Dose-Escalation, Safety, Pharmacokinetics Study of Cabazitaxel With Gemcitabine In Patients With Solid Tumor

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Dose-Escalation, Single Arm, Combination Study of Cabazitaxel With Gemcitabine to Determine The Safety, And Pharmacokinetics In Subjects With Advanced Solid Malignancies

Conditions
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Neoplasms, Malignant

Intervention / Treatment
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* Drug: cabazitaxel
* Drug: gemcitabine


Participation Criteria
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Eligibility Criteria
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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/exclusion criteria Other severe acute or chronic medical or psychiatric condition, or significant laboratory abnormality requiring further investigation that may cause undue risk for the patient's safety, inhibit protocol participation, or interfere with interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study Symptomatic brain metastases or leptomeningeal disease. Patients with asymptomatic or stable brain metastases are allowed Women of childbearing potential not protected by highly effective contraceptive method of birth control. All patients of childbearing potential that do not have a negative pregnancy test within the 7 days prior to registration Patients who are pregnant or breastfeeding For part 2, absence of measurable disease as defined by the most current version of the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. For the Part 1 component, patients with non-measurable disease are accepted Inadequate bone marrow or liver or renal organ function Any condition which is considered a contraindication to gemcitabine in the local labelling Prior treatment with cabazitaxel within the last 2 years History of severe hypersensitivity grade 3 or 4 to taxanes, Polysorbate-80, or to compounds with similar chemical structures The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cabazitaxel + gemcitabine<br>Cabazitaxel and gemcitabine on Day 1 then gemcitabine alone on Day 8 every 3 weeks until disease progression or unacceptable toxicities, withdrawal of consent or Investigator's decision. On Day 1, cabazitaxel was given either first followed by gemcitabine (part 1a) or after gemcitabine with 1 hour gap between the two infusions (part 1b). Required premedication with antihistamine, corticosteroid and H2 antagonist was administered intravenously 30 minutes before each dose of cabazitaxel. | Drug: cabazitaxel<br>* 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<br>* Other names: Jevtana;Drug: gemcitabine<br>* 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.<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Day 1 to Day 21 of the first treatment cycle | 
| 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. | Fron Day 1 up to a maximum of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Fron Day 1 up to a maximum of 12 months | 
| 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. | Fron Day 1 up to a maximum of 12 months | 
| 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. | from first dose of study medication up to 30 days after the last dose of study medication (maximum follow-up of 68 weeks) | 
| 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. | 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: 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) | Area under the plasma concentration versus time curve calculated using the trapezoidal method from time 0 to the last measurable concentration at time t. | 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 (AUC) | Area under the plasma concentration versus time curve extrapolated to infinity | 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: 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) | 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. | 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: 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) | 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. | 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: 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) | 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. | 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: 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) | 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. | 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: 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 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 | 
| 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 | Ratio Day 1/Day 8 for AUClast and AUC were calculated to assess the effect of cabazitaxel on gemcitabine exposure. | 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) |