Hydroxychloroquine and Temozolomide in Treating Patients With Metastatic or Unresectable Solid Tumors
Condition: Unspecified Adult Solid Tumor, Protocol Specific
MeSH terms: Neoplasms
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): hydroxychloroquine; temozolomide; TdT-mediated dUTP nick end labeling assay; western blotting; electron microscopy; high performance liquid chromatography; immunoenzyme technique; immunohistochemistry staining method; laboratory biomarker analysis; mass spectrometry; pharmacological study
Intervention type(s): Drug; Drug; Genetic; Genetic; Other; Other; Other; Other; Other; Other; Other
Intervention MeSH terms: Hydroxychloroquine; Temozolomide
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: unspecified adult solid tumor, protocol specific