Lung Cancer, Non-Small Cell Lung Cancer
Conditions
Keywords
Lung cancer, Non-small cell lung cancer, NSCLC, Clinical Trial, Panitumumab, AMG 706, Anti-angiogenesis, Immunex, Abgenix, Amgen, Stage IIIB, Stage IV, Unresectable
Brief summary
The purpose of this trial is: - To characterize the safety profile of motesanib when used in combination with carboplatin/paclitaxel (CP), with panitumumab or with CP and panitumumab in patients with advanced non-small cell lung cancer (NSCLC). - To establish the pharmacokinetic (PK) profile of motesanib when it is used in combination with CP, with panitumumab, or with CP and panitumumab. - To compare the paclitaxel and motesanib PK profiles when the medications are administered 30 minutes (min) or approximately 48 hours (hrs) apart. - To characterize the panitumumab and paclitaxel exposure in the combination regimens of motesanib with CP, motesanib with panitumumab, or motesanib with CP and panitumumab. - To describe the objective response rate (ORR) in each dose cohort. - To measure the immunogenicity of panitumumab in patients administered motesanib with panitumumab and motesanib with CP and panitumumab.
Detailed description
This was a multicenter, open-label, dose-finding clinical trial examining the safety and PK of once or twice daily motesanib administered with CP or with CP and panitumumab in chemotherapy naïve patients, and with panitumumab in patients with no more than one prior chemotherapy regimen for NSCLC. Participants were enrolled into the Panitumumab + Paclitaxel + Carboplatin + Motesanib once a safe and tolerable dose of AMG 706 was established in the other treatment arms.
Interventions
BIOLOGICALPanitumumab
9.0 mg/kg on Day 1 of each 21-day cycle administered by intravenous infusion over approximately 60 minutes.
Dose-finding with an initial dose of 50 mg once daily and up to 125 mg once daily. 75 mg twice daily was also to be tested.
DRUGPaclitaxel
Paclitaxel 200 mg/m\^2 administered by IV infusion over 3 hours.
DRUGCarboplatin
Carboplatin was administered IV over approximately 30 minutes. Carboplatin was dosed using the glomerular filtration rate (GFR) and Calvert formula to AUC/time curve of 6 mg/mL×min.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of unresectable stage IIIB or IV non-small cell lung cancer (NSCLC) * No more than one prior chemotherapy * Adequate hematologic, renal and hepatic function * Measurable disease or evaluable disease on CAT scan or MRI * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Able to fast for 10 hrs twice during the study - Able to tolerate oral medications * Life expectancy of at least 3 months
Exclusion criteria
* Symptomatic or untreated central nervous system metastases requiring current treatment * History of arterial thrombosis within 1 year prior to enrollment * Anticoagulant therapy, except for warfarin of less than 2mg per day * Symptomatic peripheral neuropathy * History of pulmonary hemorrhage or hemoptysis * Myocardial infarction within 1 year before enrollment * Uncontrolled hypertension \[diastolic greater than 85 mmHg; systolic greater than 145 mmHg\] * History of other cancer, unless treated with no known active disease for longer than 3 years * Previous treatment with AMG 706 or panitumumab, previous treatment with inhibitors of VEGF or EGF * No antibody treatment for 6 weeks prior to enrollment * Known HIV positive, hepatitis C positive or hepatitis B surface antigen positive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 2 | Cycle 2, Day 1, 24 hours post-dose | The trough plasma concentration for motesanib at 24 hours postdose in Cycle 2. For the 75 BID cohort, C24 is the observed concentration at 24 hours (ie, after the second daily dose). |
| Time to Maximum Plasma Concentration of Motesanib (Tmax) for Cycle 1 | Cycle 1, Day 3 at predose, 15 and 30 minutes, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose. | The time after dosing that the maximal plasma concentration of motesanib was observed in Cycle 1. For the 75 mg BID cohorts, Tmax is reported for the first daily dose. |
| Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 1 | Cycle 1, Day 3 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose. | The maximal observed plasma concentration of motesanib after a single dose dose in Cycle 1. For the 75 mg BID cohorts, Cmax is reported for the first daily dose. |
| Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 1 | Cycle 1, Day 3 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours postdose. | The terminal-phase elimination half-life (t1/2,z) of motesanib was calculated as ln(2)/λz. The terminal elimination rate constant (λz) was determined by linear regression of the natural logarithms of at least the last 3 measurable concentrations during the terminal phase. For the 75 mg BID cohorts, t1/2,z is reported for the first daily dose. |
| Area Under the Plasma Concentration-time Curve for Motesanib in Cycle 1 | Cycle 1, Day 3 at predose, 15 and 30 minutes, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose. | Area under the plasma concentration-time curve for motesanib in Cycle 1 calculated using the using the linear/log trapezoidal method. AUC from time zero to infinity (AUC0-inf) is reported for the 50 and 125 mg QD cohorts and AUC from time 0 to 24 hours post-dose (AUC0-24) is reported for the 75 mg BID cohort, where AUC0-24 is the sum of AUC0-12 for the first and second daily dose. |
| Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 1 | Cycle 1, Day 3, 24 hours post-dose | The trough plasma concentration for motesanib at 24 hours postdose in Cycle 1. For the 75 BID cohort, C24 is the observed concentration at 24 hours (ie, after the second daily dose). |
| Time to Maximum Plasma Concentration of Motesanib (Tmax) in Cycle 2 | Cycle 2, Day 1 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose. | The time after dosing that the maximal plasma concentration of motesanib was observed in Cycle 2. For the 75 mg BID cohorts, Tmax is reported for the first daily dose. |
| Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 2 | Cycle 2, Day 1 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose. | The maximal observed plasma concentration of motesanib in Cycle 2, after multiple doses. For the 75 mg BID cohorts, Cmax is reported for the first daily dose. |
| Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 2 | Cycle 2, Day 1 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose. | The terminal-phase elimination half-life (t1/2,z) of motesanib was calculated as ln(2)/λz. The terminal elimination rate constant (λz) was determined by linear regression of the natural logarithms of at least the last 3 measurable concentrations during the terminal phase. For the 75 mg BID cohorts, t1/2,z is reported for the first daily dose. |
| Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Motesanib in Cycle 2 | Cycle 2, Day 1 at predose, 15 and 30 minutes, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose. | Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) for motesanib in Cycle 2 calculated using the using the linear/log trapezoidal method. For the 75 mg BID cohort AUC0-24 is the sum of AUC0-12 for the first and second daily dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Overall Objective Response | After 9 weeks of treatment (at the end of Cycle 3) | Confirmed objective tumor response defined as a complete response (CR) or partial response (PR) using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Tumor response was evaluated by computed tomography (CT) scan or magnetic resonance imaging (MRI). Responding disease (CR or PR) was confirmed no less than 4 weeks after the criteria for response were first met. A complete response defined as the disappearance of all target lesions and all non-target lesions, no new lesions and normalization of tumor marker level. Partial response defined as either the disappearance of all target lesions and the persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diamer (LD) of target lesions, taking as reference the baseline sum LD and no new lesions and/or unequivocal progression of existing non-target lesions. |
Participant flow
Recruitment details
Participants were enrolled from 18 January 2005 through 25 September 2006
Participants by arm
| Arm | Count |
|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD Chemotherapy naïve participants received paclitaxel 200 mg/m\^2 and carboplatin chemotherapy administered by intravenous (IV) infusion on Day 1 of each 21-day cycle, and motesanib, 50 mg once daily (QD) orally self-administered on Days 3-21 of Cycle 1 and then on Days 1 to 21 of Cycle 2 and all cycles thereafter. | 6 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD Chemotherapy naïve participants received paclitaxel 200 mg/m\^2 and carboplatin chemotherapy administered by intravenous (IV) infusion on Day 1 of each 21-day cycle, and motesanib, 125 mg QD orally self-administered on Days 3-21 of Cycle 1 and then on Days 1 to 21 of Cycle 2 and all cycles thereafter. | 11 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID Chemotherapy naïve participants received paclitaxel 200 mg/m\^2 and carboplatin chemotherapy administered by intravenous (IV) infusion on Day 1 of each 21-day cycle, and motesanib, 75 mg twice daily (BID) orally self-administered on Days 3-21 of Cycle 1 and then on Days 1 to 21 of Cycle 2 and all cycles thereafter. | 6 |
| Panitumumab + Motesanib 50 mg QD Participants with no more than one prior chemotherapy regimen for NSCLC received panitumumab 9.0 mg/kg IV on Day 1 of each 21-day cycle, and motesanib 50 mg QD, orally self-administered on Days 3-21 of Cycle 1 and then on Days 1 to 21 of Cycle 2 and all cycles thereafter. | 4 |
| Panitumumab + Motesanib 125 mg QD Participants with no more than one prior chemotherapy regimen for NSCLC received panitumumab 9.0 mg/kg IV on Day 1 of each 21-day cycle, and motesanib 125 mg QD, orally self-administered on Days 3-21 of Cycle 1 and then on Days 1 to 21 of Cycle 2 and all cycles thereafter. | 7 |
| Panitumumab + Motesanib 75 mg BID Participants with no more than one prior chemotherapy regimen for NSCLC received panitumumab 9.0 mg/kg IV on Day 1 of each 21-day cycle, and motesanib 75 mg BID, orally self-administered on Days 3-21 of Cycle 1 and then on Days 1 to 21 of Cycle 2 and all cycles thereafter. | 5 |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD Chemotherapy naïve participants received panitumumab 9.0 mg/kg, paclitaxel 200 mg/m\^2 and carboplatin chemotherapy administered by IV infusion on Day 1 of each 21-day cycle, and motesanib 125 mg QD, orally on Days 3-21 of Cycle 1 and then on Days 1 to 21 of Cycle 2 and all cycles thereafter. | 6 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Non-compliance | 1 | 2 | 2 | 0 | 2 | 2 | 1 |
| Overall Study | Other | 1 | 1 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Paclitaxel/Carboplatin + Motesanib 50 mg QD | Paclitaxel/Carboplatin + Motesanib 125 mg QD | Paclitaxel/Carboplatin + Motesanib 75 mg BID | Panitumumab + Motesanib 50 mg QD | Panitumumab + Motesanib 125 mg QD | Panitumumab + Motesanib 75 mg BID | Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 67.8 years STANDARD_DEVIATION 7.8 | 55.7 years STANDARD_DEVIATION 12.7 | 64.5 years STANDARD_DEVIATION 6.1 | 57.5 years STANDARD_DEVIATION 9.9 | 64.0 years STANDARD_DEVIATION 9.6 | 51.6 years STANDARD_DEVIATION 14.6 | 59.0 years STANDARD_DEVIATION 5.5 | 59.9 years STANDARD_DEVIATION 10.8 |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White or Caucasian | 6 participants | 11 participants | 5 participants | 4 participants | 6 participants | 4 participants | 5 participants | 41 participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 3 Participants | 0 Participants | 5 Participants | 1 Participants | 3 Participants | 16 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 3 Participants | 4 Participants | 2 Participants | 4 Participants | 3 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 11 / 11 | 6 / 6 | 4 / 4 | 7 / 7 | 5 / 5 | 6 / 6 |
| serious Total, serious adverse events | 5 / 6 | 2 / 11 | 3 / 6 | 0 / 4 | 1 / 7 | 4 / 5 | 2 / 6 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve for Motesanib in Cycle 1
Area under the plasma concentration-time curve for motesanib in Cycle 1 calculated using the using the linear/log trapezoidal method. AUC from time zero to infinity (AUC0-inf) is reported for the 50 and 125 mg QD cohorts and AUC from time 0 to 24 hours post-dose (AUC0-24) is reported for the 75 mg BID cohort, where AUC0-24 is the sum of AUC0-12 for the first and second daily dose.
Time frame: Cycle 1, Day 3 at predose, 15 and 30 minutes, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
Population: PK Population. Participants with elevated motesanib concentrations at 24 hours were excluded from the calculations. Summary results are not presented for the Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD treatment group for which the sample size was smaller than 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Area Under the Plasma Concentration-time Curve for Motesanib in Cycle 1 | 0.971 μg*hr/mL | Standard Deviation 0.3 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Area Under the Plasma Concentration-time Curve for Motesanib in Cycle 1 | 3.21 μg*hr/mL | Standard Deviation 1.12 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Area Under the Plasma Concentration-time Curve for Motesanib in Cycle 1 | 2.91 μg*hr/mL | Standard Deviation 1.01 |
| Panitumumab + Motesanib 50 mg QD | Area Under the Plasma Concentration-time Curve for Motesanib in Cycle 1 | 1.74 μg*hr/mL | Standard Deviation 0.63 |
| Panitumumab + Motesanib 125 mg QD | Area Under the Plasma Concentration-time Curve for Motesanib in Cycle 1 | 3.23 μg*hr/mL | Standard Deviation 1.83 |
| Panitumumab + Motesanib 75 mg BID | Area Under the Plasma Concentration-time Curve for Motesanib in Cycle 1 | 2.04 μg*hr/mL | Standard Deviation 1.06 |
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Motesanib in Cycle 2
Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC0-24) for motesanib in Cycle 2 calculated using the using the linear/log trapezoidal method. For the 75 mg BID cohort AUC0-24 is the sum of AUC0-12 for the first and second daily dose.
Time frame: Cycle 2, Day 1 at predose, 15 and 30 minutes, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
Population: PK Population. Participants with elevated motesanib concentrations at 24 hours were excluded from the calculations. Summary results are not presented for two treatment groups for which the sample size was smaller than 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Motesanib in Cycle 2 | 4.50 μg*hr/mL | Standard Deviation 2.62 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Motesanib in Cycle 2 | 3.11 μg*hr/mL | Standard Deviation 2.38 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Motesanib in Cycle 2 | 1.26 μg*hr/mL | Standard Deviation 0.61 |
| Panitumumab + Motesanib 50 mg QD | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Motesanib in Cycle 2 | 3.92 μg*hr/mL | Standard Deviation 2.65 |
| Panitumumab + Motesanib 125 mg QD | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Motesanib in Cycle 2 | 3.16 μg*hr/mL | Standard Deviation 1.2 |
Primary
Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 1
The terminal-phase elimination half-life (t1/2,z) of motesanib was calculated as ln(2)/λz. The terminal elimination rate constant (λz) was determined by linear regression of the natural logarithms of at least the last 3 measurable concentrations during the terminal phase. For the 75 mg BID cohorts, t1/2,z is reported for the first daily dose.
Time frame: Cycle 1, Day 3 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours postdose.
Population: PK Population. Participants with elevated motesanib concentrations at 24 hours were excluded from the calculations. Summary results are not presented for the Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD treatment group for which the sample size was smaller than 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 1 | 7.34 hours | Standard Deviation 2.07 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 1 | 5.33 hours | Standard Deviation 1.05 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 1 | 5.77 hours | Standard Deviation 1.45 |
| Panitumumab + Motesanib 50 mg QD | Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 1 | 6.47 hours | Standard Deviation 2.31 |
| Panitumumab + Motesanib 125 mg QD | Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 1 | 7.57 hours | Standard Deviation 2.6 |
| Panitumumab + Motesanib 75 mg BID | Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 1 | 8.28 hours | Standard Deviation 2.62 |
Primary
Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 2
The terminal-phase elimination half-life (t1/2,z) of motesanib was calculated as ln(2)/λz. The terminal elimination rate constant (λz) was determined by linear regression of the natural logarithms of at least the last 3 measurable concentrations during the terminal phase. For the 75 mg BID cohorts, t1/2,z is reported for the first daily dose.
Time frame: Cycle 2, Day 1 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
Population: PK Population. Participants with elevated motesanib concentrations at 24 hours were excluded from the calculations. Summary results are not presented for three treatment groups for which the sample size was smaller than 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 2 | 6.41 hours | Standard Deviation 2.08 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 2 | 6.36 hours | Standard Deviation 1.7 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 2 | 7.08 hours | Standard Deviation 0.35 |
| Panitumumab + Motesanib 50 mg QD | Estimated Terminal-phase Half-life (t1/2,z) of Motesanib in Cycle 2 | 4.90 hours | Standard Deviation 1.21 |
Primary
Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 1
The maximal observed plasma concentration of motesanib after a single dose dose in Cycle 1. For the 75 mg BID cohorts, Cmax is reported for the first daily dose.
Time frame: Cycle 1, Day 3 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 1 | 158 ng/mL | Standard Deviation 55 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 1 | 525 ng/mL | Standard Deviation 250 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 1 | 448 ng/mL | Standard Deviation 112 |
| Panitumumab + Motesanib 50 mg QD | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 1 | 328 ng/mL | Standard Deviation 214 |
| Panitumumab + Motesanib 125 mg QD | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 1 | 444 ng/mL | Standard Deviation 130 |
| Panitumumab + Motesanib 75 mg BID | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 1 | 198 ng/mL | Standard Deviation 55 |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 1 | 360 ng/mL | Standard Deviation 243 |
Primary
Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 2
The maximal observed plasma concentration of motesanib in Cycle 2, after multiple doses. For the 75 mg BID cohorts, Cmax is reported for the first daily dose.
Time frame: Cycle 2, Day 1 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
Population: PK population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 2 | 148 ng/mL | Standard Deviation 25 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 2 | 748 ng/mL | Standard Deviation 701 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 2 | 390 ng/mL | Standard Deviation 319 |
| Panitumumab + Motesanib 50 mg QD | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 2 | 265 ng/mL | Standard Deviation 190 |
| Panitumumab + Motesanib 125 mg QD | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 2 | 672 ng/mL | Standard Deviation 336 |
| Panitumumab + Motesanib 75 mg BID | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 2 | 242 ng/mL | Standard Deviation 153 |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | Maximum Observed Plasma Concentration of Motesanib (Cmax) in Cycle 2 | 651 ng/mL | Standard Deviation 605 |
Primary
Time to Maximum Plasma Concentration of Motesanib (Tmax) for Cycle 1
The time after dosing that the maximal plasma concentration of motesanib was observed in Cycle 1. For the 75 mg BID cohorts, Tmax is reported for the first daily dose.
Time frame: Cycle 1, Day 3 at predose, 15 and 30 minutes, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
Population: The pharmacokinetic (PK) population consisted of all consented patients who received motesanib and had evaluable pharmacokinetic data and did not have significant protocol deviations that affected the data or key-dosing information that was missing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Time to Maximum Plasma Concentration of Motesanib (Tmax) for Cycle 1 | 0.75 hours |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Time to Maximum Plasma Concentration of Motesanib (Tmax) for Cycle 1 | 1.0 hours |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Time to Maximum Plasma Concentration of Motesanib (Tmax) for Cycle 1 | 0.75 hours |
| Panitumumab + Motesanib 50 mg QD | Time to Maximum Plasma Concentration of Motesanib (Tmax) for Cycle 1 | 1.5 hours |
| Panitumumab + Motesanib 125 mg QD | Time to Maximum Plasma Concentration of Motesanib (Tmax) for Cycle 1 | 1.0 hours |
| Panitumumab + Motesanib 75 mg BID | Time to Maximum Plasma Concentration of Motesanib (Tmax) for Cycle 1 | 0.58 hours |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | Time to Maximum Plasma Concentration of Motesanib (Tmax) for Cycle 1 | 1.0 hours |
Primary
Time to Maximum Plasma Concentration of Motesanib (Tmax) in Cycle 2
The time after dosing that the maximal plasma concentration of motesanib was observed in Cycle 2. For the 75 mg BID cohorts, Tmax is reported for the first daily dose.
Time frame: Cycle 2, Day 1 at predose, 15 and 30 min, and at 1, 2, 4, 6, 10 (QD cohorts only), and 24 hours post-dose.
Population: PK population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Time to Maximum Plasma Concentration of Motesanib (Tmax) in Cycle 2 | 1.5 hours |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Time to Maximum Plasma Concentration of Motesanib (Tmax) in Cycle 2 | 1.0 hours |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Time to Maximum Plasma Concentration of Motesanib (Tmax) in Cycle 2 | 0.63 hours |
| Panitumumab + Motesanib 50 mg QD | Time to Maximum Plasma Concentration of Motesanib (Tmax) in Cycle 2 | 1.0 hours |
| Panitumumab + Motesanib 125 mg QD | Time to Maximum Plasma Concentration of Motesanib (Tmax) in Cycle 2 | 0.75 hours |
| Panitumumab + Motesanib 75 mg BID | Time to Maximum Plasma Concentration of Motesanib (Tmax) in Cycle 2 | 1.0 hours |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | Time to Maximum Plasma Concentration of Motesanib (Tmax) in Cycle 2 | 2.0 hours |
Primary
Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 1
The trough plasma concentration for motesanib at 24 hours postdose in Cycle 1. For the 75 BID cohort, C24 is the observed concentration at 24 hours (ie, after the second daily dose).
Time frame: Cycle 1, Day 3, 24 hours post-dose
Population: PK Population. Participants with elevated motesanib concentrations at 24 hours were excluded from the calculations. Summary results are not presented for the Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD treatment group for which the sample size was smaller than 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 1 | 9.12 ng/mL | Standard Deviation 4.17 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 1 | 26.5 ng/mL | Standard Deviation 16.8 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 1 | 56.7 ng/mL | Standard Deviation 27.4 |
| Panitumumab + Motesanib 50 mg QD | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 1 | 14.0 ng/mL | Standard Deviation 11.7 |
| Panitumumab + Motesanib 125 mg QD | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 1 | 32.5 ng/mL | Standard Deviation 21.5 |
| Panitumumab + Motesanib 75 mg BID | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 1 | 56.8 ng/mL | Standard Deviation 21.1 |
Primary
Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 2
The trough plasma concentration for motesanib at 24 hours postdose in Cycle 2. For the 75 BID cohort, C24 is the observed concentration at 24 hours (ie, after the second daily dose).
Time frame: Cycle 2, Day 1, 24 hours post-dose
Population: PK Population. Participants with elevated motesanib concentrations at 24 hours were excluded from the calculations. Summary results are not presented for two treatment groups for which the sample size was smaller than 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 2 | 43.4 ng/mL | Standard Deviation 44.8 |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 2 | 45.4 ng/mL | Standard Deviation 35.9 |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 2 | 10.4 ng/mL | Standard Deviation 5.3 |
| Panitumumab + Motesanib 50 mg QD | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 2 | 61.1 ng/mL | Standard Deviation 72.6 |
| Panitumumab + Motesanib 125 mg QD | Trough Plasma Concentration at 24 Hours Post-dose (C24) for Motesanib in Cycle 2 | 45.1 ng/mL | Standard Deviation 37.9 |
Secondary
Percentage of Participants With an Overall Objective Response
Confirmed objective tumor response defined as a complete response (CR) or partial response (PR) using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Tumor response was evaluated by computed tomography (CT) scan or magnetic resonance imaging (MRI). Responding disease (CR or PR) was confirmed no less than 4 weeks after the criteria for response were first met. A complete response defined as the disappearance of all target lesions and all non-target lesions, no new lesions and normalization of tumor marker level. Partial response defined as either the disappearance of all target lesions and the persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits, or, at least a 30% decrease in the sum of the longest diamer (LD) of target lesions, taking as reference the baseline sum LD and no new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: After 9 weeks of treatment (at the end of Cycle 3)
Population: Efficacy analysis set, composed of all enrolled participants who received at least one dose of motesanib in treatment arms 1-3 or at least one dose of motesanib with one dose of panitumumab in treatmnt arms 4-7.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paclitaxel/Carboplatin + Motesanib 50 mg QD | Percentage of Participants With an Overall Objective Response | 33 Percentage of participants |
| Paclitaxel/Carboplatin + Motesanib 125 mg QD | Percentage of Participants With an Overall Objective Response | 18 Percentage of participants |
| Paclitaxel/Carboplatin + Motesanib 75 mg BID | Percentage of Participants With an Overall Objective Response | 0 Percentage of participants |
| Panitumumab + Motesanib 50 mg QD | Percentage of Participants With an Overall Objective Response | 0 Percentage of participants |
| Panitumumab + Motesanib 125 mg QD | Percentage of Participants With an Overall Objective Response | 0 Percentage of participants |
| Panitumumab + Motesanib 75 mg BID | Percentage of Participants With an Overall Objective Response | 0 Percentage of participants |
| Panitumumab + Paclitaxel/Carboplatin + Motesanib 125 mg QD | Percentage of Participants With an Overall Objective Response | 17 Percentage of participants |