Breast Cancer, Metastatic Breast Cancer
Conditions
Brief summary
The primary objective of this study is to investigate the safety and tolerability of the anti-VEGFR-2 monoclonal antibody ramucirumab drug product in combination with docetaxel in Japanese participants with metastatic, or locally advanced breast cancer, with the aim of confirming the recommended dose of ramucirumab drug product (DP) in combination with docetaxel.
Interventions
BIOLOGICALRamucirumab
Ramucirumab administered as an intravenous (I.V.) infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks.
DRUGDocetaxel
Docetaxel administered by intravenous (I.V.) infusion at a dose of 75 milligrams per square meter (mg/m\^2) every 3 weeks.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant is Japanese * The participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * The participant has a histopathologically or cytologically confirmed diagnosis of breast adenocarcinoma that is now metastatic or locally-recurrent and inoperable with curative intent * The participant has measurable and/or non-measurable disease * The participants' primary and/or metastatic tumor is Human Epidermal Growth Factor Receptor 2 (HER2) negative * The participant received neo adjuvant or adjuvant taxane therapy ≥ 6 months prior to the study * The participant received neo adjuvant or adjuvant biologic therapy ≥ 6 weeks prior to the study * The participant completed all prior radiotherapy ≥ 3 weeks prior to the study registration date * The participant received prior hormonal therapy for breast cancer in the neo adjuvant, adjuvant,and/or the metastatic setting ≥ 2 weeks prior to the study registration date * The participant's left ventricular ejection fraction (LVEF) is within normal ranges * The participant has adequate hematologic, hepatic, and coagulation function. * Eligible participants of reproductive potential agree to use adequate contraceptive methods (hormonal or barrier methods) during the study period and for 12 weeks after the last dose of study medication
Exclusion criteria
* The participant has a concurrent active malignancy other than breast adenocarcinoma, adequately treated non-melanomatous skin cancer, or other non-invasive carcinoma or in situ neoplasm. Participants with previous treatment of malignancy is eligible, provided that she has been disease free for \>3 years * The participant has a known sensitivity to docetaxel * The participant has a known sensitivity to agents of similar biologic composition as ramucirumab * The participant has a history of chronic diarrheal disease within 6 months prior to the study registration date * The participant has received irradiation to a major bone marrow area within 30 days prior to the study registration date * The participant has received any experimental agents within 4 weeks prior to the study registration date * The participant has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders * The participant has Grade 3-4 bleeding within 3 months prior to the study registration date * The participant has an ongoing or active infection requiring antibiotic, antifungal, or antiviral therapy * The participant has uncontrolled hypertension, symptomatic congestive heart failure, psychiatric illness, or any other serious uncontrolled medical disorders * The participant has brain metastases * The participant has known human immunodeficiency virus infection or acquired immunodeficiency syndrome related illness * The participant is pregnant or lactating * The participant has not fully recovered from effects of prior chemotherapy * The participant has undergone major surgery within 28 days prior to the study registration date
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Baseline up to data cut off (approximately 48.3 weeks) | Number participants with drug related dose-limiting toxicities (DLT) during Cycle 1; ramucirumab related: treatment-emergent adverse events (TEAE), serious adverse events (SAE), Grade 3 or higher TEAE, or TEAE leading to discontinuation or ramucirumab dose modification. DLT=G4 neutropenia \>7days; G ≥3 neutropenia with fever ≥38.5°C requiring IV antibiotics or bacteriemia or sepsis; G4 thrombocytopenia; G ≥3 thrombocytopenia with bleeding requiring platelets; G≥3 prothrombin time and/or partial thromboplastin time in absence of anticoagulants; G≥2 hyperbilirubinemia ≥5 days; QTc \>500 milliseconds (ms) or increase ≥100 ms or arrhythmia; G≥4 or uncontrollable hypertension; G≥3 nonhematologic toxicity (excluding G3: hypersensitivity, injection-site reaction, arthralgia/myalgia, asthenia/fatigue, diarrhea without loperamide therapy, nausea/vomiting without antiemetics, transient G3/4 elevation of aminotransferases); treatment delay \>2 weeks due to toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration (Cmax) of Ramucirumab | Day 1 of Cycle 1 and Cycle 4 (cycle=21 days) | Cmax (Cycle 1) and Cmax at steady state (Cmax,ss, Cycle 4) of ramucirumab are provided. |
| Area Under the Curve (AUC) of Ramucirumab | Day 1 of Cycles 1 and 4 (cycle=21 days) | AUC from time zero to infinity (AUC\[0-inf\], Cycle 1) and at steady state (AUC tau, Cycle 4) of ramucirumab are provided. |
| Serum Anti-IMC-1121B Antibody Assessment (Immunogenicity) | Baseline up to data cut off (approximately 48.3 weeks) | The number of participants with a positive anti-IMC-1121B titer at any point during the study. |
| Clearance (Cl) of Ramucirumab | Day 1 of Cycle 1 and Cycle 4 (cycle=21 days) | Clearance (Cycle 1) and at steady state (Clss, Cycle 4) of ramucirumab are provided. |
| Steady State Volume of Distribution (Vss) of Ramucirumab | Day 1 of Cycle 1 and 4 (cycle=21 days) | — |
| Half Life (t 1/2) of Ramucirumab | Day 1 of Cycles 1 and 4 (cycle=21 days) | — |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab and Docetaxel Combination Docetaxel: Docetaxel administered by intravenous infusion at a dose of 75 milligrams per square meter (mg/m\^2) every 3 weeks.
Ramucirumab: Ramucirumab administered as an intravenous infusion at a dose of 10 milligrams per kilogram (mg/kg) every 3 weeks. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Ramucirumab and Docetaxel Combination |
|---|---|
| Age, Customized >=65 years | 1 participants |
| Age, Customized Between 20 and 65 years | 6 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants |
| Race/Ethnicity, Customized Asian | 7 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants |
| Race/Ethnicity, Customized Other | 0 participants |
| Race/Ethnicity, Customized White | 0 participants |
| Region of Enrollment Japan | 7 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 7 / 7 |
Outcome results
Primary
Number of Participants With Adverse Events
Number participants with drug related dose-limiting toxicities (DLT) during Cycle 1; ramucirumab related: treatment-emergent adverse events (TEAE), serious adverse events (SAE), Grade 3 or higher TEAE, or TEAE leading to discontinuation or ramucirumab dose modification. DLT=G4 neutropenia \>7days; G ≥3 neutropenia with fever ≥38.5°C requiring IV antibiotics or bacteriemia or sepsis; G4 thrombocytopenia; G ≥3 thrombocytopenia with bleeding requiring platelets; G≥3 prothrombin time and/or partial thromboplastin time in absence of anticoagulants; G≥2 hyperbilirubinemia ≥5 days; QTc \>500 milliseconds (ms) or increase ≥100 ms or arrhythmia; G≥4 or uncontrollable hypertension; G≥3 nonhematologic toxicity (excluding G3: hypersensitivity, injection-site reaction, arthralgia/myalgia, asthenia/fatigue, diarrhea without loperamide therapy, nausea/vomiting without antiemetics, transient G3/4 elevation of aminotransferases); treatment delay \>2 weeks due to toxicity.
Time frame: Baseline up to data cut off (approximately 48.3 weeks)
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramucirumab and Docetaxel Combination | Number of Participants With Adverse Events | Dose Limiting Toxicity (DLT) during Cycle 1 | 2 participants |
| Ramucirumab and Docetaxel Combination | Number of Participants With Adverse Events | TEAE related to ramucirumab | 7 participants |
| Ramucirumab and Docetaxel Combination | Number of Participants With Adverse Events | SAE related to ramucirumab | 4 participants |
| Ramucirumab and Docetaxel Combination | Number of Participants With Adverse Events | TEAE of Grade ≥3 related to ramucirumab | 6 participants |
| Ramucirumab and Docetaxel Combination | Number of Participants With Adverse Events | TEAE resulting in ramucirumab discontinuation | 3 participants |
| Ramucirumab and Docetaxel Combination | Number of Participants With Adverse Events | TEAE with ramucirumab dose modification/delay | 5 participants |
Secondary
Area Under the Curve (AUC) of Ramucirumab
AUC from time zero to infinity (AUC\[0-inf\], Cycle 1) and at steady state (AUC tau, Cycle 4) of ramucirumab are provided.
Time frame: Day 1 of Cycles 1 and 4 (cycle=21 days)
Population: All participants with evaluable AUC data at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab and Docetaxel Combination | Area Under the Curve (AUC) of Ramucirumab | AUC(0-inf) at Cycle 1 | 1700 micrograms*day/milliliter (mcg*day/mL) | Geometric Coefficient of Variation 25 |
| Ramucirumab and Docetaxel Combination | Area Under the Curve (AUC) of Ramucirumab | AUC tau at Cycle 4 (n=6) | 2320 micrograms*day/milliliter (mcg*day/mL) | Geometric Coefficient of Variation 24 |
Secondary
Clearance (Cl) of Ramucirumab
Clearance (Cycle 1) and at steady state (Clss, Cycle 4) of ramucirumab are provided.
Time frame: Day 1 of Cycle 1 and Cycle 4 (cycle=21 days)
Population: All participants with evaluable clearance data at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab and Docetaxel Combination | Clearance (Cl) of Ramucirumab | Clearance at Cycle 1 | 13.6 milliliters per hour (mL/hr) | Geometric Coefficient of Variation 24 |
| Ramucirumab and Docetaxel Combination | Clearance (Cl) of Ramucirumab | Clearance at steady state (Clss) at Cycle 4 (n=6) | 10.2 milliliters per hour (mL/hr) | Geometric Coefficient of Variation 24 |
Secondary
Half Life (t 1/2) of Ramucirumab
Time frame: Day 1 of Cycles 1 and 4 (cycle=21 days)
Population: All participants with evaluable t1/2 data at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab and Docetaxel Combination | Half Life (t 1/2) of Ramucirumab | t1/2 at Cycle 1 | 6.57 days | Geometric Coefficient of Variation 49 |
| Ramucirumab and Docetaxel Combination | Half Life (t 1/2) of Ramucirumab | t1/2 at Cycle 4 (n=6) | 11.9 days | Geometric Coefficient of Variation 26 |
Secondary
Maximum Concentration (Cmax) of Ramucirumab
Cmax (Cycle 1) and Cmax at steady state (Cmax,ss, Cycle 4) of ramucirumab are provided.
Time frame: Day 1 of Cycle 1 and Cycle 4 (cycle=21 days)
Population: All participants with evaluable Cmax data at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab and Docetaxel Combination | Maximum Concentration (Cmax) of Ramucirumab | Cmax at Cycle 1 | 261 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 22 |
| Ramucirumab and Docetaxel Combination | Maximum Concentration (Cmax) of Ramucirumab | Cmax,ss at Cycle 4 (n=6) | 335 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 22 |
Secondary
Serum Anti-IMC-1121B Antibody Assessment (Immunogenicity)
The number of participants with a positive anti-IMC-1121B titer at any point during the study.
Time frame: Baseline up to data cut off (approximately 48.3 weeks)
Population: All participants with evaluable antibody assessment data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab and Docetaxel Combination | Serum Anti-IMC-1121B Antibody Assessment (Immunogenicity) | 0 participants |
Secondary
Steady State Volume of Distribution (Vss) of Ramucirumab
Time frame: Day 1 of Cycle 1 and 4 (cycle=21 days)
Population: All participants with evaluable Vss data at the specified time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab and Docetaxel Combination | Steady State Volume of Distribution (Vss) of Ramucirumab | Vss at Cycle 1 | 2.96 liters (L) | Geometric Coefficient of Variation 32 |
| Ramucirumab and Docetaxel Combination | Steady State Volume of Distribution (Vss) of Ramucirumab | Vss at Cycle 4 (n=6) | 3.92 liters (L) | Geometric Coefficient of Variation 18 |