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

• Part 1: DLTs of the combination of cabazitaxel and gemcitabine [ Time Frame: 3 weeks (cycle 1) ] [ Designated as safety issue: Yes ]
• Part 2: Anti-tumor activity based on RECIST1.1 criteria [ Time Frame: up to a maximum of 12 months ] [ Designated as safety issue: No ]

• Time To Progression (TTP) [ Time Frame: up to a maximum of 12 months ] [ Designated as safety issue: No ]
• Overall Response Rate (ORR) [ Time Frame: up to a maximum of 12 months ] [ Designated as safety issue: No ]
• Duration of Response (DR) [ Time Frame: up to a maximum of 12 months ] [ Designated as safety issue: No ]
• Safety profile of the combination in terms of AEs/SAEs and laboratory parameters [ Time Frame: on-treatment period + 30 days ] [ Designated as safety issue: Yes ]
• PK of cabazitaxel, gemcitabine and its metabolite (2,2 difluoridine) and, of midazolam. [ Time Frame: 3 weeks (cycle 1) ] [ Designated as safety issue: Yes ]

Primary Objectives:

• 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.
• 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, and 2,2 difluoridine 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.
• To assess the potential inhibitory effect of cabazitaxel on CYP3A4 using midazolam, a CYP3A4 probe since cabazitaxel inhibits CYP3A4 in vitro.

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 2 additional weeks in case of unresolved toxicity. Patients will be treated until disease progression or unacceptable toxicities, withdrawal of consent or Investigator's decision.There will be a 30-day follow-up visit after the last dose of study medication. Patients who discontinue study treatment prior to disease progression will continue to have tumor assessments every 6 weeks until disease progression or start of an other anticancer therapy.

The cut off date for the study is defined as follows: all patients will be followed up until disease progression, unacceptable toxicity, consent withdrawal or when the last patient had completed 26 weeks or 6 cycles on study treatment, whichever comes first. Patients may continue to be treated on study as long as they are benefiting from study treatment and have not met study withdrawal criteria. After withdrawal from study treatment, further treatment, if any, is at the discretion of the Investigator.

• Drug: cabazitaxel (XRP6258)

  Pharmaceutical form: solution

  Route of administration: Intravenous

• Drug: gemcitabine

  Pharmaceutical form: solution

  Route of administration: Intravenous

• Drug: midazolam

  Pharmaceutical form: solution

  Route of administration: oral

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:

• 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 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 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 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
• Any treatment known to potentially interact with midazolam

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.