A Phase II With a Lead in Phase I Study to Examine the Tolerability, Safety Profile and Efficacy of Hydroxychloroquine and Gefitinib in Advanced Non-Small Cell Lung Cancer
Non-small cell lung cancer (NSCLC) is the most common cause of cancer mortality in men and
women in Singapore.Chemotherapy and biologically targeted agents can extend survival only
modestly for these patients; therefore, discovery of novel ways to prolong the disease
course is a top research priority.
The epidermal growth factor receptor (EGFR) signaling pathway plays a central role in the
neoplastic transformation of NSCLC and promotes cancer cell survival, metastasis, and
angiogenesis. The predominance of EGFR signaling in NSCLC makes the pathway an attractive
candidate for the development of targeted therapeutics. Over the last three years, the FDA
has approved two drugs for salvage treatment of NSCLC, gefitinib (Iressa ®, formerly known
as ZD1839) and erlotinib (Tarceva ®, formerly known as OSI-774). Both are small molecule
orally-bioavailable tyrosine kinase inhibitors (TKIs) of the EGFR TK domain, and have been
shown to improve survival compared to placebo in asian patients when administered after
failure of first or second line chemotherapy for advanced NSCLC.
Recently, it was found that somatic mutations in the EGFR gene sensitize NSCLC tumors to
TKIs. These mutations are present in approximately 50 % of asian patients with NSCLC.
Retrospective studies suggest that patients harboring a mutation may derive greater clinical
benefit from treatment with TKIs than patients without a mutation.
Nevertheless, all patients that benefit from TKI treatment ultimately develop resistance to
therapy manifesting as progression of their cancer, after which there remains few, if any
treatment options. Hence, there would be vast clinical utility in understanding the
mechanisms of TKI resistance and developing strategies to reverse or prevent it.
We have preliminary data which shows that the combination of hydroxychloroquine and
gefitinib results in delayed acquired resistance to gefitinib in cell lines that harbour the
EGFR mutation. In addition, the addition of hydroxychloroquine to gefitinib can result in
reversal of acquired resistance to gefitinib. Much parallel has been observed in resistance
mechanisms between NSCLC cell lines and molecular changes observed in patients thus far.
The long term aim therefore is to examine the efficacy of this combination in delaying
acquired resistance to gefitinib in NSCLC patients.
First, however, the MTD and DLT of each drug when used in combination therapy will be
examined in this study. The other aim is to examine the pharmacokinetic effect and
interactions of hydroxychloroquine on gefitinib, and vice versa. Gefitinib is usually well
tolerated, with main toxicities of rash and diarrhoea. Hydroxychloroquine is also FDA
approved and widely used and generally well-tolerated for rheumatological conditions.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
For the phase I lead in study: To identify the tolerability, the dose limiting toxicity (DLT) and the general safety profile of HCQ and gefitinib when used in combination.
Tan Min Chin, MD
National University Hospital, Singapore
Singapore: Domain Specific Review Boards