Hydroxychloroquine, Radiation, and Temozolomide Treating Patients With Newly Diagnosed Glioblastoma Multiforme
Condition: Brain and Central Nervous System Tumors
MeSH terms: Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving
      hydroxychloroquine together with temozolomide and radiation therapy may kill more tumor
      cells.

      PURPOSE: This phase I/II trial is studying the side effects and best dose of
      hydroxychloroquine when given together with radiation therapy and temozolomide and to see how
      well they work in treating patients with newly diagnosed glioblastoma multiforme.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the maximum tolerated dose of hydroxychloroquine when administered in
           combination with radiotherapy and temozolomide in patients with newly diagnosed
           glioblastoma multiforme. (Phase I)

        -  Assess the toxicity of this regimen in these patients. (Phase I)

        -  Determine the overall survival of patients treated with this regimen. (Phase II)

      Secondary

        -  Assess the frequency of toxicity of this regimen in these patients. (Phase II)

        -  Evaluate the pharmacokinetics and pharmacodynamics of this regimen in these patients.

        -  Correlate the average change in autophagic vesicles from baseline with genotype,
           toxicity, and clinical outcomes.

        -  Correlate the presence of TP53 and PTEN genes and BECN1 with toxicity and clinical
           outcomes.

      OUTLINE: This is a multicenter, open-label, phase I, dose-escalation study of
      hydroxychloroquine followed by a phase II study.

        -  Phase I:

             -  Initiation therapy: Patients receive oral temozolomide daily for 6 weeks and
                undergo conformal or intensity-modulated radiotherapy 5 days a week for 6 weeks.
                Patients also receive oral hydroxychloroquine daily for 10 weeks beginning
                concurrently with temozolomide and radiotherapy.

      Cohorts of 3-6 patients receive escalating doses of hydroxychloroquine until the maximum
      tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
      of 3 or 2 of 6 patients experience dose-limiting toxicity.

        -  Maintenance therapy: Beginning 28 days after completion of radiotherapy, patients
           receive oral temozolomide on days 1-5 and oral hydroxychloroquine on days 1-28.
           Treatment repeats every 4 weeks for up to 6 courses in the absence of disease
           progression or unacceptable toxicity. Patients may then continue to receive
           hydroxychloroquine alone as above in the absence of disease progression or unacceptable
           toxicity.

             -  Phase II:

        -  Initiation therapy: Patients receive hydroxychloroquine at the MTD determined in phase
           I, temozolomide, and radiotherapy as in phase I.

        -  Maintenance therapy: Patients receive hydroxychloroquine at the MTD determined in phase
           I and temozolomide as in phase I.

      Patients undergo blood and tissue sample collection periodically for pharmacological and
      correlative studies. Samples are analyzed for the mutational status of TP53 and PTEN genes
      and copy number of BECN1 via PCR; changes in autophagy protein LC3 via gel electrophoresis;
      and differences in the formation of LC3-II via immunoblotting.

      After completion of study treatment, patients are followed every 2 months.
    

Intervention name(s): hydroxychloroquine; temozolomide; pharmacological study; Radiation
Intervention type(s): Drug; Drug; Other; Radiation
Intervention description(s): see arm description, the first 10 week cycle is call initiation cycle, Post the 10 week cycle of just HCQ, 4 week cycles are called Maintenance Cycles; TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle); Seven samples in total will be collected baseline, initiation cycle -week3-4, week9-10, Maintenance Cycle 1 Week 4 (C1W4), Cycle2 Week4, Cycle3 Week4, Cycle6 Week4; Radiation during the first six weeks of treatment Monday-Friday
Other intervention name(s): Plaquenil; HCQ; Temodar; TMZ; PK; correlative studies; RT
Intervention MeSH terms: Hydroxychloroquine; Temozolomide
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: adult glioblastoma; adult gliosarcoma; adult giant cell glioblastoma