MTD Study PXD-101 in Combination With Paclitaxel + Carboplatin in Chemotherapy-Naive Patients With Stage IV NSCLC

This is a Phase 1/2, multi-center, open label single arm study. Patients meeting all inclusion and exclusion criteria will receive up to 6 cycles of combination therapy of belinostat plus carboplatin (AUC 6) and paclitaxel 200 mg/m2.

During phase I the Maximum Tolerated Dose (MTD) of belinostat in combination with carboplatin and paclitaxel will be determined in patients with Stage IV non-small cell lung cancer who have received no prior systemic chemotherapy. The dose escalation study will be conducted using traditional escalation rule of 3+3 design, during the first cycle of therapy. Belinostat will be assessed at a starting dose level of 1000 mg/m2 and multiple dose levels may be evaluated. Doses of belinostat, carboplatin and paclitaxel will remain constant throughout the study, unless dose modification is required by toxicity. Treatment is given on days 1-5 of every 21-day cycle. Routine safety evaluations will be conducted on days, 1, 8, and 15 of every cycle. Tumor measurement will be done after every 2 cycles of the treatment.

Additional 20 patients will be treated at the MTD defined dose during phase II expansion portion of the study.

All patients will receive up to 6 cycles of combination therapy and be followed until occurrence of unacceptable toxicity, disease progression, withdrawal of consent or death.

Inclusion criteria

• A histologically or cytologically confirmed diagnosis of Stage IV (M1a or M1b) NSCLC. Patients with mixed non-small cell histologies are eligible
• No prior chemotherapy for the treatment of advanced NSCLC
• Prior adjuvant therapy for early stage lung cancer is allowed if completed ≥ 12 months prior to enrollment
• Age >= 18 years
• Adequate organ function
• Any treatment with investigational agent must have completed ≥ 4 weeks prior to enrollment
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Negative pregnancy test for women of childbearing potential.
• Patients with brain metastases allowed if:

• Directed local therapy was completed 2 weeks prior to enrollment;
• There is no evidence of disease progression and;
• Steroids are not required

Exclusion criteria

• Patients with mixed tumors of small cell features
• Known infection with HIV, hepatitis B or hepatitis C
• Baseline prolongation of QT/QTcF interval or required concomitant medication that may cause Torsade de Pointes
• Preexisting ≥Grade 2 neuropathy
• Valproic acid treatment within 2 weeks of study enrollment
• Systemic steroids, for any indication, stabilized at >10 mg/day prednisone
• Known allergy or hypersensitivity to any component of belinostat, paclitaxel or carboplatin
• Co-existing active infection or any other uncontrolled medical condition likely to interfere with trial procedures
• Active concurrent malignancy (except basal cell carcinoma or cervical intraepithelial neoplasia, other potentially cured malignancy that has been in remission for five years or prior adjuvant therapy for early stage lung cancer that is completed ≥ 12 months ago)
• Pregnant or breast-feeding women