flow
Pre-assignment details
Participants completed the study if they had at least 1 dose of study drug in Cycle 2 (or later) and had at least 1 post-baseline radiological tumor assessment or if the participant had a progression of disease or death. Non-completers were those that were lost to follow-up or who withdrew their consent to trial participation.
Participants by arm
| Arm | Count |
|---|---|
| LY2523355 + Pegfilgrastim or Filgrastim LY2523355 administered intravenously as a 1-hour infusion on Days 1, 2, and 3 of a 21-day Cycle for 2 Cycles. Dosage determined by calculating participant's body surface area (5 milligrams per meter squared per day \[mg/m\^2/day\]).
Pegfilgrastim or filgrastim administered intravenously on Day 4 of 21-day Cycle for 2 Cycles. Dosage is determined by standard of care.
If at the end of 2 Cycles the participant was receiving benefit, the participant may have remained on study drug for additional cycles until a criterion for study discontinuation was met. | 26 |
| Ixabepilone Ixabepilone administered intravenously as a 3-hour infusion on Day 1 of a 21-day Cycle for 2 Cycles.
Dosage determined by calculating participant's body surface area (40 mg/m\^2).
If at the end of 2 Cycles the participant was receiving benefit, the participant may have remained on study drug for additional cycles until a criterion for study discontinuation was met. | 13 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Started New Therapy | 2 | 0 |
Baseline characteristics
| Characteristic | LY2523355 + Pegfilgrastim or Filgrastim | Total | Ixabepilone |
|---|---|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 9.9 | 60.8 years STANDARD_DEVIATION 10 | 57.8 years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 39 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 30 Participants | 9 Participants |
| Region of Enrollment United States | 26 participants | 39 participants | 13 participants |
| Sex: Female, Male Female | 26 Participants | 39 Participants | 13 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 26 | 12 / 13 |
| serious Total, serious adverse events | 5 / 26 | 4 / 13 |
Outcome results
Primary
Change in Tumor Size (CTS) From Baseline to the End of Cycle 2
The log ratio of tumor size at Cycle 2 to tumor size at baseline is calculated for each participant, where the tumor size is the sum of the target lesion measurements at each assessment.
Time frame: Baseline up to end of Cycle 2 (Day 42)
Population: Participants who received at least 1 dose of study medication (LY2523355 or ixabepilone) and who had target lesion measurements at both baseline and the end of Cycle 2. One participant was mistakenly dosed with 6 mg/m\^2/day in Cycle 1 and for 2 doses in Cycle 2. The dose was subsequently corrected and the participant is included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LY2523355 + Pegfilgrastim or Filgrastim | Change in Tumor Size (CTS) From Baseline to the End of Cycle 2 | -0.0 log ratio of end of Cycle 2 to baseline | Standard Deviation 0.08 |
| Ixabepilone | Change in Tumor Size (CTS) From Baseline to the End of Cycle 2 | -0.1 log ratio of end of Cycle 2 to baseline | Standard Deviation 0.37 |
Comparison: This measure is compared between two treatment arms using a one-sided t-test. This measure followed a normal distribution.p-value: 0.344t-test, 1 sided
Secondary
Percentage of Participants Achieving a Clinical Benefit (Clinical Benefit Rate)
Clinical benefit rate is the proportion of participants who achieve a best response of complete response (CR), partial response (PR), or stable disease (SD) as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guidelines. CR is a disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 millimeters (mm). PR is an at least 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. SD is neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as progressive disease, taking as reference the smallest sum diameter since treatment started. Clinical benefit rate is calculated as a total number of participants with CR, PR, or SD divided by the total number of participants with measurable disease, multiplied by 100.
Time frame: Baseline to measured progressive disease or date of death from any cause (up to 423 days)
Population: Participants who received at least 1 dose of study medication (LY2523355 or ixabepilone). One participant was mistakenly dosed with 6 mg/m\^2/day in Cycle 1 and for 2 doses in Cycle 2. The dose was subsequently corrected and the participant is included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2523355 + Pegfilgrastim or Filgrastim | Percentage of Participants Achieving a Clinical Benefit (Clinical Benefit Rate) | 46.2 percentage of responders |
| Ixabepilone | Percentage of Participants Achieving a Clinical Benefit (Clinical Benefit Rate) | 61.5 percentage of responders |
p-value: 0.365Chi-squared
Secondary
Percentage of Participants Achieving an Overall Response (Overall Response Rate)
Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guidelines. CR is a disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 millimeters (mm). PR is an at least 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with measurable disease, multiplied by 100.
Time frame: Baseline to measured progressive disease or date of death from any cause (up to 423 days)
Population: Participants who received at least 1 dose of study medication (LY2523355 or ixabepilone). One participant was mistakenly dosed with 6 mg/m\^2/day in Cycle 1 and for 2 doses in Cycle 2. The dose was subsequently corrected and the participant is included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2523355 + Pegfilgrastim or Filgrastim | Percentage of Participants Achieving an Overall Response (Overall Response Rate) | 3.8 percentage of responders |
| Ixabepilone | Percentage of Participants Achieving an Overall Response (Overall Response Rate) | 7.7 percentage of responders |
p-value: 0.608Chi-squared
Secondary
Pharmacokinetics, Intracycle Accumulation Ration (Ra) of LY2523355
The intracycle accumulation ratio (Ra) is defined as the LY2523355 Cmax on Day 3 of Cycle 1 to the LY2523355 Cmax on Day 1 of Cycle 1 after a 1-hour intravenous infusion of LY2523355 on Day 1 and Day 3 of Cycle 1.
Time frame: Cycle 1: Day 1 and Day 3
Population: Participants who received 1-dose of LY2523355 on Day 1 and Day 3 of Cycle 1 and who have evaluable pharmacokinetic data to enable estimation of the LY2523355 Cmax on Day 1 and Day 3 of Cycle 1. One participant was mistakenly dosed with 6 mg/m\^2/day in Cycle 1 and for 2 doses in Cycle 2, and is not included in this analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2523355 + Pegfilgrastim or Filgrastim | Pharmacokinetics, Intracycle Accumulation Ration (Ra) of LY2523355 | 0.92 unitless ratio | Geometric Coefficient of Variation 77 |
Secondary
Pharmacokinetics, Maximum Plasma Concentration (Cmax) of LSN2546307
Cmax is the maximum plasma concentration of LSN2546307 (metabolite) after a 1-hour intravenous infusion of LY2523355 on Day 1 and Day 3 of Cycle 1.
Time frame: Cycle 1: Day 1 and Day 3
Population: Participants who received 1 dose of LY2523355 on Day 1 and Day 3 of Cycle 1 and who have evaluable pharmacokinetic data to enable estimation of the LSN2546307 Cmax on Day 1 and Day 3 of Cycle 1.One participant was mistakenly dosed with 6 mg/m\^2/day in Cycle 1 and for 2 doses in Cycle 2, and is not included in this analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2523355 + Pegfilgrastim or Filgrastim | Pharmacokinetics, Maximum Plasma Concentration (Cmax) of LSN2546307 | Cycle 1, Day 1 | 5.08 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 57 |
| LY2523355 + Pegfilgrastim or Filgrastim | Pharmacokinetics, Maximum Plasma Concentration (Cmax) of LSN2546307 | Cycle1, Day 3 | 5.53 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 67 |
Secondary
Pharmacokinetics, Maximum Plasma Concentration (Cmax) of LY2523355
Cmax is the maximum plasma concentration of LY2523355 after a 1-hour intravenous infusion of LY2523355 on Day 1 and Day 3 of Cycle 1.
Time frame: Cycle 1: Day 1 and Day 3
Population: Participants who received 1 dose of LY2523355 on Day 1 and Day 3 of Cycle 1 and who have evaluable pharmacokinetic data to enable estimation of the LY2523355 Cmax on Day 1 and Day 3 of Cycle 1. One participant was mistakenly dosed with 6 mg/m\^2/day in Cycle 1 and for 2 doses in Cycle 2, and is not included in this analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2523355 + Pegfilgrastim or Filgrastim | Pharmacokinetics, Maximum Plasma Concentration (Cmax) of LY2523355 | Cycle 1, Day 1 | 161 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 81 |
| LY2523355 + Pegfilgrastim or Filgrastim | Pharmacokinetics, Maximum Plasma Concentration (Cmax) of LY2523355 | Cycle 1, Day 3 | 150 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 56 |
Secondary
Progression-free Survival (PFS)
Progression-free survival (PFS) is the time from the date of randomization to the first date of progressive disease (PD) or death due to any cause, whichever occurs first. PD is as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guidelines, and is defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if that was the smallest on study). In addition, the sum must have demonstrated an absolute increase of at least 5 millimeter (mm) (the appearance of 1 or more new lesions was considered progression). Kaplan-Meier analysis was performed on the observed distribution of PFS. Participants were censored from analysis for the following reasons: lack of disease assessment, lost to follow-up, and further anticancer therapy started. Median PFS is presented.
Time frame: Baseline to measured progressive disease or date of death from any cause (up to 423 days)
Population: Participants who received at least 1 dose of study medication (LY2523355 or ixabepilone). The total number of participants censored is 7. One participant was mistakenly dosed with 6 mg/m\^2/day in Cycle 1 and for 2 doses in Cycle 2. The dose was subsequently corrected and the participant is included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LY2523355 + Pegfilgrastim or Filgrastim | Progression-free Survival (PFS) | 1.71 months |
| Ixabepilone | Progression-free Survival (PFS) | 2.76 months |
Other Pre-specified
Percentage of Deaths on Study Through the Follow-up Period
The percentage of participants who died through the follow-up period of the study; the cause of death was not captured. A summary of serious and other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Time frame: Baseline through end of treatment follow-up (up to 423 days)
Population: Participants who received at least 1 dose of study medication (LY2523355 or ixabepilone). One participant was mistakenly dosed with 6 mg/m\^2/day in Cycle 1 and for 2 doses in Cycle 2. The dose was subsequently corrected and the participant is included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2523355 + Pegfilgrastim or Filgrastim | Percentage of Deaths on Study Through the Follow-up Period | 7.7 percentage of participants |
| Ixabepilone | Percentage of Deaths on Study Through the Follow-up Period | 15.4 percentage of participants |