NCT00714181

Hydroxychloroquine and Temozolomide in Treating Patients With Metastatic or Unresectable Solid Tumors

A Phase I Study of Hydroxychloroquine in Combination With Temozolomide in Patients With Advanced Solid Tumors

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 38 (actual)
• Sponsor: Abramson Cancer Center at Penn Medicine · Academic / Other
• Sex: All
• Age: 18 Years – 120 Years
• Healthy volunteers: Not accepted

Summary

RATIONALE: Drugs used in chemotherapy, such as hydroxychloroquine and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of hydroxychloroquine when given together with temozolomide in treating patients with metastatic or unresectable solid tumors.

Detailed description

OBJECTIVES: Primary * 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. Secondary * To determine the toxicity and toxicity rate of HCQ when administered at the MTD in combination with TMZ in these patients. Tertiary * 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 exposure. * 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.

Conditions

• Unspecified Adult Solid Tumor, Protocol Specific

Interventions

Type	Name	Description
DRUG	hydroxychloroquine
DRUG	temozolomide
GENETIC	TdT-mediated dUTP nick end labeling assay
GENETIC	western blotting
OTHER	electron microscopy
OTHER	high performance liquid chromatography
OTHER	immunoenzyme technique
OTHER	immunohistochemistry staining method
OTHER	laboratory biomarker analysis
OTHER	mass spectrometry
OTHER	pharmacological study

Timeline

• Start date: 2008-06-01
• Primary completion: 2011-07-01
• Completion: 2013-06-01
• First posted: 2008-07-14
• Last updated: 2016-02-18

Locations

1 site across 1 country: United States