A Phase II, Open-Label Trial of Bortezomib (VELCADE®) in Combination With Gemcitabine and Cisplatin in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer
By its mechanism of action i.e., inhibiting protein degradation, VELCADE targets a
wide-range of pathways that are relevant to tumor progression and therapy resistance.
Preclinical data in cell lines indicate anti-tumor activity in NSCLC. Preliminary work in
vivo (animal models) suggests an enhanced anti-tumor effect in combination with cytotoxic
agents commonly used in the treatment of lung cancer, including gemcitabine and CPT-11 and
additive tumor growth delay when combined with cisplatin or paclitaxel.
Platinum- or non-platinum- based combinations including the newer agents represent the
standard front-line treatment for patients with stage IIIB/IV NSCLC. However, despite the
introduction of the newer agents, the efficacy of cytotoxic chemotherapy seems to have
reached a plateau. The incorporation of molecularly targeted agents in NSCLC treatment is
likely to improve the treatment outcomes. Recently, an initial Phase 2 of VELCADE in
combination with gemcitabine/carboplatin in the first-line treatment of NSCLC was completed.
A response rate of 21% with impressive progression-free survival and overall survival rates
of 5 and 11 months, respectively, were reported.
Combining VELCADE with a currently approved standard regimen such as cisplatin/gemcitabine,
may lead to a better response rate, TTP, and OS than chemotherapy alone. VELCADE combined
with gemcitabine and cisplatin has been shown safe in a phase I trial in patients with
advanced solid tumors. The maximum tolerated dose (MTD) of VELCADE was 1 mg/m2 on either a
weekly or a biweekly schedule when combined with gemcitabine 1000 mg/m2 and cisplatin 70
mg/m2. Treatment was generally well tolerated with the weekly regimen of VELCADE being
associated with less myelotoxicity. Plasma pharmacokinetic profiles of gemcitabine and
cisplatin were not altered by VELCADE. Interestingly enough, among 27 patients with NSCLC an
encouraging response rate of 37% and disease stabilization rate of 52% was recorded.
In this trial VELCADE alone will be administered on the first treatment cycle to examine
molecular correlates of VELCADE activity. Subsequent cycles will include the combination of
VELCADE with cisplatin plus gemcitabine.
Data from the phase I study of VELCADE plus cisplatin/gemcitabine contributed to the
selection of the drug doses for patients that will be enrolled in the current study.
Specifically, the doses employed are those identified as the MTD level of the phase I study.
The anti-tumor activity of the combination of VELCADE and cisplatin/gemcitabine in the
first-line treatment of NSCLC will be tested in this study according to a Simon 2-stage
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Overall Response Rate
Participants will be evaluated for response to the study treatment after the first three treatment cycles (cycle repeated every 21 days) and then every two treatment cycles (completion of cycles 5, 7, 9 etc.) until documentation of disease progression.
Up to 9 weeks
Vassilis Georgoulias, MD
University Hospital of Heraklion
Greece: Ethics Committee