Multiple Myeloma
Conditions
Brief summary
The purpose of the study is to compare the progression-free survival (PFS) of once-weekly carfilzomib dosing in combination with dexamethasone to twice-weekly carfilzomib dosing in combination with dexamethasone in adults with relapsed and refractory multiple myeloma, previously treated with bortezomib and an immunomodulatory agent (IMiD).
Interventions
DRUGCarfilzomib
Carfilzomib was administered as an IV infusion
DRUGDexamethasone
Commercially available dexamethasone was obtained by the investigational site.
Sponsors
Amgen
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
Key Inclusion Criteria: 1. Relapsed multiple myeloma 2. Refractory multiple myeloma defined as meeting 1 or more of the following: * Nonresponsive to most recent therapy (stable disease only or PD while on treatment), or * Disease progression within 60 days of discontinuation from most recent therapy 3. At least 2 but no more than 3 prior therapies for multiple myeloma 4. Prior exposure to an immunomodulatory agent (IMiD) 5. Prior exposure to a proteasome inhibitor (PI) 6. Documented response of at least partial response (PR) to 1 line of prior therapy 7. Measurable disease with at least 1 of the following assessed within the 21 days prior to randomization: * Serum M-protein ≥ 0.5 g/dL * Urine M-protein ≥ 200 mg/24 hours * In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) \> 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio 8. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 9. Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days prior to randomization 10. Adequate organ and bone marrow function within the 21 days prior to randomization defined by: * Bilirubin \< 1.5 times the upper limit of normal (ULN) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 times the ULN * Absolute neutrophil count (ANC) ≥ 1000/mm³ (screening ANC should be independent of growth factor support for ≥ 1 week) * Hemoglobin ≥ 8.0 g/dL (Use of erythropoietic stimulating factors and red blood cell \[RBC\] transfusion per institutional guidelines is allowed, however the most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.) * Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is \> 50%. Subjects should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count.) * Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min Key
Exclusion criteria
1. Waldenström macroglobulinemia 2. Multiple myeloma of Immunoglobin M (IgM) subtype 3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 4. Plasma cell leukemia (\> 2.0 × 10⁹/L circulating plasma cells by standard differential) 5. Myelodysplastic syndrome 6. Second malignancy within the past 5 years except: * Adequately treated basal cell or squamous cell skin cancer * Carcinoma in situ of the cervix * Prostate cancer \< Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months * Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins) * Treated medullary or papillary thyroid cancer * Similar condition with an expectation of \> 95% five-year disease-free survival 7. History of or current amyloidosis 8. Cytotoxic chemotherapy within the 28 days prior to randomization 9. Immunotherapy within the 21 days prior to randomization 10. Glucocorticoid therapy within the 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or 1000 mg prednisone 11. Radiation therapy: * Focal therapy within the 7 days prior to randomization * Extended field therapy within the 21 days prior to randomization 12. Prior treatment with either carfilzomib or oprozomib 13. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib) 14. Contraindication to dexamethasone or any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment 15. Active congestive heart failure (New York Heart Association \[NYHA\] Class III or IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial infarction within 6 months prior to enrollment 16. Active infection within the 14 days prior to randomization requiring systemic antibiotics 17. Pleural effusions requiring thoracentesis within the 14 days prior to randomization 18. Ascites requiring paracentesis within the 14 days prior to randomization 19. Ongoing graft-versus-host disease 20. Uncontrolled hypertension or uncontrolled diabetes despite medication 21. Significant neuropathy (≥ Grade 3) within the 14 days prior to randomization 22. Known cirrhosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for PFS was 12.0 (0, 20) and 12.6 (0, 19) months in each treatment group respectively. | Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease status was assessed at a central laboratory with serum and urine protein electrophoresis, immunofixation, serum-free light chain (SFLC) assay, bone marrow sample evaluation, serum calcium, plasmacytoma evaluation, and skeletal survey. Response and disease progression were determined using a validated computer algorithm based on the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Median PFS was derived using the Kaplan-Meier method; participants still alive with no disease progression were censored at the time of their last disease assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Disease response was assessed every 28 days until progressive disease, up to the data cut-off date of 15 June 2017; median time on follow-up was 12.0 and 12.6 months in each treatment group respectively. | Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response rate was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in BM biopsy; VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein \<100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to \< 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. |
| Overall Survival | From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for OS was 12.6 (0, 20) and 13.2 (0, 19) months in each treatment group respectively. | Overall Survival (OS) was defined as the time from randomization to death due to any cause. Median overall survival was derived using the Kaplan-Meier method; participants still alive were censored at the date last known to be alive. |
| Number of Participants With Adverse Events (AEs) | From first dose of study drug up to 30 days after last dose, up to the end of study; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) weeks in each treatment group respectively. | The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, where where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal. Treatment-related adverse events are adverse events considered related to at least 1 investigational product by the investigator, including those with unknown relationship. |
| Plasma Carfilzomib Concentration During Cycle 2 | Cycle 2 day 1 predose, 15 minutes after the start of infusion (once-weekly carfilzomib only), end of infusion, and 30 minutes after the end of infusion | Concentrations of carfilzomib in plasma were measured using a validated assay method. The lower limit of quantification was 0.100 ng/mL. |
Countries
Australia, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Japan, New Zealand, Norway, Poland, Romania, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled from September 2015 to August 2016 at 118 sites in Australia, New Zealand, Japan, North America, and Europe.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive a regimen consisting of either once-weekly or twice weekly carfilzomib in combination with dexamethasone. Randomization was stratified by International Staging System (ISS) stage (stage 1 vs stages 2 or 3), refractory to bortezomib treatment (yes vs no), and age (\< 65 vs ≥ 65 years).
Participants by arm
| Arm | Count |
|---|---|
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter).
Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. | 238 |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter).
Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15. | 240 |
| Total | 478 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Withdrawal by Subject | 19 | 10 |
Baseline characteristics
| Characteristic | Total | Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone |
|---|---|---|---|
| Age, Continuous | 66.0 years | 66.0 years | 66.0 years |
| Age, Customized 18 - 64 years | 208 Participants | 104 Participants | 104 Participants |
| Age, Customized 65 - 74 years | 192 Participants | 90 Participants | 102 Participants |
| Age, Customized 75 - 84 years | 77 Participants | 45 Participants | 32 Participants |
| Age, Customized ≥ 85 years | 1 Participants | 1 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active) | 236 Participants | 118 Participants | 118 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory) | 241 Participants | 121 Participants | 120 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work) | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 461 Participants | 235 Participants | 226 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Asian | 45 Participants | 30 Participants | 15 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Missing | 13 Participants | 3 Participants | 10 Participants |
| Race/Ethnicity, Customized Other | 13 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 402 Participants | 200 Participants | 202 Participants |
| Sex: Female, Male Female | 218 Participants | 108 Participants | 110 Participants |
| Sex: Female, Male Male | 260 Participants | 132 Participants | 128 Participants |
| Stratification Factor: International Staging System (ISS) stage Stage 1 | 200 Participants | 100 Participants | 100 Participants |
| Stratification Factor: International Staging System (ISS) stage Stage 2 or 3 | 278 Participants | 140 Participants | 138 Participants |
| Stratification Factor: Refractory to Bortezomib Treatment No | 302 Participants | 152 Participants | 150 Participants |
| Stratification Factor: Refractory to Bortezomib Treatment Yes | 176 Participants | 88 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 127 / 238 | 119 / 240 |
| other Total, other adverse events | 204 / 235 | 217 / 238 |
| serious Total, serious adverse events | 102 / 235 | 118 / 238 |
Outcome results
Primary
Progression Free Survival
Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease status was assessed at a central laboratory with serum and urine protein electrophoresis, immunofixation, serum-free light chain (SFLC) assay, bone marrow sample evaluation, serum calcium, plasmacytoma evaluation, and skeletal survey. Response and disease progression were determined using a validated computer algorithm based on the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Median PFS was derived using the Kaplan-Meier method; participants still alive with no disease progression were censored at the time of their last disease assessment.
Time frame: From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for PFS was 12.0 (0, 20) and 12.6 (0, 19) months in each treatment group respectively.
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Progression Free Survival | 7.6 months |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Progression Free Survival | 11.2 months |
Comparison: To ensure proper control of type I error, analysis of PFS was performed under a group sequential design framework with the stopping boundaries constructed using the Lan-DeMets spending function with an O'Brien-Fleming approach. The inferential comparison between the 2 treatment groups for PFS used the 1-sided log-rank test stratified by the randomization stratification factors. A 1-sided p-value was compared against the prespecified adjusted alpha value of 0.011 to determine significance.p-value: 0.001495% CI: [0.544, 0.883]Log Rank
p-value: 0.003395% CI: [0.567, 0.913]Log Rank
Secondary
Number of Participants With Adverse Events (AEs)
The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, where where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal. Treatment-related adverse events are adverse events considered related to at least 1 investigational product by the investigator, including those with unknown relationship.
Time frame: From first dose of study drug up to 30 days after last dose, up to the end of study; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) weeks in each treatment group respectively.
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Adverse events Grade ≥ 3 | 152 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAEs) | 176 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | AEs leading to discontinuation of carfilzomib | 29 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events Grade ≥ 3 | 82 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Adverse events (AEs) | 230 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Serious treatment-related adverse events | 31 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | AEs leading to discontinuation of dexamethasone | 31 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of carfilzomib | 11 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Serious adverse events | 102 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 20 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Fatal treatment-related adverse events | 3 Participants |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | TRAEs leading to discontinuation of dexamethasone | 13 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Fatal treatment-related adverse events | 5 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Adverse events (AEs) | 233 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Adverse events Grade ≥ 3 | 181 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Serious adverse events | 118 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | AEs leading to discontinuation of carfilzomib | 35 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | AEs leading to discontinuation of dexamethasone | 40 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 21 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAEs) | 180 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events Grade ≥ 3 | 108 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | Serious treatment-related adverse events | 57 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of carfilzomib | 23 Participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Number of Participants With Adverse Events (AEs) | TRAEs leading to discontinuation of dexamethasone | 29 Participants |
Secondary
Overall Response Rate
Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response rate was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in BM biopsy; VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein \<100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to \< 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.
Time frame: Disease response was assessed every 28 days until progressive disease, up to the data cut-off date of 15 June 2017; median time on follow-up was 12.0 and 12.6 months in each treatment group respectively.
Population: Intent-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Overall Response Rate | 40.8 percentage of participants |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Overall Response Rate | 62.9 percentage of participants |
p-value: <0.000195% CI: [1.716, 3.598]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [1.707, 3.563]Fisher Exact
Secondary
Overall Survival
Overall Survival (OS) was defined as the time from randomization to death due to any cause. Median overall survival was derived using the Kaplan-Meier method; participants still alive were censored at the date last known to be alive.
Time frame: From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for OS was 12.6 (0, 20) and 13.2 (0, 19) months in each treatment group respectively.
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Overall Survival | NA months |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Overall Survival | NA months |
p-value: 0.10795% CI: [0.563, 1.138]Log Rank
p-value: 0.132695% CI: [0.578, 1.164]Log Rank
Secondary
Plasma Carfilzomib Concentration During Cycle 2
Concentrations of carfilzomib in plasma were measured using a validated assay method. The lower limit of quantification was 0.100 ng/mL.
Time frame: Cycle 2 day 1 predose, 15 minutes after the start of infusion (once-weekly carfilzomib only), end of infusion, and 30 minutes after the end of infusion
Population: Participants at a subset of sites who participated in the sparse pharmacokinetic sampling, with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Plasma Carfilzomib Concentration During Cycle 2 | End of infusion | 1640 ng/mL | Standard Deviation 1900 |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Plasma Carfilzomib Concentration During Cycle 2 | Predose | 36.2 ng/mL | Standard Deviation 162 |
| Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone | Plasma Carfilzomib Concentration During Cycle 2 | 30 minutes after end of infusion | 104 ng/mL | Standard Deviation 293 |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Plasma Carfilzomib Concentration During Cycle 2 | 30 minutes after end of infusion | 480 ng/mL | Standard Deviation 2300 |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Plasma Carfilzomib Concentration During Cycle 2 | End of infusion | 1130 ng/mL | Standard Deviation 928 |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Plasma Carfilzomib Concentration During Cycle 2 | Predose | 203 ng/mL | Standard Deviation 1380 |
| Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone | Plasma Carfilzomib Concentration During Cycle 2 | 15 minutes after start of infusion | 1370 ng/mL | Standard Deviation 1410 |