Neoplasms, Malignant
Conditions
Brief summary
Primary Objectives: * Study part 1: To determine the Maximum Tolerated Dose (MTD) and the Dose Limiting Toxicities (DLTs) of cabazitaxel administered as a 1-hour infusion in combination with gemcitabine, every 3 weeks in patients with advanced solid malignancies. * Study part 2: To determine the antitumor activity of cabazitaxel in combination with gemcitabine, in an additional extended cohort of 15 patients with advanced solid malignancies treated with the defined MTD, as assessed by objective response rate (ORR) according to the revised guideline for Response Evaluation Criteria in Solid Tumours (RECIST 1.1 criteria). Secondary Objectives: * To assess the safety profile of the combination regimen of cabazitaxel with gemcitabine. * To assess the pharmacokinetics (PK) of cabazitaxel, gemcitabine and its metabolite 2',2' difluorodeoxyuridine (dFdU) when given in combination. * To determine Time to Progression (TTP), Objective Response Rate (ORR), and Duration of Response (DR), in the extended cohort of patients treated at the MTD in Part 2 of the study and the patients who received the MTD in Part 1 component. For study part 1, dose levels were to be escalated according to predefined dose escalation decision rules. The Maximum Administered Dose (MAD) was reached at the dose level when at least 2 patients developed a DLT during the first 3 weeks of treatment. There was no further dose escalation when this dose was achieved. The MTD was defined as the highest dose at which 0 or 1 of 3 to 6 patients, respectively, experienced DLT during the first 3 weeks of treatment.
Detailed description
The study consisted of a screening phase (maximum length of 21-day), a treatment phase with 21-day treatment cycles and a 30-day follow-up visit after the last dose of study medication. The cut-off date for study part 1 was when last participant completed the first treatment cycle and the subsequent 30 days follow-up. The cut off date for study part 2 was when all participants experienced disease progression, unacceptable toxicity, consent withdrawal or the last participant had completed 26 weeks or 6 cycles on study treatment, whichever came first. Participants could continue to be treated on study as long as they were benefiting from study treatment and had not met study withdrawal criteria. After withdrawal from study treatment, further treatment, if any, was at the discretion of the Investigator.
Interventions
DRUGcabazitaxel
Pharmaceutical form: 60 mg/1.5 ml concentrate solution for infusion Route of administration: Intravenous infusion over 60 minutes Dosage: * Study part 1: 15, 20 or 25 mg/m\^2 according to pre-defined dose escalation schedule * Study part 2: MTD as determined in Study part 1
DRUGgemcitabine
Pharmaceutical form: According to United States Package Insert (USPI) Route of administration: Intravenous infusion over 30 minutes Dosage: * Study part 1: 700, 900 or 1000 mg/m\^2 according to pre-defined dose escalation schedule * Study part 2: MTD as determined in Study part 1.
Sponsors
Sanofi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed advanced solid malignancy that is metastatic or unresectable, and for which standard curative measures do not exist.
Exclusion criteria
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) \> or =2 * Anticipation of need for a major surgical procedure or radiation therapy during the study treatment * Absence of completion of all prior chemotherapy, biological therapy, targeted non-cytotoxic therapy \> or = 3 weeks; and radiotherapy \> or = 4 weeks prior to registration. For part 2 only, prior treatment with radiotherapy, chemoembolization therapy, or cryotherapy is allowed if these therapies are not directed to the areas of measurable disease being used for the purposes of this protocol. (4 weeks of washout period is required prior to start the treatment in Part 2) * Concurrent treatment in another clinical trial or with any other cancer therapy or patients planning to receive these treatments during the study * Other concurrent serious illness or medical condition, including active infection or human immunodeficiency virus (HIV) disease * History of any other malignancy with the exception of adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri * Patients without resolution of all clinically significant toxic effects (excluding alopecia) of any prior therapy to grade \< or = 1 by National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3.0 or to within the limits listed in the specific inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Dose Limiting Toxicities During Dose Escalation | Day 1 to Day 21 of the first treatment cycle | Dose Limiting Toxicities (DLTs) were defined as clinical adverse events (AE) or laboratory abnormalities considered drug-related as assessed by the Investigator or Sponsor, and achieving a Common Terminology Criteria for Adverse Events v3.0 (CTCAE) severity rating of severe (3) or life-threatening (4). |
| Objective Response Rate With MTD | Fron Day 1 up to a maximum of 12 months | Objective response was defined as a confirmed complete response (CR) or a confirmed partial response (PR) during the treatment period, based on RECIST 1.1, as assessed by the Investigator. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion. The objective response rate (ORR) was to be calculated as the proportion of participants with confirmed objective response relative to the total number of participants in the analysis population. Due to the inability to determine MTD during the study part 1, the analysis was not performed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Adverse Events | from first dose of study medication up to 30 days after the last dose of study medication (maximum follow-up of 68 weeks) | Summary of participants with adverse events (AEs) according to severity and relationship to study drug as assessed by the investigator. The National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE), version 3.0 was used to grade the severity of AE. Treatment-emergent adverse events (TEAEs) are AEs that occurred or worsened from start of treatment up to 30 days after treatment ceased. NCI CTCAE v.3.0 grade 3 =severe and grade 4= life-threatening or disabling. |
| Pharmacokinetic of Cabazitaxel on Cycle 1: Maximum Plasma Concentration Observed (Cmax) | before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion | Blood samples for cabazitaxel assay were collected during cycle 1 and cabazitaxel plasma concentrations were determined using a validated liquid chromatography with tandem mass spectometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1 ng/mL. Pharmacokinetic (PK) parameters were calculated from plasma concentrations using non-compartmental analysis. |
| Pharmacokinetic of Cabazitaxel on Cycle 1: Time to Maximum Concentration (Tmax) | before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion | — |
| Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion | Area under the plasma concentration versus time curve calculated using the trapezoidal method from time 0 to the last measurable concentration at time t. |
| Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve (AUC) | before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion | Area under the plasma concentration versus time curve extrapolated to infinity |
| Pharmacokinetic of Cabazitaxel on Cycle 1: Terminal Half-life (t1/2z) | before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion | — |
| Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance (CL) | before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion | — |
| Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State (Vss) | before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion | — |
| Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion | — |
| Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | Blood samples for gemcitabine assay were collected on Day 1 of cycle 1 at the following timepoints: * Cabazitaxel + Gemcitabine: prior the start of cabazitaxel infusion, immediately before the end of gemcitabine infusion, 15, 30 minutes, 1.5, 3.5 and 22.5 hours after the end of gemcitabine infusion; * Gemcitabine + cabazitaxel: prior the start of gemcitabine infusion, immediately before the end of gemcitabine infusion, 15, 30 minutes, 1, 1.5, 2.5, 9 and 23.5 hours after the end of cabazitaxel infusion; Gemcitabine plasma concentrations were determined using validated LC-MS/MS methods with a LLOQ of 50 ng/mL. PK parameters were calculated from plasma concentrations using non-compartmental analysis. |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Terminal Half-life (t1/2z) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance (CL) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State (Vss) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Maximum Plasma Concentration Observed (Cmax) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | Blood samples for gemcitabine assay were collected on Day 8 of cycle 1 at the following timepoints: * Cabazitaxel + Gemcitabine: prior the start of infusion, immediately before the end of infusion, 15, 30 minutes, 1.5, 3.5 and 22.5 hours after the end of infusion; * Gemcitabine + cabazitaxel: prior the start of infusion, immediately before the end of infusion, 15, 30 minutes, 1, 1.5, 2.5, 9 and 23.5 hours after the end of infusion; Gemcitabine plasma concentrations were determined using validated LC-MS/MS methods with a LLOQ of 50 ng/mL. PK parameters were calculated from plasma concentrations using non-compartmental analysis. |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Time to Maximum Concentration (Tmax) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Terminal Half-life (t1/2z) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Area Under the Time Concentration Curve (AUC) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Total Plasma Clearance (CL) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Volume of Distribution at Steady State (Vss) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | Blood samples collected for gemcitabine assay were used to assay gemcitabine metabolite, 2',2' difluorodeoxyuridine(dFdU). 2',2' difluorodeoxyuridine plasma concentrations were determined using validated LC-MS/MS methods with a LLOQ of 50 ng/mL. PK parameters were calculated from plasma concentrations using non-compartmental analysis. |
| Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Terminal Half-life (t1/2z) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC) | 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Maximum Plasma Concentration Observed (Cmax) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | Blood samples collected for gemcitabine assay were used to assay gemcitabine metabolite, 2',2' difluorodeoxyuridine(dFdU). 2',2' difluorodeoxyuridine plasma concentrations were determined using validated LC-MS/MS methods with a LLOQ of 50 ng/mL. PK parameters were calculated from plasma concentrations using non-compartmental analysis. |
| Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Time to Maximum Concentration (Tmax) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Time To Progression With MTD | Fron Day 1 up to a maximum of 12 months | Time to progression (TTP) was defined as the time from first treatment administration to first documentation of RECIST-defined objective tumor progression (\>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of \>=1 new lesion and/or unequivocal progression of existing non-target lesions). Median TTP was to be estimated using the Kaplan-Meier method. Due to the inability to determine MTD during the study part 1, the analysis was not performed. |
| Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Terminal Half-life (t1/2z) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Area Under the Time Concentration Curve (AUC) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Pharmacokinetic of Gemcitabine on Cycle 1: Ratio Day 1/Day 8 for AUClast and AUC | Day 1 (7 to 9 timepoints from start of infusion up to 24h hours after the end of infusion) and Day 8 (7 to 9 timepoints from start of infusion up to 24h hours after the end of infusion) | Ratio Day 1/Day 8 for AUClast and AUC were calculated to assess the effect of cabazitaxel on gemcitabine exposure. |
| Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1 | — |
| Duration of Response With MTD | Fron Day 1 up to a maximum of 12 months | Duration of Response (DR) was defined as the time from the first documentation of RECIST-defined objective tumor response to the first documentation of RECIST-defined objective tumor progression or death. Median DR was to be estimated using the Kaplan-Meier method. Due to the inability to determine MTD during the study part 1, the analysis was not performed. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled in 4 sites in the United States. Since it was not possible to determine the maximum Tolerated Dose (MTD) in study part 1, no participant was enrolled in study part 2 and the study was stopped.
Pre-assignment details
At each dose level, there was a 1-week gap between the treatment of the first participant and the next 2 participants to evaluate toxicity. Before escalating to the next dose level, at least 3 participants were to be evaluable for the criteria defining dose limiting toxicity (DLT).
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Cabazitaxel + Gemcitabine Dose Level 0 Cabazitaxel 20 mg/m\^2 IV followed by gemcitabine 1000 mg/m\^2 IV on Day 1 then, gemcitabine 1000 mg/m\^2 IV on Day 8
21-day treatment cycles until disease progression or unacceptable toxicities, withdrawal of consent or Investigator's decision | 5 |
| Part 1: Cabazitaxel + Gemcitabine Dose Level -1 Cabazitaxel 15 mg/m\^2 IV followed by gemcitabine 900 mg/m\^2 IV on Day 1 then, gemcitabine 900 mg/m\^2 IV on Day 8
21-day treatment cycles until disease progression or unacceptable toxicities, withdrawal of consent or Investigator's decision | 5 |
| Part 1: Cabazitaxel + Gemcitabine Dose Level -2 Cabazitaxel 15 mg/m\^2 IV followed by gemcitabine 700 mg/m\^2 IV on Day 1 then, gemcitabine 700 mg/m\^2 IV on Day 8
21-day treatment cycles until disease progression or unacceptable toxicities, withdrawal of consent or Investigator's decision | 3 |
| Part 1: Gemcitabine + Cabazitaxel Dose Level 0 Gemcitabine 700 mg/m\^2 IV followed by cabazitaxel 15 mg/m\^2 IV on Day 1 then, gemcitabine 700 mg/m\^2 IV on Day 8
21-day treatment cycles until disease progression or unacceptable toxicities, withdrawal of consent or Investigator's decision | 6 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 0 | 2 | 0 |
| Overall Study | Disease progression | 3 | 2 | 2 | 4 | 0 |
| Overall Study | Not treated; protocol exclusion | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Other | 1 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1: Cabazitaxel + Gemcitabine Dose Level 0 | Part 1: Cabazitaxel + Gemcitabine Dose Level -1 | Part 1: Cabazitaxel + Gemcitabine Dose Level -2 | Part 1: Gemcitabine + Cabazitaxel Dose Level 0 | Total |
|---|---|---|---|---|---|
| Age Continuous | 60.8 years STANDARD_DEVIATION 6.6 | 59.2 years STANDARD_DEVIATION 9.2 | 53.0 years STANDARD_DEVIATION 14.8 | 56.3 years STANDARD_DEVIATION 16.1 | 57.7 years STANDARD_DEVIATION 11.5 |
| Body Surface Area | 1.87 m^2 STANDARD_DEVIATION 0.32 | 1.82 m^2 STANDARD_DEVIATION 0.21 | 1.98 m^2 STANDARD_DEVIATION 0.42 | 1.84 m^2 STANDARD_DEVIATION 0.12 | 1.87 m^2 STANDARD_DEVIATION 0.24 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 0 participants | 2 participants | 1 participants | 1 participants | 4 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 5 participants | 3 participants | 2 participants | 5 participants | 15 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Histological Type Adenocarcinoma | 2 participants | 4 participants | 0 participants | 2 participants | 8 participants |
| Histological Type Other | 3 participants | 0 participants | 3 participants | 4 participants | 10 participants |
| Histological Type Squamous cell carcinoma | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Number of Organs Involved | 4.0 organs STANDARD_DEVIATION 1.6 | 2.6 organs STANDARD_DEVIATION 0.5 | 3.3 organs STANDARD_DEVIATION 0.6 | 2.0 organs STANDARD_DEVIATION 0.6 | 2.9 organs STANDARD_DEVIATION 1.2 |
| Primary Tumor Site Bladder | 0 participants | 0 participants | 1 participants | 1 participants | 2 participants |
| Primary Tumor Site Colon | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Primary Tumor Site Head/neck | 0 participants | 1 participants | 1 participants | 0 participants | 2 participants |
| Primary Tumor Site Lung | 2 participants | 1 participants | 1 participants | 0 participants | 4 participants |
| Primary Tumor Site Muscle/soft tissue | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Primary Tumor Site Other | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Primary Tumor Site Ovaries | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Primary Tumor Site Pancreas | 1 participants | 1 participants | 0 participants | 1 participants | 3 participants |
| Primary Tumor Site Pelvis | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Primary Tumor Site Prostate | 2 participants | 0 participants | 0 participants | 0 participants | 2 participants |
| Primary Tumor Site Skin | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian/Oriental | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian/White | 4 participants | 4 participants | 2 participants | 6 participants | 16 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 11 Participants |
| Stage at Diagnosis Stage I | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Stage at Diagnosis Stage II | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Stage at Diagnosis Stage III | 0 participants | 3 participants | 0 participants | 1 participants | 4 participants |
| Stage at Diagnosis Stage IV | 5 participants | 0 participants | 0 participants | 2 participants | 7 participants |
| Stage at Diagnosis Unknown | 0 participants | 1 participants | 3 participants | 3 participants | 7 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 5 / 5 | 2 / 2 | 6 / 6 |
| serious Total, serious adverse events | 5 / 5 | 2 / 5 | 2 / 2 | 4 / 6 |
Outcome results
Primary
Objective Response Rate With MTD
Objective response was defined as a confirmed complete response (CR) or a confirmed partial response (PR) during the treatment period, based on RECIST 1.1, as assessed by the Investigator. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion. The objective response rate (ORR) was to be calculated as the proportion of participants with confirmed objective response relative to the total number of participants in the analysis population. Due to the inability to determine MTD during the study part 1, the analysis was not performed.
Time frame: Fron Day 1 up to a maximum of 12 months
Primary
Participants With Dose Limiting Toxicities During Dose Escalation
Dose Limiting Toxicities (DLTs) were defined as clinical adverse events (AE) or laboratory abnormalities considered drug-related as assessed by the Investigator or Sponsor, and achieving a Common Terminology Criteria for Adverse Events v3.0 (CTCAE) severity rating of severe (3) or life-threatening (4).
Time frame: Day 1 to Day 21 of the first treatment cycle
Population: DLT population: All participants who completed assessments for DLT evaluation for Cycle 1 and either:~* received study treatment during Cycle 1 and had DLT or~* did not have DLT and received a full dose of study treatment (no delay/reduction) during Cycle 1 and did not receive hematopoietic growth factors.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Dose Limiting Toxicities During Dose Escalation | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Dose Limiting Toxicities During Dose Escalation | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Dose Limiting Toxicities During Dose Escalation | 2 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Dose Limiting Toxicities During Dose Escalation | 2 participants |
Secondary
Duration of Response With MTD
Duration of Response (DR) was defined as the time from the first documentation of RECIST-defined objective tumor response to the first documentation of RECIST-defined objective tumor progression or death. Median DR was to be estimated using the Kaplan-Meier method. Due to the inability to determine MTD during the study part 1, the analysis was not performed.
Time frame: Fron Day 1 up to a maximum of 12 months
Secondary
Participants With Adverse Events
Summary of participants with adverse events (AEs) according to severity and relationship to study drug as assessed by the investigator. The National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE), version 3.0 was used to grade the severity of AE. Treatment-emergent adverse events (TEAEs) are AEs that occurred or worsened from start of treatment up to 30 days after treatment ceased. NCI CTCAE v.3.0 grade 3 =severe and grade 4= life-threatening or disabling.
Time frame: from first dose of study medication up to 30 days after the last dose of study medication (maximum follow-up of 68 weeks)
Population: all treated (AT) population: All enrolled participants who received at least 1 part of a dose of study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | - Drug-related serious TEAE | 3 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | Grade 3-4 TEAE | 5 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | AE leading to dose delay | 4 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | - Drug-related AE leading to drug withdrawn | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | AE leading to dose reduction | 3 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | - Grade 3-4 drug-related TEAE | 4 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | - Drug-related TEAE | 5 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | Any TEAE | 5 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | AE leading to drug withdrawn | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | Serious TEAE | 5 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | Any AE | 5 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participants With Adverse Events | AE leading to death | 1 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | Any TEAE | 5 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | - Drug-related serious TEAE | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | Any AE | 5 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | - Drug-related AE leading to drug withdrawn | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | AE leading to drug withdrawn | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | - Drug-related TEAE | 5 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | AE leading to dose reduction | 4 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | Grade 3-4 TEAE | 5 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | AE leading to dose delay | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | - Grade 3-4 drug-related TEAE | 5 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | AE leading to death | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participants With Adverse Events | Serious TEAE | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | - Drug-related AE leading to drug withdrawn | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | Any AE | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | Any TEAE | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | - Drug-related TEAE | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | Grade 3-4 TEAE | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | - Grade 3-4 drug-related TEAE | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | Serious TEAE | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | - Drug-related serious TEAE | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | AE leading to drug withdrawn | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | AE leading to death | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | AE leading to dose reduction | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participants With Adverse Events | AE leading to dose delay | 1 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | - Drug-related AE leading to drug withdrawn | 1 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | Serious TEAE | 4 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | - Grade 3-4 drug-related TEAE | 6 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | Any AE | 6 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | Grade 3-4 TEAE | 6 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | - Drug-related TEAE | 6 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | AE leading to dose delay | 4 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | AE leading to dose reduction | 4 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | Any TEAE | 6 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | AE leading to drug withdrawn | 2 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | - Drug-related serious TEAE | 3 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participants With Adverse Events | AE leading to death | 0 participants |
Secondary
Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Two participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC) | 273000 ng*hr/ml | Standard Deviation 58100 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC) | 285000 ng*hr/ml | Standard Deviation 61200 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC) | 191000 ng*hr/ml | Standard Deviation 66900 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC) | 151000 ng*hr/ml | Standard Deviation 37700 |
Secondary
Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 227000 ng*hr/ml | Standard Deviation 27500 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 235000 ng*hr/ml | Standard Deviation 47400 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 167000 ng*hr/ml | Standard Deviation 47500 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 168000 ng*hr/ml | Standard Deviation 57000 |
Secondary
Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax)
Blood samples collected for gemcitabine assay were used to assay gemcitabine metabolite, 2',2' difluorodeoxyuridine(dFdU). 2',2' difluorodeoxyuridine plasma concentrations were determined using validated LC-MS/MS methods with a LLOQ of 50 ng/mL. PK parameters were calculated from plasma concentrations using non-compartmental analysis.
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax) | 32200 ng/ml | Standard Deviation 10000 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax) | 32500 ng/ml | Standard Deviation 10800 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax) | 25500 ng/ml | Standard Deviation 8770 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax) | 21100 ng/ml | Standard Deviation 5980 |
Secondary
Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Terminal Half-life (t1/2z)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Terminal Half-life (t1/2z) | 9.07 hours | Standard Deviation 2.22 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Terminal Half-life (t1/2z) | 9.41 hours | Standard Deviation 0.837 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Terminal Half-life (t1/2z) | 7.96 hours | Standard Deviation 1.87 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Terminal Half-life (t1/2z) | 12.1 hours | Standard Deviation 5.17 |
Secondary
Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax) | 0.73 hours |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax) | 0.77 hours |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax) | 0.65 hours |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax) | 0.77 hours |
Secondary
Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Area Under the Time Concentration Curve (AUC)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Area Under the Time Concentration Curve (AUC) | 240000 ng*hr/ml | Standard Deviation 11300 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Area Under the Time Concentration Curve (AUC) | 340000 ng*hr/ml | Standard Deviation 100000 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Area Under the Time Concentration Curve (AUC) | 168000 ng*hr/ml | Standard Deviation 27600 |
Secondary
Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 216000 ng*hr/ml | Standard Deviation 3700 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 287000 ng*hr/ml | Standard Deviation 77500 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 141000 ng*hr/ml | Standard Deviation 26400 |
Secondary
Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Maximum Plasma Concentration Observed (Cmax)
Blood samples collected for gemcitabine assay were used to assay gemcitabine metabolite, 2',2' difluorodeoxyuridine(dFdU). 2',2' difluorodeoxyuridine plasma concentrations were determined using validated LC-MS/MS methods with a LLOQ of 50 ng/mL. PK parameters were calculated from plasma concentrations using non-compartmental analysis.
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: All enrolled participants who received at least 1 part of a dose of study treatment and had at least 1 post treatment analyzable PK sample and with no prohibited concomitant medications.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Maximum Plasma Concentration Observed (Cmax) | 27400 ng/ml | Standard Deviation 3180 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Maximum Plasma Concentration Observed (Cmax) | 34800 ng/ml | Standard Deviation 8630 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Maximum Plasma Concentration Observed (Cmax) | 18700 ng/ml | Standard Deviation 4740 |
Secondary
Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Terminal Half-life (t1/2z)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Terminal Half-life (t1/2z) | 7.29 hours | Standard Deviation 1.11 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Terminal Half-life (t1/2z) | 8.55 hours | Standard Deviation 0.82 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Terminal Half-life (t1/2z) | 9.10 hours | Standard Deviation 0.484 |
Secondary
Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Time to Maximum Concentration (Tmax)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Time to Maximum Concentration (Tmax) | 0.69 hours |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Time to Maximum Concentration (Tmax) | 0.68 hours |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of 2',2' Difluorodeoxyuridine on Cycle 1 Day 8: Time to Maximum Concentration (Tmax) | 0.72 hours |
Secondary
Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve (AUC)
Area under the plasma concentration versus time curve extrapolated to infinity
Time frame: before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion
Population: PK population as previously defined. Six participants' assays could not be used for AUC.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve (AUC) | 876 ng*hr/ml | Standard Deviation 730 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve (AUC) | 420 ng*hr/ml | Standard Deviation 77.3 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve (AUC) | 462 ng*hr/ml | Standard Deviation 156 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve (AUC) | 306 ng*hr/ml | Standard Deviation 50.1 |
Secondary
Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast)
Area under the plasma concentration versus time curve calculated using the trapezoidal method from time 0 to the last measurable concentration at time t.
Time frame: before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 556 ng*hr/ml | Standard Deviation 500 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 352 ng*hr/ml | Standard Deviation 101 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 344 ng*hr/ml | Standard Deviation 114 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 315 ng*hr/ml | Standard Deviation 208 |
Secondary
Pharmacokinetic of Cabazitaxel on Cycle 1: Maximum Plasma Concentration Observed (Cmax)
Blood samples for cabazitaxel assay were collected during cycle 1 and cabazitaxel plasma concentrations were determined using a validated liquid chromatography with tandem mass spectometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1 ng/mL. Pharmacokinetic (PK) parameters were calculated from plasma concentrations using non-compartmental analysis.
Time frame: before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion
Population: PK population: All enrolled participants who received at least 1 part of a dose of study treatment and had at least 1 post treatment analyzable PK sample, and with no prohibited concomitant medications
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Maximum Plasma Concentration Observed (Cmax) | 123 ng/ml | Standard Deviation 43.7 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Cabazitaxel on Cycle 1: Maximum Plasma Concentration Observed (Cmax) | 150 ng/ml | Standard Deviation 80.9 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Cabazitaxel on Cycle 1: Maximum Plasma Concentration Observed (Cmax) | 273 ng/ml | Standard Deviation 21.9 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Maximum Plasma Concentration Observed (Cmax) | 118 ng/ml | Standard Deviation 43.9 |
Secondary
Pharmacokinetic of Cabazitaxel on Cycle 1: Terminal Half-life (t1/2z)
Time frame: before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Terminal Half-life (t1/2z) | 92.1 hours (hr) | Standard Deviation 40.3 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Cabazitaxel on Cycle 1: Terminal Half-life (t1/2z) | 88.3 hours (hr) | Standard Deviation 35.1 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Cabazitaxel on Cycle 1: Terminal Half-life (t1/2z) | 75.6 hours (hr) | Standard Deviation 27.8 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Terminal Half-life (t1/2z) | 70.3 hours (hr) | Standard Deviation 43.1 |
Secondary
Pharmacokinetic of Cabazitaxel on Cycle 1: Time to Maximum Concentration (Tmax)
Time frame: before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion
Population: PK population as previously defined
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Time to Maximum Concentration (Tmax) | 1.00 hours (hr) |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Cabazitaxel on Cycle 1: Time to Maximum Concentration (Tmax) | 0.94 hours (hr) |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Cabazitaxel on Cycle 1: Time to Maximum Concentration (Tmax) | 0.94 hours (hr) |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Time to Maximum Concentration (Tmax) | 0.93 hours (hr) |
Secondary
Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance (CL)
Time frame: before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion
Population: PK population as previously defined. Six participants' assays could not be used for CL.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance (CL) | 61.0 L/hr | Standard Deviation 38.4 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance (CL) | 64.3 L/hr | Standard Deviation 16.2 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance (CL) | 59.5 L/hr | Standard Deviation 6.38 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance (CL) | 90.8 L/hr | Standard Deviation 7.15 |
Secondary
Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA)
Time frame: before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion
Population: PK population as previously defined. Six participants' assays could not be used for CL/BSA.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 32.4 L/hr/m^2 | Standard Deviation 18.3 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 36.1 L/hr/m^2 | Standard Deviation 6.58 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 31.9 L/hr/m^2 | Standard Deviation 12.6 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 49.6 L/hr/m^2 | Standard Deviation 8.56 |
Secondary
Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA)
Time frame: before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion
Population: PK population as previously defined. One participant's assays could not be used for Vss/BSA.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 3530 L/m^2 | Standard Deviation 1650 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 2690 L/m^2 | Standard Deviation 434 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 1980 L/m^2 | Standard Deviation 8.83 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 3020 L/m^2 | Standard Deviation 1130 |
Secondary
Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State (Vss)
Time frame: before the start of infusion and 5 minutes before the end of infusion, then 5, 15, 30 minutes, 1, 2, 3, 5, 7, 10, 24, 48, 72, 120 and 168 hours after the end of infusion
Population: PK population as previously defined. One participant's assay could not be used for Vss.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State (Vss) | 6780 L | Standard Deviation 3250 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State (Vss) | 4980 L | Standard Deviation 818 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State (Vss) | 3930 L | Standard Deviation 1170 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Cabazitaxel on Cycle 1: Volume of Distribution at Steady State (Vss) | 5570 L | Standard Deviation 2100 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Five participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC) | 6290 ng*hr/ml | Standard Deviation 1440 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC) | 21900 ng*hr/ml | Standard Deviation 10800 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC) | 8530 ng*hr/ml | — |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve (AUC) | 9970 ng*hr/ml | Standard Deviation 5310 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 7320 ng*hr/ml | Standard Deviation 1650 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 16000 ng*hr/ml | Standard Deviation 11100 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 6120 ng*hr/ml | Standard Deviation 3350 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 9920 ng*hr/ml | Standard Deviation 5290 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax)
Blood samples for gemcitabine assay were collected on Day 1 of cycle 1 at the following timepoints: * Cabazitaxel + Gemcitabine: prior the start of cabazitaxel infusion, immediately before the end of gemcitabine infusion, 15, 30 minutes, 1.5, 3.5 and 22.5 hours after the end of gemcitabine infusion; * Gemcitabine + cabazitaxel: prior the start of gemcitabine infusion, immediately before the end of gemcitabine infusion, 15, 30 minutes, 1, 1.5, 2.5, 9 and 23.5 hours after the end of cabazitaxel infusion; Gemcitabine plasma concentrations were determined using validated LC-MS/MS methods with a LLOQ of 50 ng/mL. PK parameters were calculated from plasma concentrations using non-compartmental analysis.
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax) | 14600 ng/ml | Standard Deviation 6050 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax) | 35600 ng/ml | Standard Deviation 27200 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax) | 11400 ng/ml | Standard Deviation 3270 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Maximum Plasma Concentration Observed (Cmax) | 19000 ng/ml | Standard Deviation 9130 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Terminal Half-life (t1/2z)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Five participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Terminal Half-life (t1/2z) | 0.295 hours | Standard Deviation 0.118 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Terminal Half-life (t1/2z) | 0.254 hours | Standard Deviation 0.057 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Terminal Half-life (t1/2z) | 0.202 hours | — |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Terminal Half-life (t1/2z) | 0.256 hours | Standard Deviation 0.0933 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax) | 0.49 hours (hr) |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax) | 0.38 hours (hr) |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax) | 0.60 hours (hr) |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Time to Maximum Concentration (Tmax) | 0.42 hours (hr) |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance (CL)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Five participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance (CL) | 313 L/hr | Standard Deviation 120 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance (CL) | 85.1 L/hr | Standard Deviation 40.6 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance (CL) | 123 L/hr | — |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance (CL) | 174 L/hr | Standard Deviation 106 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Five participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 159 L/hr/m^2 | Standard Deviation 31.3 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 49.8 L/hr/m^2 | Standard Deviation 27 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 78.4 L/hr/m^2 | — |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 96.4 L/hr/m^2 | Standard Deviation 62.8 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Five participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 66.5 L/m^2 | Standard Deviation 31.7 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 17.3 L/m^2 | Standard Deviation 18.9 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 29.9 L/m^2 | — |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 28.7 L/m^2 | Standard Deviation 17.4 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State (Vss)
Time frame: 7 to 9 timepoints from start of Day 1 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Five participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State (Vss) | 135 L | Standard Deviation 86.2 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State (Vss) | 28.9 L | Standard Deviation 30.4 |
| Cabazitaxel + Gemcitabine Dose Level -2 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State (Vss) | 47.0 L | — |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 1: Volume of Distribution at Steady State (Vss) | 51.6 L | Standard Deviation 28.8 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Area Under the Time Concentration Curve (AUC)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Two participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Area Under the Time Concentration Curve (AUC) | 6360 ng*hr/ml | — |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Area Under the Time Concentration Curve (AUC) | 18500 ng*hr/ml | Standard Deviation 12300 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Area Under the Time Concentration Curve (AUC) | 7780 ng*hr/ml | Standard Deviation 6880 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 5530 ng*hr/ml | Standard Deviation 1150 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 15300 ng*hr/ml | Standard Deviation 11900 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Area Under the Time Concentration Curve From Time 0 To the Real Time Tlast (AUClast) | 7710 ng*hr/ml | Standard Deviation 6840 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Maximum Plasma Concentration Observed (Cmax)
Blood samples for gemcitabine assay were collected on Day 8 of cycle 1 at the following timepoints: * Cabazitaxel + Gemcitabine: prior the start of infusion, immediately before the end of infusion, 15, 30 minutes, 1.5, 3.5 and 22.5 hours after the end of infusion; * Gemcitabine + cabazitaxel: prior the start of infusion, immediately before the end of infusion, 15, 30 minutes, 1, 1.5, 2.5, 9 and 23.5 hours after the end of infusion; Gemcitabine plasma concentrations were determined using validated LC-MS/MS methods with a LLOQ of 50 ng/mL. PK parameters were calculated from plasma concentrations using non-compartmental analysis.
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Maximum Plasma Concentration Observed (Cmax) | 10200 ng/ml | Standard Deviation 283 |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Maximum Plasma Concentration Observed (Cmax) | 34500 ng/ml | Standard Deviation 30800 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Maximum Plasma Concentration Observed (Cmax) | 14100 ng/ml | Standard Deviation 12200 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Terminal Half-life (t1/2z)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Two participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Terminal Half-life (t1/2z) | 0.222 hours (hr) | — |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Terminal Half-life (t1/2z) | 0.282 hours (hr) | Standard Deviation 0.0218 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Terminal Half-life (t1/2z) | 0.317 hours (hr) | Standard Deviation 0.113 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Time to Maximum Concentration (Tmax)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Time to Maximum Concentration (Tmax) | 0.52 hours (hr) |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Time to Maximum Concentration (Tmax) | 0.45 hours (hr) |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Time to Maximum Concentration (Tmax) | 0.47 hours (hr) |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Total Plasma Clearance (CL)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Two participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Total Plasma Clearance (CL) | 262 L/hr | — |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Total Plasma Clearance (CL) | 110 L/hr | Standard Deviation 55.8 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Total Plasma Clearance (CL) | 252 L/hr | Standard Deviation 158 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Two participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 157 L/hr/m^2 | — |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 62.8 L/hr/m^2 | Standard Deviation 32.7 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Total Plasma Clearance Normalized to Body Surface Area (CL/BSA) | 143 L/hr/m^2 | Standard Deviation 93.3 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Two participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 62.2 L/m^2 | — |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 20.6 L/m^2 | Standard Deviation 11.6 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Volume of Distribution at Steady State Normalized to Body Surface Area (Vss/BSA) | 52.3 L/m^2 | Standard Deviation 28.6 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Volume of Distribution at Steady State (Vss)
Time frame: 7 to 9 timepoints from start of Day 8 infusion up to 24h hours after the end of infusion depending on the sequence of treatment on Day 1
Population: PK population as previously defined. Two participants' assays could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Volume of Distribution at Steady State (Vss) | 104 L | — |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Volume of Distribution at Steady State (Vss) | 36.2 L | Standard Deviation 19.4 |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1 Day 8: Volume of Distribution at Steady State (Vss) | 93.3 L | Standard Deviation 51.7 |
Secondary
Pharmacokinetic of Gemcitabine on Cycle 1: Ratio Day 1/Day 8 for AUClast and AUC
Ratio Day 1/Day 8 for AUClast and AUC were calculated to assess the effect of cabazitaxel on gemcitabine exposure.
Time frame: Day 1 (7 to 9 timepoints from start of infusion up to 24h hours after the end of infusion) and Day 8 (7 to 9 timepoints from start of infusion up to 24h hours after the end of infusion)
Population: Enrolled participants who received at least 1 part of a dose of study treatment and had valid Day 1 and Day 8 PK samples. Valid PK samples included at least 1 post treatment analyzable PK sample and no prohibited concomitant medications.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1: Ratio Day 1/Day 8 for AUClast and AUC | AUClast | 1.15 ratio |
| Cabazitaxel + Gemcitabine Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1: Ratio Day 1/Day 8 for AUClast and AUC | AUC | 1.15 ratio |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1: Ratio Day 1/Day 8 for AUClast and AUC | AUClast | 1.17 ratio |
| Cabazitaxel + Gemcitabine Dose Level -1 | Pharmacokinetic of Gemcitabine on Cycle 1: Ratio Day 1/Day 8 for AUClast and AUC | AUC | 1.24 ratio |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1: Ratio Day 1/Day 8 for AUClast and AUC | AUClast | 1.11 ratio |
| Gemcitabine + Cabazitaxel Dose Level 0 | Pharmacokinetic of Gemcitabine on Cycle 1: Ratio Day 1/Day 8 for AUClast and AUC | AUC | 1.11 ratio |
Secondary
Time To Progression With MTD
Time to progression (TTP) was defined as the time from first treatment administration to first documentation of RECIST-defined objective tumor progression (\>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of \>=1 new lesion and/or unequivocal progression of existing non-target lesions). Median TTP was to be estimated using the Kaplan-Meier method. Due to the inability to determine MTD during the study part 1, the analysis was not performed.
Time frame: Fron Day 1 up to a maximum of 12 months
Post Hoc
Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1
Participant Best response was assessed by investigator using the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1: * Complete response (CR): Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to \<10 mm: * Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion; * Progressive disease (PD): \>=20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of \>=1 new lesion and/or unequivocal progression of existing non-target lesions; * Stable disease (SD): not a CR, PR or PD.
Time frame: Up to a maximum of 22 cycles (median 4 cycles)
Population: all treated (AT) population: All enrolled participants who received at least 1 part of a dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cabazitaxel + Gemcitabine Dose Level 0 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Progressive disease | 1 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Partial response | 1 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Not evaluable | 1 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Stable disease | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level 0 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Complete response | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Stable disease | 3 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Progressive disease | 1 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Not evaluable | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Partial response | 1 participants |
| Cabazitaxel + Gemcitabine Dose Level -1 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Complete response | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Stable disease | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Complete response | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Partial response | 0 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Progressive disease | 2 participants |
| Cabazitaxel + Gemcitabine Dose Level -2 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Not evaluable | 0 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Progressive disease | 2 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Partial response | 1 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Complete response | 0 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Stable disease | 3 participants |
| Gemcitabine + Cabazitaxel Dose Level 0 | Participant Best Response as Per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Not evaluable | 0 participants |