A Dose Finding Study of XRP6258 in Patients With Advanced Solid Tumors

A Phase I Dose Finding Study of XRP6258 Administered as a Weekly 1-hour Intravenous Infusion to Patients With Advanced Solid Tumors

Primary Objective:

- To determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of XRP6258 when given as a weekly 1-hour intravenous (i.v.) infusion for the first 4 consecutive weeks of each 5-week treatment cycle (Day 1, Day 8, Day 15, Day 22 of each 5-week treatment cycle).

Secondary Objectives :

• To define the safety profile of the drug
• To establish the recommended dose and time interval for future Phase II trials
• To determine the pharmacokinetic (PK) profile of XRP6258 in man
• To assess the absolute oral bioavailability of XRP6258 at the i.v. recommended dose (following Protocol Amendment No. 2)
• To look for evidence of antitumor activity

The duration of the study will include the following periods:

• Pretreatment: 28 to 7 days before first infusion
• Treatment: Weekly for the first four consecutive weeks during 5-week treatment cycle
• Post-treatment: 3 - 4 weeks after last infusion.

Treatment may be continued until disease progression or unacceptable toxicity or patient refusal.

Inclusion criteria:

1. Signed informed consent prior to beginning protocol specific procedures
2. Histologically proven cancer at the first diagnosis. At study entry, it was desirable but not required to have histological or cytological proof of metastasis in the case of a 1 single metastatic target lesion.
3. Advanced neoplastic disease that was refractory to conventional treatment or for which no standard therapy existed
4. Progressive disease
5. Age 18-70 years
6. ECOG (Eastern Cooperative Oncology Group) performance status of 0 to 2
7. Off previous anticancer (radio- or chemo-) therapy for at least 4 weeks and 6 weeks if prior nitrosoureas, mitomycin C; recovery from the toxic effects of prior treatment (Grade ≤1, except alopecia any grade)
8. Off previous immunotherapy for at least 1 week provided that patients did not have any residual signs of any toxicity
9. Adequate organ function including: neutrophils ≥2.0 × 109/L; platelets ≥100 × 109/L, creatinine <120 μmol/L (if borderline creatinine values, the creatinine clearance had to be ≥60 mL/min); total bilirubin within normal limit; alanine aminotransferase (ALT)/aspartate aminotransferase (AST)/alkaline phosphatase (ALP) ≤2.5-fold the upper normal limits of the institutional norms (ALP ≤2.5 UNL)
10. Patients registered in this trial had to be treated and followed at the participating centers
11. Patients who had received previous treatment with paclitaxel or docetaxel could be included provided that they did not have any residual signs of taxane toxicity (except alopecia any grade and peripheral neuropathy Grade 1)

Exclusion Criteria:

1. Hematological malignancies

2. Pregnant or lactating women or women of childbearing potential (eg, not using adequate contraception)

3. Symptomatic brain metastases

4. Previous extensive radiotherapy (>20% of bone marrow area)

5. Current peripheral neuropathy of any origin including significant residual symptoms due to the use of eg, vinca-alkaloids or platinum ≥Grade 2 according to the National Cancer Institute common terminology criteria for adverse events.

6. Other serious illness or medical conditions:

   • Congestive heart failure or angina pectoris even if medically controlled, previous history of myocardial infarction within 1 year from study entry, uncontrolled hypertension or arrhythmias
   • Existence of significant neurological or psychiatric disorders including dementia or seizures
   • Active infection
   • Uncontrolled peptic ulcer, unstable diabetes mellitus, or other contraindications for the use of corticosteroids

7. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to patient registration

8. Concurrent treatment with any other anticancer therapy

9. Concomitant radiotherapy

10. Concomitant treatment with corticosteroids. However, patients receiving chronic treatment with corticosteroids (≤20 mg of methylprednisolone or ≤4 mg of dexamethasone or equivalent dose of other corticosteroids), for whatever reason, were eligible.

11. More than 2 prior chemotherapy regimens containing mitomycin C or nitrosoureas

12. More than 2 prior chemotherapy regimens for advanced disease

13. Prior history of severe allergic reaction to docetaxel or paclitaxel

14. Prior intensive chemotherapy with autologous stem cell rescue

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