A Phase I Study of Hydroxychloroquine in Combination With Temozolomide in Patients With Advanced Solid Tumors
- To determine the maximum tolerated dose (MTD) of hydroxychloroquine (HCQ) when
administered in combination with temozolomide (TMZ) in patients with metastatic or
unresectable solid tumors.
- To determine the toxicity and toxicity rate of HCQ when administered at the MTD in
combination with TMZ in these patients.
- To construct a population pharmacokinetic (PK) model using a limited sampling of whole
blood to determine the drug exposure of HCQ and HCQ metabolites in these patients.
- To measure changes in autophagic vesicle accumulation by immunoblotting against the
autophagy marker LC3 in protein lysates prepared from peripheral blood mononuclear
cells (PBMC) collected from patients treated with HCQ and TMZ.
- To measure changes in median number of autophagic vesicles by electron microscopy in
PBMC collected from patients treated with HCQ and TMZ.
- To assess tumor changes in LC3 and caspase 3 cleavage by western blotting.
- To assess tumor cell death characteristics by immunohistochemical methods (Ki67, TUNEL
staining, cleaved caspase 3).
- To evaluate autophagy by electron microscopy.
- To define associations between changes in LC3 levels from baseline in PBMC with HCQ
- To measure the levels of HMGB1 in the serum of patients treated with HCQ and TMZ.
OUTLINE: This is a dose-escalation study of hydroxychloroquine (HCQ).
Patients receive oral HCQ alone once or twice daily for 14 days. Patients then receive oral
HCQ once or twice daily on days 1-28 and oral temozolomide once daily on days 1-7 and 15-21.
Treatment with HCQ and temozolomide repeats every 28 days in the absence of disease
progression or unacceptable toxicity.
Patients undergo blood sample collection periodically for pharmacodynamic and
pharmacokinetic correlative studies. Autophagic vesicles in blood samples are quantified by
immunoblotting against the autophagy protein LC3 and by electron microscopy.
Pharmacokinetics are analyzed by high-performance liquid chromatography with tandem mass
spectrometry. Patients with tumors amenable to biopsy also undergo serial biopsies. Tumor
tissue samples are assessed for tumor cell apoptosis and proliferation using Ki67 and TUNEL
staining and for the number of autophagic vesicles and nuclear changes characteristic of
apoptotic, autophagic, or necrotic cell death by western blotting and electron microscopy.
After completion of study treatment, patients are followed periodically.
Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of hydroxychloroquine
Ravi Amaravadi, MD
Abramson Cancer Center of the University of Pennsylvania
|Abramson Cancer Center of the University of Pennsylvania||Philadelphia, Pennsylvania 19104-4283|