Solid Tumor
Conditions
Brief summary
This study will evaluate the safety, tolerability, and pharmacokinetics of the combination of rhuMab 2C4(Perjeta) and capecitabine (Xeloda) in participants with advanced solid tumors that have progressed during or after standard therapy, or for which no standard therapy is available. Participants will be enrolled and evaluated for dose-limiting toxicities (DLTs) in escalating-dose cohorts in order to determine the maximum tolerated dose (MTD).
Interventions
DRUGCapecitabine
Participants will receive capecitabine on Days 1 to 14 of each 3-week cycle as 825, 1000, or 1250 mg/m\^2 PO twice daily. Treatment may continue until disease progression, unacceptable toxicity, or consent withdrawal.
DRUGRhuMab 2C4
Participants will receive rhuMab 2C4 on Day 1 of each 3-week cycle as 1050 mg via IV infusion. Treatment may continue until disease progression, unacceptable toxicity, or consent withdrawal.
Sponsors
Hoffmann-La Roche
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
* Adults at least 18 years of age * Easter Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Life expectancy at least 12 weeks * Locally advanced or metastatic solid tumor with at least 1 measurable lesion, which has progressed during/after standard therapy * Human epidermal growth factor receptor 2 (HER2)-negative among participants with breast cancer * Negative pregnancy test or use of an adequate contraceptive method among women of childbearing potential * Adequate hematologic, hepatic, and renal function
Exclusion criteria
* Clinical evidence of central nervous system (CNS) metastases * Prior chemotherapy, radiotherapy, or immunotherapy within 4 weeks, or hormone therapy within 2 weeks of study Day 1 * History of palmar plantar syndrome Grade 2 or worse, or any unresolved residual chemotherapy effects * Prior HER2-active agents, continuous intravenous (IV) 5-fluorouracil, capecitabine, or other fluoropyrimidine * Any investigational agent within 28 days of study start * Prior cumulative doxorubicin dose greater than (\>) 360 mg/m\^2 or equivalent * Significant cardiovascular disease * Active/uncontrolled concurrent illness or infection- * Major surgery or trauma within 4 weeks of study Day 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of the Combination of Pertuzumab and Capecitabine | Cycle 1 (3 Weeks) | MTD was defined as the highest tolerated dose combination of capecitabine (825 mg, 1000 mg or 1250 mg) and pertuzumab, without causing Dose Limiting Toxicities (DLTs). DLTs were defined as follows: 1) Any non-hematological toxicity greater than or equal to (≥) Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 except for fever, chills and flu-like symptoms, in spite of adequate toxicity management; 2) Grade 4 neutropenia lasting \> 7 days; 3) Febrile neutropenia; 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion; 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds. Participants who withdrew from the study without completing the first treatment cycle for reasons other than DLT were not considered evaluable for DLT. MTD was measured in mg/m\^2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Half-Life (t1/2) of Pertuzumab | Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and Predose on Days 8, 15 and 22 | The biological half-life or terminal half-life of pertuzumab is the time in days it takes for it to lose half of its pharmacologic activity. t1/2 was measured in days. |
| Maximum Plasma Concentration (Cmax) of Pertuzumab | Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22 | Cmax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose and was measured as nanograms per milliliter (ng/mL). |
| Time to Maximum Plasma Concentration (Tmax) of Pertuzumab | Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22 | Tmax is defined as the time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination. Tmax was measured in days. |
| Area Under the Concentration Curve From Time Zero to Last Measurement (AUC 0-last) of Pertuzumab | Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22 | The area under the plot of plasma concentration of drug against time after drug administration is defined as the area under the curve (AUC). The AUC0-last is calculated from time 0 (prior to administration of medication) to last measured data point. The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUC was measured as ng\*day/mL. |
| AUC From Time Zero to Infinity (AUC 0-infinity) of Pertuzumab | Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22 | The AUC0-infinity is calculated from time 0 (prior to administration of medication) to infinity (the time of complete elimination of the drug). The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUC is measured as nanograms times days per milliliter (ng\*day/mL). |
| Percentage of Participants With DLTs | Cycle 1 (3 Weeks) | DLTs were defined as follows: 1)Any non-hematological toxicity greater than or equal to (≥) Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 except for fever, chills and flu-like symptoms, in spite of adequate toxicity management; 2) Grade 4 neutropenia lasting \> 7 days; 3) Febrile neutropenia; 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion; 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds. Participants who withdrew from the study without completing the first treatment cycle for reasons other than DLT were not considered evaluable for DLT. |
| Apparent Total Clearance of Pertuzumab | Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22 | Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). It is measured as milliliters per day (mL/day). |
| Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose | Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and α-fluoro-β-alanine (FBAL). The biological half-life or terminal half-life is the time in days it takes for it to lose half of its pharmacologic activity. |
| Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose | Capecitabine is an oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety 5-FU in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-DFCR, 5'-DFUR, and FBAL. Cmax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose and is measures as nanograms per milliliter (ng/mL). |
| Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose | Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and α-fluoro-β-alanine (FBAL). Tmax is defined as the time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination. |
| Apparent Volume of Distribution of Pertuzumab | Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22 | The volume of distribution at steady state (Vss), also known as apparent volume of distribution, is a pharmacological, theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. Vss was measured in mL |
Countries
Spain, United Kingdom
Participant flow
Pre-assignment details
Participants were grouped into three cohorts and received either 825 mg, 1000 mg or 1250 mg capecitabine to determine the maximum tolerated dose.
Participants by arm
| Arm | Count |
|---|---|
| Capecitabine + Pertuzumab Participants received a single dose of capecitabine either 825, 1000 or 1250 mg/m\^2 orally on Day -7 and subsequently on Days 1 to 14 of each 3-week cycle administered twice daily. Participants also received pertuzumab on Day 1 of each 3-week cycle as a fixed-dose of 1050-mg IV infusion until progression of the disease, occurrence of unacceptable toxicity or withdrawal of consent. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Insufficient Therapeutic Response | 3 | 3 | 1 |
| Overall Study | Refused Treatment | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Capecitabine + Pertuzumab |
|---|---|
| Age, Continuous | 60.9 years STANDARD_DEVIATION 9.1 |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 7 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 | 5 / 5 | 6 / 6 | 7 / 7 |
| serious Total, serious adverse events | 0 / 5 | 1 / 6 | 1 / 7 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of the Combination of Pertuzumab and Capecitabine
MTD was defined as the highest tolerated dose combination of capecitabine (825 mg, 1000 mg or 1250 mg) and pertuzumab, without causing Dose Limiting Toxicities (DLTs). DLTs were defined as follows: 1) Any non-hematological toxicity greater than or equal to (≥) Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 except for fever, chills and flu-like symptoms, in spite of adequate toxicity management; 2) Grade 4 neutropenia lasting \> 7 days; 3) Febrile neutropenia; 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion; 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds. Participants who withdrew from the study without completing the first treatment cycle for reasons other than DLT were not considered evaluable for DLT. MTD was measured in mg/m\^2.
Time frame: Cycle 1 (3 Weeks)
Population: The Safety Population included all participants who received any amount of study medication and who had at least one post-baseline safety follow-up.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Capecitabine + Pertuzumab | Maximum Tolerated Dose (MTD) of the Combination of Pertuzumab and Capecitabine | 1250 mg/m^2 |
Secondary
Apparent Total Clearance of Pertuzumab
Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). It is measured as milliliters per day (mL/day).
Time frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Capecitabine + Pertuzumab | Apparent Total Clearance of Pertuzumab | 283.0 mL/day | Standard Deviation 98 |
Secondary
Apparent Volume of Distribution of Pertuzumab
The volume of distribution at steady state (Vss), also known as apparent volume of distribution, is a pharmacological, theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. Vss was measured in mL
Time frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Capecitabine + Pertuzumab | Apparent Volume of Distribution of Pertuzumab | 5202 mL | Standard Deviation 1007 |
Secondary
Area Under the Concentration Curve From Time Zero to Last Measurement (AUC 0-last) of Pertuzumab
The area under the plot of plasma concentration of drug against time after drug administration is defined as the area under the curve (AUC). The AUC0-last is calculated from time 0 (prior to administration of medication) to last measured data point. The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUC was measured as ng\*day/mL.
Time frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Capecitabine + Pertuzumab | Area Under the Concentration Curve From Time Zero to Last Measurement (AUC 0-last) of Pertuzumab | 2742561 ng*day/mL | Standard Deviation 743598 |
Secondary
AUC From Time Zero to Infinity (AUC 0-infinity) of Pertuzumab
The AUC0-infinity is calculated from time 0 (prior to administration of medication) to infinity (the time of complete elimination of the drug). The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUC is measured as nanograms times days per milliliter (ng\*day/mL).
Time frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Capecitabine + Pertuzumab | AUC From Time Zero to Infinity (AUC 0-infinity) of Pertuzumab | 4096501 ng*day/mL | Standard Deviation 1282130 |
Secondary
Maximum Plasma Concentration (Cmax) of Pertuzumab
Cmax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose and was measured as nanograms per milliliter (ng/mL).
Time frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Capecitabine + Pertuzumab | Maximum Plasma Concentration (Cmax) of Pertuzumab | 355111 ng/mL | Standard Deviation 59051 |
Secondary
Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab
Capecitabine is an oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety 5-FU in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-DFCR, 5'-DFUR, and FBAL. Cmax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose and is measures as nanograms per milliliter (ng/mL).
Time frame: Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Capecitabine + Pertuzumab | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab Capecitabine | 8060 ng/mL | Standard Deviation 4800 |
| Capecitabine + Pertuzumab | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab FBAL | 3674 ng/mL | Standard Deviation 1121 |
| Capecitabine + Pertuzumab | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFCR | 4508 ng/mL | Standard Deviation 2317 |
| Capecitabine + Pertuzumab | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFUR | 5274 ng/mL | Standard Deviation 1832 |
| Capecitabine + Pertuzumab | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5-FU | 201 ng/mL | Standard Deviation 94 |
| Capecitabine + Pertuzumab | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone Capecitabine | 4802 ng/mL | Standard Deviation 3159 |
| Capecitabine + Pertuzumab | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone FBAL | 3214 ng/mL | Standard Deviation 396 |
| Capecitabine + Pertuzumab | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFCR | 4909 ng/mL | Standard Deviation 2518 |
| Capecitabine + Pertuzumab | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFUR | 5736 ng/mL | Standard Deviation 1831 |
| Capecitabine + Pertuzumab | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5-FU | 219 ng/mL | Standard Deviation 106 |
| Capecitabine 1000 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFUR | 4103 ng/mL | Standard Deviation 1595 |
| Capecitabine 1000 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab Capecitabine | 3367 ng/mL | Standard Deviation 1741 |
| Capecitabine 1000 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone Capecitabine | 9112 ng/mL | Standard Deviation 6189 |
| Capecitabine 1000 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5-FU | 355 ng/mL | Standard Deviation 119 |
| Capecitabine 1000 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab FBAL | 3498 ng/mL | Standard Deviation 809 |
| Capecitabine 1000 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5-FU | 187 ng/mL | Standard Deviation 92 |
| Capecitabine 1000 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFCR | 3917 ng/mL | Standard Deviation 1411 |
| Capecitabine 1000 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFCR | 7687 ng/mL | Standard Deviation 1443 |
| Capecitabine 1000 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone FBAL | 3963 ng/mL | Standard Deviation 947 |
| Capecitabine 1000 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFUR | 7657 ng/mL | Standard Deviation 2708 |
| Capecitabine 1250 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFCR | 6569 ng/mL | Standard Deviation 2827 |
| Capecitabine 1250 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFUR | 10311 ng/mL | Standard Deviation 3323 |
| Capecitabine 1250 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5-FU | 369 ng/mL | Standard Deviation 107 |
| Capecitabine 1250 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone Capecitabine | 7543 ng/mL | Standard Deviation 2944 |
| Capecitabine 1250 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFUR | 8683 ng/mL | Standard Deviation 4142 |
| Capecitabine 1250 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone FBAL | 5290 ng/mL | Standard Deviation 576 |
| Capecitabine 1250 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab Capecitabine | 4731 ng/mL | Standard Deviation 3198 |
| Capecitabine 1250 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5-FU | 345 ng/mL | Standard Deviation 214 |
| Capecitabine 1250 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab FBAL | 5136 ng/mL | Standard Deviation 843 |
| Capecitabine 1250 + Pertuzumab 1050 | Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFCR | 8647 ng/mL | Standard Deviation 3254 |
Secondary
Percentage of Participants With DLTs
DLTs were defined as follows: 1)Any non-hematological toxicity greater than or equal to (≥) Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 except for fever, chills and flu-like symptoms, in spite of adequate toxicity management; 2) Grade 4 neutropenia lasting \> 7 days; 3) Febrile neutropenia; 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion; 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds. Participants who withdrew from the study without completing the first treatment cycle for reasons other than DLT were not considered evaluable for DLT.
Time frame: Cycle 1 (3 Weeks)
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Capecitabine + Pertuzumab | Percentage of Participants With DLTs | 0.0 percentage of participants |
| Capecitabine 1000 + Pertuzumab 1050 | Percentage of Participants With DLTs | 0.0 percentage of participants |
| Capecitabine 1250 + Pertuzumab 1050 | Percentage of Participants With DLTs | 0.0 percentage of participants |
Secondary
Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab
Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and α-fluoro-β-alanine (FBAL). The biological half-life or terminal half-life is the time in days it takes for it to lose half of its pharmacologic activity.
Time frame: Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Capecitabine + Pertuzumab | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFCR | 0.89 hours | Standard Deviation 0.27 |
| Capecitabine + Pertuzumab | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFUR | 0.75 hours | Standard Deviation 0.26 |
| Capecitabine + Pertuzumab | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5-FU | 0.67 hours | Standard Deviation 0.22 |
| Capecitabine + Pertuzumab | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone Capecitabine | 0.54 hours | Standard Deviation 0.19 |
| Capecitabine + Pertuzumab | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone FBAL | 2.54 hours | Standard Deviation 0.3 |
| Capecitabine + Pertuzumab | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFCR | 0.78 hours | Standard Deviation 0.38 |
| Capecitabine + Pertuzumab | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFUR | 0.62 hours | Standard Deviation 0.13 |
| Capecitabine + Pertuzumab | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5-FU | 0.73 hours | Standard Deviation 0.4 |
| Capecitabine + Pertuzumab | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab Capecitabine | 0.42 hours | Standard Deviation 0.14 |
| Capecitabine + Pertuzumab | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab FBAL | 2.59 hours | Standard Deviation 0.64 |
| Capecitabine 1000 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab Capecitabine | 0.62 hours | Standard Deviation 0.28 |
| Capecitabine 1000 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFCR | 0.82 hours | Standard Deviation 0.28 |
| Capecitabine 1000 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFCR | 0.76 hours | Standard Deviation 0.18 |
| Capecitabine 1000 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone FBAL | 2.69 hours | Standard Deviation 0.39 |
| Capecitabine 1000 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFUR | 0.76 hours | Standard Deviation 0.23 |
| Capecitabine 1000 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab FBAL | 2.58 hours | Standard Deviation 0.57 |
| Capecitabine 1000 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5-FU | 0.67 hours | Standard Deviation 0.14 |
| Capecitabine 1000 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5-FU | 0.64 hours | Standard Deviation 0.13 |
| Capecitabine 1000 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFUR | 0.73 hours | Standard Deviation 0.21 |
| Capecitabine 1000 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone Capecitabine | 0.40 hours | Standard Deviation 0.1 |
| Capecitabine 1250 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5-FU | 0.80 hours | Standard Deviation 0.35 |
| Capecitabine 1250 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone Capecitabine | 0.36 hours | Standard Deviation 0.11 |
| Capecitabine 1250 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone FBAL | 3.08 hours | Standard Deviation 0.78 |
| Capecitabine 1250 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFCR | 0.75 hours | Standard Deviation 0.14 |
| Capecitabine 1250 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab Capecitabine | 0.54 hours | Standard Deviation 0.28 |
| Capecitabine 1250 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFUR | 0.79 hours | Standard Deviation 0.28 |
| Capecitabine 1250 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFCR | 0.82 hours | Standard Deviation 0.23 |
| Capecitabine 1250 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab FBAL | 2.81 hours | Standard Deviation 0.44 |
| Capecitabine 1250 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFUR | 0.66 hours | Standard Deviation 0.09 |
| Capecitabine 1250 + Pertuzumab 1050 | Plasma Half-Life of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5-FU | 0.70 hours | Standard Deviation 0.16 |
Secondary
Plasma Half-Life (t1/2) of Pertuzumab
The biological half-life or terminal half-life of pertuzumab is the time in days it takes for it to lose half of its pharmacologic activity. t1/2 was measured in days.
Time frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and Predose on Days 8, 15 and 22
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Capecitabine + Pertuzumab | Plasma Half-Life (t1/2) of Pertuzumab | 14.6 days | Standard Deviation 41 |
Secondary
Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab
Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps through the intermediate metabolites 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and α-fluoro-β-alanine (FBAL). Tmax is defined as the time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination.
Time frame: Day -7: Predose, 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours postdose; Cycle 1 Day 1: Predose, 0 and 30 minutes, 1, 2, 3, 4, 5, 6 and 10 hours Postdose
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFCR | 1.3 hours | Standard Deviation 0.66 |
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFUR | 1.3 hours | Standard Deviation 0.66 |
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5-FU | 1.3 hours | Standard Deviation 0.66 |
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone Capecitabine | 1.2 hours | Standard Deviation 0.75 |
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone FBAL | 2.4 hours | Standard Deviation 0.55 |
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFCR | 0.9 hours | Standard Deviation 0.65 |
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFUR | 1.0 hours | Standard Deviation 0.61 |
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5-FU | 0.9 hours | Standard Deviation 0.65 |
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab Capecitabine | 0.7 hours | Standard Deviation 0.28 |
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab FBAL | 2.6 hours | Standard Deviation 0.9 |
| Capecitabine 1000 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab Capecitabine | 1.17 hours | Standard Deviation 0.4 |
| Capecitabine 1000 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFCR | 0.82 hours | Standard Deviation 0.26 |
| Capecitabine 1000 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFCR | 1.42 hours | Standard Deviation 0.66 |
| Capecitabine 1000 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone FBAL | 2.69 hours | Standard Deviation 0.41 |
| Capecitabine 1000 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFUR | 0.76 hours | Standard Deviation 0.49 |
| Capecitabine 1000 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab FBAL | 3.16 hours | Standard Deviation 1.17 |
| Capecitabine 1000 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5-FU | 1.84 hours | Standard Deviation 1.17 |
| Capecitabine 1000 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5-FU | 0.64 hours | Standard Deviation 0.49 |
| Capecitabine 1000 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFUR | 2.0 hours | Standard Deviation 1.1 |
| Capecitabine 1000 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone Capecitabine | 0.4 hours | Standard Deviation 0.28 |
| Capecitabine 1250 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5-FU | 1.93 hours | Standard Deviation 1.24 |
| Capecitabine 1250 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone Capecitabine | 0.77 hours | Standard Deviation 0.35 |
| Capecitabine 1250 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone FBAL | 2.21 hours | Standard Deviation 0.4 |
| Capecitabine 1250 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFCR | 1.86 hours | Standard Deviation 1.32 |
| Capecitabine 1250 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab Capecitabine | 1.15 hours | Standard Deviation 0.62 |
| Capecitabine 1250 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab 5'-DFUR | 1.86 hours | Standard Deviation 1.32 |
| Capecitabine 1250 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFCR | 1.05 hours | Standard Deviation 0.51 |
| Capecitabine 1250 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine + Pertuzumab FBAL | 2.50 hours | Standard Deviation 1.39 |
| Capecitabine 1250 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5'-DFUR | 1.05 hours | Standard Deviation 0.51 |
| Capecitabine 1250 + Pertuzumab 1050 | Time to Maximum Plasma Concentration of Capecitabine and it's Metabolites When Given Alone and in Combination With Pertuzumab | Capecitabine Alone 5-FU | 1.05 hours | Standard Deviation 0.51 |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Pertuzumab
Tmax is defined as the time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination. Tmax was measured in days.
Time frame: Cycle 1: Days 2, 5, 8 and 15 Postdose; Cycle 2: Day 1 at drug administration, predose and 15 minutes postdose, and predose on Days 8, 15 and 22
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Capecitabine + Pertuzumab | Time to Maximum Plasma Concentration (Tmax) of Pertuzumab | 0.137 days | Standard Deviation 0.076 |