Endometrial Cancer
Conditions
Brief summary
The primary purpose of this study is to investigate whether administration of ixabepilone results in superior outcome as assessed by overall survival compared with that achieved with standard chemotherapy (paclitaxel or doxorubicin) in women with advanced endometrial cancer that has progressed following first-line chemotherapy.
Interventions
DRUGIxabepilone
DRUGDoxorubicin
DRUGPaclitaxel
Sponsors
R-Pharm
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria * Women aged 18 years and older * Histologic or cytologic diagnosis of endometrial carcinoma * Evidence that the cancer is advanced, recurrent, or metastatic and not curable by local measures, such as surgery or radiation. * Karnofsky performance status \>=70 * Measurable or nonmeasurable disease that has progressed since last treatment. * If only disease is confined to a solitary lesion, its neoplastic nature must be confirmed by histology or cytology. * Disease in a previously irradiated field is acceptable as the only site of measurable disease only if there has been clear progression since completion of radiotherapy. * All therapy directed at endometrial cancer must be discontinued 21 days prior to start of treatment, except for hormonal therapy which must be discontinued at least 1 week prior to start of study treatment. Concurrent administration of hormone replacement therapy is allowed. * Prior therapy: Participants must have failed 1 prior platinum-based chemotherapeutic regimen for endometrial cancer. May have received 2 prior chemotherapy regimens if 1 regimen was given for stage I or II disease. May have received any number of prior non-cytotoxic regimens such as monoclonal antibodies, cytokines, signal transduction inhibitors, or hormonal therapy. Previous radiation therapy is allowed. Key
Exclusion criteria
* Carcinosarcoma (malignant mixed mullerian tumor) * Endometrial leiomyosarcoma and endometrial stromal sarcomas * Participants who received no prior chemotherapy for endometrial cancer or ≥2 prior chemotherapy regimens (exceptions defined in protocol) * Known brain metastases * Receipt of prior ixabepilone therapy * Concurrent active infection requiring antibiotics or other therapy * Concurrent unstable disease or other debilitating illness, such as congestive heart failure, unstable angina, myocardial infarction, or other cardiac disease that could jeopardize participation, within the last 6 months * For participants whose prior therapy did not include an anthracycline and therefore may be randomized to doxorubicin, left ventricular ejection fraction \<50% as measured by multigated radionuclide angiography or echocardiography * History of malignancy, except nonmelanoma skin cancer, carcinoma in situ of the cervix, or carcinoma in situ of the breast, within the last 5 years that has not been treated with chemotherapy * Known human immunodeficiency viral infection * Psychiatric disorders or other conditions rendering the participant incapable of complying with protocol requirements * Absolute neutrophil count \<1500/mm\^3 * Platelets \<100,000/mm\^3 * Hemoglobin \<9 g/dL * Total bilirubin \>1.5\*upper limit of normal (ULN), except for those with Gilbert's disease * Aspartate aminotransferase or alanine aminotransferase \>2.5\*ULN * Serum creatinine \>1.5\*ULN * Grade ≥2 neuropathy (sensory or motor) * No concurrent therapy (chemotherapy, hormonal, or investigational) directed at endometrial cancer during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Date of randomization to date of death or last date censored to up to approximately 26 months | Survival was defined as the time from the date of randomization until the date of death. If the patient did not die, OS was censored on the last date he or she was known to be alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Date of randomization to date of disease progression or death (or date of last tumor assessment for those who did not die or progress) up to approximately 22 months | Progression-free survival was defined as the time from randomization to the date of documented disease progression. Patients who died without a reported prior progression were considered to have progressed on the date of their death. Those who did not progress or die were censored on the date of their last tumor assessment. Participants who did not have any on-study tumor assessments were censored on the date they were randomized. Measurable disease was present if the patient had 1 or more measurable lesions. |
| Best Overall Response Rate | Date of randomization and every 6 weeks to end of treatment (9 cycles, or approximately Day 189) | Best overall response rate was defined as the number of participants whose best response was either partial response (PR) or complete response (CR) divided by the number of participants in the treatment group. Overall tumor response was based on an integration of the evaluation of target, nontarget, and new lesions. CR=Disappearance of all clinical and radiologic evidence of target lesions. PR=At least 30% reduction in the sum of diameters of all target lesions; taking as reference the baseline study measurement. Changes in tumor measurements need not be confirmed by repeat measurements performed after the criteria for response were first met. |
| Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | From Day 1 (first dose) to 30 days past last dose (up to Day 219); 9 cycles, or 189 days + 30 days | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related to study drug=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Czechia, Denmark, France, Greece, Hungary, Italy, Mexico, Norway, Peru, Russia, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
551 participants enrolled. 496 randomized (248 ixabepilone, 248 control); 487 received treatment (248 ixabepilone, 239 to control). Reasons not treated include 1 no longer met study criteria, 1 withdrew consent, 1 condition worsened, and 6 non-specified.
Participants by arm
| Arm | Count |
|---|---|
| Ixabepilone, 40 mg/m^2, IV Participants received ixabepilone, 40 mg/m\^2, given intravenously (IV) over 3 hours every 21 days until unacceptable toxicity or disease progression | 248 |
| Control Chemotherapy Participants received either paclitaxel, 175 mg/m\^2 given IV over 3 hours, or per institutional guidelines but not exceeding 3 hours, every 21 days until disease progression or unacceptable toxicity or doxorubicin, 60 mg/m\^2 given IV per institutional guidelines every 21 days, depending on the prior therapy received, until disease progression, unacceptable toxicity, or cumulative dose of 500 mg/m\^2. | 248 |
| Total | 496 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse event unrelated to study drug | 5 | 10 |
| Overall Study | Death | 6 | 2 |
| Overall Study | Disease progression | 130 | 128 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Maximum clinical benefit | 13 | 46 |
| Overall Study | No longer meets study criteria | 2 | 2 |
| Overall Study | Not identified | 3 | 6 |
| Overall Study | Study drug toxicity | 36 | 16 |
| Overall Study | Withdrawal by Subject | 14 | 8 |
Baseline characteristics
| Characteristic | Ixabepilone, 40 mg/m^2, IV | Control Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 64.0 Years | 64.0 Years | 64.0 Years |
| Age, Customized 50 years and older | 234 Participants | 230 Participants | 464 Participants |
| Age, Customized 65 years and older | 122 Participants | 109 Participants | 231 Participants |
| Age, Customized Younger than 50 years | 14 Participants | 18 Participants | 32 Participants |
| Age, Customized Younger than 65 years | 126 Participants | 139 Participants | 265 Participants |
| Karnofsky Performance Scale Index Status 100 | 86 Participants | 86 Participants | 172 Participants |
| Karnofsky Performance Scale Index Status 70 | 19 Participants | 16 Participants | 35 Participants |
| Karnofsky Performance Scale Index Status <70 | 0 Participants | 2 Participants | 2 Participants |
| Karnofsky Performance Scale Index Status 80 | 48 Participants | 64 Participants | 112 Participants |
| Karnofsky Performance Scale Index Status 90 | 95 Participants | 79 Participants | 174 Participants |
| Karnofsky Performance Scale Index Status Not reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Black or African American | 12 Participants | 18 Participants | 30 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 12 Participants | 24 Participants |
| Race/Ethnicity, Customized White | 215 Participants | 213 Participants | 428 Participants |
| Sex: Female, Male Female | 248 Participants | 248 Participants | 496 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 233 / 248 | 160 / 171 | 63 / 68 |
| serious Total, serious adverse events | 89 / 248 | 59 / 171 | 11 / 68 |
Outcome results
Primary
Overall Survival (OS)
Survival was defined as the time from the date of randomization until the date of death. If the patient did not die, OS was censored on the last date he or she was known to be alive.
Time frame: Date of randomization to date of death or last date censored to up to approximately 26 months
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixabepilone, 40 mg/m^2, Intravenously (IV) | Overall Survival (OS) | 10.9 Months |
| Control With Chemotherapy (Paclitaxel or Doxorubicin) | Overall Survival (OS) | 12.3 Months |
p-value: 0.039795% CI: [1, 1.7]Log Rank
Secondary
Best Overall Response Rate
Best overall response rate was defined as the number of participants whose best response was either partial response (PR) or complete response (CR) divided by the number of participants in the treatment group. Overall tumor response was based on an integration of the evaluation of target, nontarget, and new lesions. CR=Disappearance of all clinical and radiologic evidence of target lesions. PR=At least 30% reduction in the sum of diameters of all target lesions; taking as reference the baseline study measurement. Changes in tumor measurements need not be confirmed by repeat measurements performed after the criteria for response were first met.
Time frame: Date of randomization and every 6 weeks to end of treatment (9 cycles, or approximately Day 189)
Population: All randomized participants with measurable disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ixabepilone, 40 mg/m^2, Intravenously (IV) | Best Overall Response Rate | 15.2 Percentage of participants |
| Control With Chemotherapy (Paclitaxel or Doxorubicin) | Best Overall Response Rate | 15.7 Percentage of participants |
Secondary
Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related to study drug=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death.
Time frame: From Day 1 (first dose) to 30 days past last dose (up to Day 219); 9 cycles, or 189 days + 30 days
Population: All participants who received at least 1 dose of ixabepilone
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone, 40 mg/m^2, Intravenously (IV) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any SAE related to study drug | 43 Participants |
| Ixabepilone, 40 mg/m^2, Intravenously (IV) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any AE leading to study drug discontinuation | 49 Participants |
| Ixabepilone, 40 mg/m^2, Intravenously (IV) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Deaths | 121 Participants |
| Ixabepilone, 40 mg/m^2, Intravenously (IV) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any peripheral neuropathy AE | 108 Participants |
| Ixabepilone, 40 mg/m^2, Intravenously (IV) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any SAEs | 89 Participants |
| Ixabepilone, 40 mg/m^2, Intravenously (IV) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any Grade 3 or higher AE | 160 Participants |
| Ixabepilone, 40 mg/m^2, Intravenously (IV) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any AE related to study drug | 223 Participants |
| Control With Chemotherapy (Paclitaxel or Doxorubicin) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any Grade 3 or higher AE | 148 Participants |
| Control With Chemotherapy (Paclitaxel or Doxorubicin) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any SAEs | 70 Participants |
| Control With Chemotherapy (Paclitaxel or Doxorubicin) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Deaths | 95 Participants |
| Control With Chemotherapy (Paclitaxel or Doxorubicin) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any AE related to study drug | 215 Participants |
| Control With Chemotherapy (Paclitaxel or Doxorubicin) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any AE leading to study drug discontinuation | 37 Participants |
| Control With Chemotherapy (Paclitaxel or Doxorubicin) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any peripheral neuropathy AE | 62 Participants |
| Control With Chemotherapy (Paclitaxel or Doxorubicin) | Number of Participants With a Serious Adverse Event (SAE), an SAE Related to Study Drug, Death as Outcome, a Peripheral Neuropathy Adverse Event (AE), a Grade 3 or Higher AE, and an AE Related to Study Drug | Any SAE related to study drug | 29 Participants |
Secondary
Progression-free Survival
Progression-free survival was defined as the time from randomization to the date of documented disease progression. Patients who died without a reported prior progression were considered to have progressed on the date of their death. Those who did not progress or die were censored on the date of their last tumor assessment. Participants who did not have any on-study tumor assessments were censored on the date they were randomized. Measurable disease was present if the patient had 1 or more measurable lesions.
Time frame: Date of randomization to date of disease progression or death (or date of last tumor assessment for those who did not die or progress) up to approximately 22 months
Population: All participants with measurable disease at randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixabepilone, 40 mg/m^2, Intravenously (IV) | Progression-free Survival | 3.4 Months |
| Control With Chemotherapy (Paclitaxel or Doxorubicin) | Progression-free Survival | 4.0 Months |
p-value: 0.801195% CI: [0.8, 1.3]Log Rank