Safety and Pharmacokinetic Study of Cabazitaxel in Patients With Advanced Solid Tumors and Liver Impairment

Study Overview
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Brief Summary
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Primary Objectives: To determine the maximum tolerated dose (MTD) and safety of Cabazitaxel when administered to advanced solid tumor patients with varying degrees of hepatic impairment To determine the pharmacokinetics (PKs) of Cabazitaxel in patients with varying degrees of hepatic impairment To correlate PK variables with pharmacodynamic (PD) safety parameters in order to guide prescribers with regard to dosing in this patient population To assess the effect of cabazitaxel at recommended dose of 25mg/m^2 on CYP3A enzyme activity using midazolam as probe in an additional cohort of cancer patients with normal hepatic function.

Detailed Description
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The study consists of: a screening phase (maximum length of 21-day). a treatment phase with 21-day study treatment cycles. Cycle lengths may be extended up to maximum of 12 additional days in case of unresolved toxicity. Patients continue to receive treatment until they experience, unacceptable toxicities/AEs, disease progression ,withdraw their consent, or the investigator decides to discontinue the patient, or study cut-off, whichever comes first. a 30-day follow-up visit after the last dose of study medication. The cut off date is when the last patient treated has completed cycle 1 and the subsequent 30 days follow-up. Patients may continue to be treated as long as they are benefiting from study treatment and have not met study withdrawal criteria.

Official Title
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Phase I Safety and Pharmacokinetic Study of XRP6258 (Cabazitaxel) In Advanced Solid Tumor Patients With Varying Degrees of Hepatic Impairment

Conditions
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Neoplasm Malignant

Intervention / Treatment
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* Drug: Cabazitaxel (XRP6258)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with a diagnosis of advanced, measurable or non-measurable, non-hematological cancer who have varying degrees of hepatic impairment. The cancer must be one that is either refractory to standard therapy or for which no standard therapy exists. Exclusion criteria: Eastern Cooperative Oncology Group (ECOG) performance status (PS) >2 Life expectancy <3 months Need for a major surgical procedure or radiation therapy during the study Evidence of another active malignancy Prior chemotherapy, other investigational drug, biological therapy, targeted non-cytotoxic therapy and radiotherapy within 3 weeks prior to registration Patients with known history of Gilbert's syndrome Prior treatment with Cabazitaxel and a history of severe (Grade ≥3) hypersensitivity to taxanes, polysorbate-80, or to compounds with similar chemical structures Prior history of bone marrow transplant Any treatment known to induce CYP isoenzymes or to inhibit CYP3A4 activities within 2 weeks before or during the test period of the pharmacokinetic sampling. Moderate inhibitors within one week prior and during the pharmacokinetic sampling. Any contra-indications to midazolam, according to the applicable labeling. 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
Maximum Age: 60 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: normal hepatic function: cabazitaxel<br>cabazitaxel 25mg/m^2 IV infusion of Cabazitaxel is given over 1 hour on Day 1 of each cycle (every 3 weeks). | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form:solution for infusion Route of administration: intravenous<br>|
| Experimental: Cohort 2: mild hepatic impairment : cabazitaxel<br>cabazitaxel 20mg/m^2 IV infusion of Cabazitaxel is given over 1 hour on Day 1 of each cycle (every 3 weeks). | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form:solution for infusion Route of administration: intravenous<br>|
| Experimental: Cohort 3: moderate hepatic impairment: cabazitaxel<br>cabazitaxel 10mg/m^2 IV infusion of Cabazitaxel is given over 1 hour on Day 1 of each cycle (every 3 weeks). | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form:solution for infusion Route of administration: intravenous<br>|
| Experimental: Cohort 4: severe hepatic impairment: cabazitaxel<br>cabazitaxel 5 mg/m^2 or 10mg/m^2 IV infusion of Cabazitaxel is given over 1 hour on Day 1 of each cycle (every 3 weeks). | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form:solution for infusion Route of administration: intravenous<br>|
| Experimental: Cohort 5: normal hepatic function: cabazitaxel and midazolam<br>cabazitaxel 25mg/m^2 IV infusion of Cabazitaxel is given over 1 hour on Day 1 of each cycle (every 3 weeks). Midazolam is given orally in single dosing on day -1 and day 1 (crossover) | Drug: Cabazitaxel (XRP6258)<br>* Pharmaceutical form:solution for infusion Route of administration: intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLT) | A clinical adverse event or a laboratory abnormality is defined as DLT when it is drug-related as assessed by the investigator and agreed upon by the study committee. | cycle 1 (3 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety investigations (physical examination, vital signs and laboratory tests) | Physical examination includes Eastern Cooperative Oncology Group (ECOG) performance status and signs and symptoms. Vital signs includes weight, temperature, blood pressure and heart rate. Laboratory tests includes hematology, coagulation, biochemistry and urinalysis. Laboratory abnormalities are graded according to the NCI CTCAE v.4.0 | up to 30 days after the last dosing | 
| Pharmacokinetic profile of Cabazitaxel (AUC, Cmax, t1/2, CL, and Vss) from plasma concentration |  | cycle 1 (3 weeks) | 
| Cabazitaxel effect on CYP3A enzyme activity |  | single dosing on day -1 and day 1 |