A Randomized Phase II Study of Paclitaxel-carboplatin-bevacizumab With or Without Nitroglycerin Patches in Patients With Stage IV Non-squamous-non-small Cell Lung Cancer: NVALT12
Standard treatment for non-small cell lung cancer (NSCLC) consists of platinum-containing
chemotherapy. It has been shown that the addition of bevacizumab to standard chemotherapy
improves progression-free survival (PFS) and overall survival (OS) in patients with
non-squamous NSCLC. There is a need for improved PFS and OS and response rates to
chemotherapy are only 25-35%.
Tumor hypoxia is a common phenomenon in lung cancer; it is a known poor prognostic marker,
related to treatment resistance. Hypoxia Inducible Factor (HIF) -1α is the major factor
regulating the response to hypoxia.
HIF directly activates vascular endothelial growth factor (VEGF) and VEGF-receptor.
Bevacizumab interacts with this pathway by blocking VEGF.
Pre-clinical studies have shown that nitric oxide (NO) donating drugs may decrease hypoxia
related drug resistance. Nitroglycerin (NTG) is a NO donating drug. NTG increases tumor
blood flow and thereby augments antitumor drug delivery to the tumor and inhibits HIF-1α.
Interestingly, it has recently been shown in mouse models that the addition of HIF-1α
inhibitors to bevacizumab significantly inhibits tumor growth by inducing apoptosis.
A randomized phase II has shown an increase in the response rate from 42% to 72%, when NTG
patches (25 mg/day, day -2 to +3) were added to vinorelbine/cisplatin in patients with
advanced NSCLC. In addition, the time to progression increased from 185 to 327 days.
The hypothesis of the present study is that adding NTG transdermal patches to bevacizumab
containing chemotherapy improves PFS, response rate and OS in patients with metastatic
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
progression free survival
every 6 weeks during chemotherapy
Anne-Marie C. Dingemans, MD PhD
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)