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Hydroxychloroquine, Radiation, and Temozolomide Treating Patients With Newly Diagnosed Glioblastoma Multiforme

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00486603
Recruitment Status : Completed
First Posted : June 14, 2007
Results First Posted : July 10, 2019
Last Update Posted : July 10, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief 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.


Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Drug: hydroxychloroquine Drug: temozolomide Other: pharmacological study Radiation: Radiation Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 92 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Hydroxychloroquine in Conjunction With Radiation Therapy and Concurrent and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme
Study Start Date : October 29, 2007
Actual Primary Completion Date : June 2013
Actual Study Completion Date : January 2014


Arm Intervention/treatment
Experimental: Phase 1: RT+TMZ+HCQ 200 mg

Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Starting dose of HCQ is 200mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase

Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.

cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.

Other: pharmacological study (PK)

pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1

Radiation (RT)

Drug: hydroxychloroquine
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
Other Names:
  • Plaquenil
  • HCQ

Drug: temozolomide
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Other Names:
  • Temodar
  • TMZ

Other: pharmacological study
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
Other Names:
  • PK
  • correlative studies

Radiation: Radiation
Radiation during the first six weeks of treatment Monday-Friday
Other Name: RT

Experimental: Phase 1: RT+TMZ+HCQ 400 mg

Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 400 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase

Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.

cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.

Other: pharmacological study (PK)

pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1

Radiation (RT)

Drug: hydroxychloroquine
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
Other Names:
  • Plaquenil
  • HCQ

Drug: temozolomide
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Other Names:
  • Temodar
  • TMZ

Other: pharmacological study
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
Other Names:
  • PK
  • correlative studies

Radiation: Radiation
Radiation during the first six weeks of treatment Monday-Friday
Other Name: RT

Experimental: Phase 1: RT+TMZ+HCQ 600 mg

Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 600 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase

Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.

cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.

Other: pharmacological study (PK)

pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1

Radiation (RT)

Drug: hydroxychloroquine
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
Other Names:
  • Plaquenil
  • HCQ

Drug: temozolomide
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Other Names:
  • Temodar
  • TMZ

Other: pharmacological study
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
Other Names:
  • PK
  • correlative studies

Radiation: Radiation
Radiation during the first six weeks of treatment Monday-Friday
Other Name: RT

Experimental: Phase 1: RT+TMZ+HCQ 800 mg

Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 800 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase

Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.

cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.

Other: pharmacological study (PK)

pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1

Radiation (RT)

Drug: hydroxychloroquine
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
Other Names:
  • Plaquenil
  • HCQ

Drug: temozolomide
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Other Names:
  • Temodar
  • TMZ

Other: pharmacological study
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
Other Names:
  • PK
  • correlative studies

Radiation: Radiation
Radiation during the first six weeks of treatment Monday-Friday
Other Name: RT

Experimental: Phase 2: RT + TMZ + HCQ MTD

Phse 2: daily hydroxychloroquine (HCQ) (MTD 600mg) on 1st day of RT and concomitant temozolomide for 6wks during RT. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase

Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.

Other: pharmacological study (PK)

Pts will continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 2

Radiation (RT)

Drug: hydroxychloroquine
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
Other Names:
  • Plaquenil
  • HCQ

Drug: temozolomide
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Other Names:
  • Temodar
  • TMZ

Other: pharmacological study
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
Other Names:
  • PK
  • correlative studies

Radiation: Radiation
Radiation during the first six weeks of treatment Monday-Friday
Other Name: RT




Primary Outcome Measures :
  1. (Phase I) Maximum Tolerated Dose (MTD) of Hydroxychloroquine (HCQ) [ Time Frame: 10 weeks ]
    Number of participants who tolerated doses of HCQ without dose limiting toxicity. The highest dose at which participants did not experience dose limiting toxicity was determined as the MTD.

  2. (Phase I) Number of Participants Who Experienced Dose Limiting Toxicity (DLT) [ Time Frame: 10 weeks ]
    Dose limiting toxicity defined as: Any DLT must be a toxicity considered at least possibly related to HCQ. DLTs will include any possibly, probably, or definitely HCQ-related Grade 3 or 4 toxicity. Known or reasonably suspected TMZ hematological toxicities will not be considered dose limiting unless the treating physician considers the toxicity to be exacerbated by HCQ. Nonhematological toxicities: Any Grades 3-4 severity (except nausea and vomiting without sufficient antiemetic prophylaxis)

  3. (Phase II) Overall Survival [ Time Frame: 2 years ]
    Number of months alive after end of study participation


Secondary Outcome Measures :
  1. (Phase II) Number of Participants With Grade 3 and 4 Toxicity [ Time Frame: up to 2 years ]
    Number of participants experiencing Grade 3 and 4 toxicity, as defined by CTCAE v3.0, with a possible, probable or definite relationship to HCQ, TMZ or both

  2. Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition [ Time Frame: up to 9 weeks ]
    Number of participants with at least 2 peripheral blood mononuclear cell (PBMC) samples that were amenable to electronmicroscopy (EM) who showed an increase of autophagic vacuoles in cells.

  3. Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition in Relation to Maximal Concentration (Cmax) of HCQ [ Time Frame: up to 9 weeks ]
    Autophagy inhibition is represented by an increase in autophagic vacuoles (AV) in participants with at least 2 peripheral blood mononuclear cell samples that were amenable to EM.

  4. Pharmacokinetics (PK) of Hydroxychloroquine as Measured by Lag Time (Tlag) [ Time Frame: up to 276 days ]
    The population model PK parameters do not specifically represent steady-state values, as they were determined from multiple repeated single doses taken from multiple repeated doses taken by the individual patient during their period on the study. To obtain steady state PK parameters, individual estimates were simulated from the population model.

  5. PK of Hydroxychloroquine as Measured by Oral Clearance (Liters/Hour) From Central Compartment (CL/F) [ Time Frame: up to 276 days ]
    The population model PK parameters do not specifically represent steady-state values, as they were determined from multiple repeated single doses taken from multiple repeated doses taken by the individual patient during their period on the study. To obtain steady state PK parameters, individual estimates were simulated from the population model.

  6. PK of Hydroxychloroquine as Measured by Volume of Distribution of Central Compartment (V/F) [ Time Frame: up to 276 days ]
    The population model PK parameters do not specifically represent steady-state values, as they were determined from multiple repeated single doses taken from multiple repeated doses taken by the individual patient during their period on the study. To obtain steady state PK parameters, individual estimates were simulated from the population model.

  7. PK of Hydroxychloroquine as Measured by Distribution Volume of Peripheral Compartment (V2/F) [ Time Frame: up to 276 days ]
    The population model PK parameters do not specifically represent steady-state values, as they were determined from multiple repeated single doses taken from multiple repeated doses taken by the individual patient during their period on the study. To obtain steady state PK parameters, individual estimates were simulated from the population model.

  8. PK of Hydroxychloroquine as Measured by First-order Absorption Rate Constant (Ka) [ Time Frame: up to 276 days ]
    The population model PK parameters do not specifically represent steady-state values, as they were determined from multiple repeated single doses taken from multiple repeated doses taken by the individual patient during their period on the study. To obtain steady state PK parameters, individual estimates were simulated from the population model.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed grade IV supratentorial astrocytoma (glioblastoma multiforme)
  • Newly diagnosed disease
  • Diagnosis must have been made by biopsy or resection ≤ 3 months prior to study entry

INCLUSION CRITERIA:

  • Patients must be at least 18 years of age.
  • Patients must have histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme), established by biopsy or resection not more than 3 months prior to registration.
  • Patients must not have received prior radiation therapy, chemotherapy, immunotherapy or therapy with biologic agents (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, TIL, LAK or gene therapy), or hormonal therapy for their brain tumor. Glucocorticoid therapy is allowed.
  • Patients must have a Karnofsky performance status ≤ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).
  • Patients must have the following hematologic, renal and liver function (i.e. absolute neutrophil count > 1500/mm3, platelets > 100,000/mm3, creatinine ≤ 2 times the upper limits of normal (ULN) total bilirubin ≤ 1.5 mg/dl, ALT and AST ≤ 4 times above the upper limits of the institutional norm.
  • Patients must be able to provide written informed consent.
  • Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Women of childbearing potential must have a negative pregnancy test. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant.
  • Patients must have a Mini Mental State Exam (MMSE) score of > 15.
  • Patients must have tumor tissue form completed and signed by a pathologist. See section 9.5.2 for details.
  • Prior concurrent therapy:

    • No prior radiotherapy, chemotherapy, immunotherapy, biologic agents (e.g., immunotoxins, immunoconjugates, antisense agents, peptide receptor antagonists, interferons, interleukins, tumor-infiltrating lymphocytes, lymphokine-activated killer cell therapy, or gene therapy), or hormonal therapy for brain tumor
    • No prior polifeprosan 20 with carmustine implant (Gliadel wafer) or GliaSite® brachytherapy
    • No concurrent cytochrome P450 enzyme-inducing anticonvulsant drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, or oxcarbazepine)
    • No other concurrent chemotherapeutic or investigational agents for this cancer
    • Concurrent glucocorticoids allowed

EXCLUSION CRITERIA:

  • Patients with serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety.
  • Patients who are pregnant or breast-feeding.
  • Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents).
  • Patients with a concurrent or prior malignancy, unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Patients who have been free of disease (any prior malignancy) for five years are eligible for this study.
  • Patients who have received Gliadel wafers or GliaSite brachytherapy are not eligible.
  • Due to risk of disease exacerbation patients with porphyria are not eligible.
  • Due to risk of disease exacerbation patients with psoriasis are ineligible unless the disease is well controlled and they are under the care of a specialist for the disorder who agrees to monitor the patient for exacerbations.
  • Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (EIADs) (i.e. phenytoin, carbamazepine, Phenobarbital, primidone or oxcarbazepine).
  • Patients with previously documented macular degeneration or diabetic retinopathy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00486603


Locations
Layout table for location information
United States, Alabama
University of Alabama at Birmingham Comprehensive Cancer Center
Birmingham, Alabama, United States, 35294
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
Tampa, Florida, United States, 33612-9497
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Michigan
Josephine Ford Cancer Center at Henry Ford Hospital
Detroit, Michigan, United States, 48202
United States, North Carolina
Wake Forest University Comprehensive Cancer Center
Winston-Salem, North Carolina, United States, 27157-1096
United States, Ohio
Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106-5065
United States, Pennsylvania
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104-4283
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Study Chair: Myrna Rosenfeld, MD, PhD New Approaches to Brain Tumor Therapy/Adult Brain Tumor Consortium
Publications of Results:
Layout table for additonal information
Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT00486603    
Other Study ID Numbers: NABTT-0603
U01CA062475 ( U.S. NIH Grant/Contract )
ABTC-0603 ( Other Identifier: Adult Brain Tumor Consortium )
CDR0000549734 ( Other Identifier: NCI PDQ )
NA_00012420 ( Other Identifier: JHM IRB )
First Posted: June 14, 2007    Key Record Dates
Results First Posted: July 10, 2019
Last Update Posted: July 10, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
adult glioblastoma
adult gliosarcoma
adult giant cell glioblastoma
Additional relevant MeSH terms:
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Glioblastoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Hydroxychloroquine
Temozolomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Antirheumatic Agents