Dose Escalating Study of the Safety and Efficacy of Patupilone, q3w, in Patients With Non-small Cell Lung Cancer

Inclusion criteria

• Patients with histologic or cytologic confirmation of unresectable locally advanced or metastatic NSCLC (stage IIIB with pleural effusion only / stage IV) documented before first line therapy.
• Prior treatment with a platinum-containing regimen
• Age ≥18 years.
• Performance status of 0-1 on the WHO scale.
• Life expectancy of ≥3 months.
• NSCLC patients should have at least one measurable lesion as defined by modified RECIST criteria. If the patient has had previous radiation to the marker lesion(s), the lesion must have demonstrated progression since the radiation.
• NSCLC patients with controlled brain metastases are eligible to be enrolled in the brain metastases cohort at the MTD. "Controlled brain metastases" patients are defined as patients who are neurologically stable, i.e. have not experienced an increase in dose of steroidal or anticonvulsive therapy for at least 14 days prior to study entry.
• Patients with brain metastases must be verified to have metastases secondary to NSCLC based on histology of primary and by temporal sequence of events (note: these patients are eligible even if lung disease is quiescent).
• Patients with brain metastases must show evidence of residual disease or progression of disease since prior radiological or surgical therapy.
• Patients with brain metastases should have at least one bidimensionally measurable intracranial lesion of minimum diameter 2 cm. Multifocal disease is permitted, but the eligibility of BM patients presenting with more than 6 intracranial lesions should be discussed with Novartis prior to enrolling the patient.
• Patients with adequate hematologic parameters:
• ANC ≥1.5 x 10^9/L;
• Hb ≥9.0 g/dL,
• Platelet count ≥100 x 10^9/L (untransfused).
• Demonstrate the following blood chemistry laboratory values:
• total bilirubin ≤ 1.5 x ULN;
• AST/ALT ≤ 2.5 X ULN; (≤ 5 x ULN if hepatic metastasis is present)
• alkaline phosphatase ≤ 2.5 x ULN; (≤ 5 x ULN if hepatic and/or bone metastasis are present)
• serum creatinine < 2 x ULN.
• Female patients must have a negative serum pregnancy test at screening. (Not applicable to patients with bilateral oophorectomy and/or hysterectomy or to those patients who are postmenopausal).
• All patients of reproductive potential must agree to use an effective method of contraception during the study and three months following termination of treatment.
• All patients must use a barrier method for contraception for sexual intercourse or avoid this for the first 5 days after patupilone infusion.
• Written informed consent must be obtained.

Exclusion criteria

• Patients who have received more than one prior chemotherapy regimen or any other systemic antineoplastic treatment including immunotherapy.
• Patients who have received any investigational compound within the past 28 days or who are planning to receive other investigational drugs while participating in the study.
• Patients with brain metastases who have received any prior chemotherapy regimen or any other systemic antineoplastic treatment for brain metastases.
• Patients with brain metastases who have experienced a dose increase of 25% or more above previous dose, in concomitant steroidal or anticonvulsive therapy within 14 days prior to study entry.
• Patients with brain metastases receiving steroidal or anticonvulsive therapy for whom a dose increase has been required within 14 days prior to start of study drug.
• Patients with brain metastases who have leptomeningeal disease.
• Patients with brain metastases who have extracranial metastases in more than two organs.
• Patients with any peripheral polyneuropathy > Grade 1.
• Patients with unresolved diarrhea > Grade 1.
• Patients receiving hematopoietic growth factors except erythropoietin (refer Section 3.4.4).
• Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable cardiac or coronary artery disease.
• Patients taking warfarin or other agents containing warfarin, with the exception of low dose warfarin (1 mg or less daily) administered prophylactically for maintenance of in-dwelling lines or ports.
• Patients who have not recovered fully from surgery for any cause, including brain metastases patients who have had a biopsy or surgical resection of the brain tumor within 2 weeks prior to starting study drug or who are not fully recovered from any prior biopsy or surgical resection.
• Patients who have received radiation therapy or chemotherapy within the last four weeks. Palliative radiotherapy of metastasis in extremities is allowed but such lesions cannot be used as tumor markers.
• Patients with the presence of active or suspected acute or chronic uncontrolled infection, including abscess or fistulae.
• Patients known to be HIV positive.
• History of another malignancy within 3 years prior to study entry, except curatively treated non-melanotic skin cancer or cervical cancer in situ.
• For patients enrolling in the brain metastases cohort, any of the following exclusions to MRI imaging:

Cardiac pacemaker Ferromagnetic metal implants other than those approved as safe for use in MRI scanners Claustrophobia Obesity (exceeding the limits of scanning equipment)

• Pregnant or lactating females.
• A history of noncompliance to medical regimens or inability or unwillingness to return for all scheduled visits.

Other protocol-dependent inclusion / exclusion criteria may apply