Brain and Central Nervous System TumorsPhase 1/2NCT00486603
Hydroxychloroquine, Radiation, and Temozolomide Treating Patients With Newly Diagnosed Glioblastoma Multiforme
A Phase 1/2 study testing hydroxychloroquine, temozolomide and pharmacological study in people with Brain and Central Nervous System Tumors, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 9 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Brain and Central Nervous System Tumors
- What is being tested?
- hydroxychloroquine, temozolomide and pharmacological study
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 92 participants
- Where
- 9 sitesUnited States
- Study dates
- 29 Oct 2007to Jan 2014
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
9 sites in 1 country.
9 sites in 1 country
United States9 sites
Winship Cancer Institute of Emory University
Atlanta, Georgia, 30322
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, 21231-2410
University of Alabama at Birmingham Comprehensive Cancer Center
Birmingham, Alabama, 35294
Massachusetts General Hospital
Boston, Massachusetts, 02114
Case Comprehensive Cancer Center
Cleveland, Ohio, 44106-5065
Josephine Ford Cancer Center at Henry Ford Hospital
Detroit, Michigan, 48202
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, Pennsylvania, 19104-4283
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
Tampa, Florida, 33612-9497
Wake Forest University Comprehensive Cancer Center
Winston-Salem, North Carolina, 27157-1096
About this study
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
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.
Read the 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.
- Conditions
- Brain and Central Nervous System Tumors
- Being tested
- hydroxychloroquine, temozolomide, pharmacological study, Radiation
- Keywords
- adult glioblastoma, adult gliosarcoma, adult giant cell glioblastoma
- Medical subject headings
- Central Nervous System Neoplasms, Glioblastoma, Gliosarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Also called Plaquenil, HCQ
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
temozolomideDrug
Also called Temodar, TMZ
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Also called PK, correlative studies
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
RadiationRadiation
Also called RT
Radiation during the first six weeks of treatment Monday-Friday
| Study group | Role | What they receive |
|---|---|---|
| Phase 1: RT+TMZ+HCQ 200 mg | Experimental | 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) Receives: Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation |
| Phase 1: RT+TMZ+HCQ 400 mg | Experimental | 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) Receives: Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation |
| Phase 1: RT+TMZ+HCQ 600 mg | Experimental | 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) Receives: Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation |
| Phase 1: RT+TMZ+HCQ 800 mg | Experimental | 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) Receives: Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation |
| Phase 2: RT + TMZ + HCQ MTD | Experimental | 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) Receives: Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation |
What is being measured
The primary outcome is the main question the study is designed to answer.
(Phase I) Maximum Tolerated Dose (MTD) of Hydroxychloroquine (HCQ)
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.
Measured: 10 weeks
(Phase I) Number of Participants Who Experienced Dose Limiting Toxicity (DLT)
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)
Measured: 10 weeks
(Phase II) Overall Survival
Number of months alive after end of study participation
Measured: 2 years
Secondary outcomes (8)
(Phase II) Number of Participants With Grade 3 and 4 Toxicity
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
Measured: up to 2 years
Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition
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.
Measured: up to 9 weeks
Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition in Relation to Maximal Concentration (Cmax) of HCQ
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.
Measured: up to 9 weeks
Pharmacokinetics (PK) of Hydroxychloroquine as Measured by Lag Time (Tlag)
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.
Measured: up to 276 days
PK of Hydroxychloroquine as Measured by Oral Clearance (Liters/Hour) From Central Compartment (CL/F)
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.
Measured: up to 276 days
PK of Hydroxychloroquine as Measured by Volume of Distribution of Central Compartment (V/F)
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.
Measured: up to 276 days
PK of Hydroxychloroquine as Measured by Distribution Volume of Peripheral Compartment (V2/F)
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.
Measured: up to 276 days
PK of Hydroxychloroquine as Measured by First-order Absorption Rate Constant (Ka)
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.
Measured: up to 276 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jun 2007 (estimated)
- Study start29 Oct 2007
- Primary completionJun 2013
- Study completionJan 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Brain and Central Nervous System TumorsStudies of the same condition, open and under way.
- More trials run by Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 92 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Myrna Rosenfeld, MD, PhD, Study chair, New Approaches to Brain Tumor Therapy/Adult Brain Tumor Consortium
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00486603
- Sponsor's protocol ID
- NABTT-0603
- Other IDs
- U01CA062475, ABTC-0603, CDR0000549734, NA_00012420
- Status last verified
- Jun 2019
- First submitted
- 13 Jun 2007
- Last updated
- 10 Jul 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Rosenfeld MR, Ye X, Supko JG, Desideri S, Grossman SA, Brem S, Mikkelson T, Wang D, Chang YC, Hu J, McAfee Q, Fisher J, Troxel AB, Piao S, Heitjan DF, Tan KS, Pontiggia L, O'Dwyer PJ, Davis LE, Amaravadi RK. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy. 2014 Aug;10(8):1359-68. doi: 10.4161/auto.28984. Epub 2014 May 20.
PubMed 24991840
Study at a glance
From the registry record, last updated by the sponsor on 10 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00486603
- Acronym / sponsor ID
- NABTT-0603
- Conditions
- Brain and Central Nervous System Tumors
- Keywords
- adult glioblastoma, adult gliosarcoma, adult giant cell glioblastoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 92 participants (actual)
- Lead sponsor
- Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- 29 Oct 2007
- Primary completion
- Jun 2013 (actual)
- Study completion
- Jan 2014 (actual)
- First posted
- 14 Jun 2007 (estimated)
- Results
- Posted 10 Jul 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Phase 1: RT+TMZ+HCQ 200 mg | Experimental | Drug: hydroxychloroquine, Drug: temozolomide, Other: pharmacological study, Radiation: RadiationPhse 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) |
| Phase 1: RT+TMZ+HCQ 400 mg | Experimental | Drug: hydroxychloroquine, Drug: temozolomide, Other: pharmacological study, Radiation: RadiationPhse 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) |
| Phase 1: RT+TMZ+HCQ 600 mg | Experimental | Drug: hydroxychloroquine, Drug: temozolomide, Other: pharmacological study, Radiation: RadiationPhse 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) |
| Phase 1: RT+TMZ+HCQ 800 mg | Experimental | Drug: hydroxychloroquine, Drug: temozolomide, Other: pharmacological study, Radiation: RadiationPhse 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) |
| Phase 2: RT + TMZ + HCQ MTD | Experimental | Drug: hydroxychloroquine, Drug: temozolomide, Other: pharmacological study, Radiation: RadiationPhse 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) |
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| hydroxychloroquineAlso: Plaquenil, HCQsee 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 | Drug | Phase 1: RT+TMZ+HCQ 200 mg, Phase 1: RT+TMZ+HCQ 400 mg, Phase 1: RT+TMZ+HCQ 600 mg, Phase 1: RT+TMZ+HCQ 800 mg, Phase 2: RT + TMZ + HCQ MTD |
| temozolomideAlso: Temodar, TMZTMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) | Drug | Phase 1: RT+TMZ+HCQ 200 mg, Phase 1: RT+TMZ+HCQ 400 mg, Phase 1: RT+TMZ+HCQ 600 mg, Phase 1: RT+TMZ+HCQ 800 mg, Phase 2: RT + TMZ + HCQ MTD |
| pharmacological studyAlso: PK, correlative studiesSeven 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 | Phase 1: RT+TMZ+HCQ 200 mg, Phase 1: RT+TMZ+HCQ 400 mg, Phase 1: RT+TMZ+HCQ 600 mg, Phase 1: RT+TMZ+HCQ 800 mg, Phase 2: RT + TMZ + HCQ MTD |
| RadiationAlso: RTRadiation during the first six weeks of treatment Monday-Friday | Radiation | Phase 1: RT+TMZ+HCQ 200 mg, Phase 1: RT+TMZ+HCQ 400 mg, Phase 1: RT+TMZ+HCQ 600 mg, Phase 1: RT+TMZ+HCQ 800 mg, Phase 2: RT + TMZ + HCQ MTD |
Primary outcome
(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.
(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)
(Phase II) Overall Survival
Time frame: 2 years
Number of months alive after end of study participation
8 secondary outcomes
(Phase II) Number of Participants With Grade 3 and 4 Toxicity
Time frame: up to 2 years
Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition
Time frame: up to 9 weeks
Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition in Relation to Maximal Concentration (Cmax) of HCQ
Time frame: up to 9 weeks
Pharmacokinetics (PK) of Hydroxychloroquine as Measured by Lag Time (Tlag)
Time frame: up to 276 days
PK of Hydroxychloroquine as Measured by Oral Clearance (Liters/Hour) From Central Compartment (CL/F)
Time frame: up to 276 days
PK of Hydroxychloroquine as Measured by Volume of Distribution of Central Compartment (V/F)
Time frame: up to 276 days
PK of Hydroxychloroquine as Measured by Distribution Volume of Peripheral Compartment (V2/F)
Time frame: up to 276 days
PK of Hydroxychloroquine as Measured by First-order Absorption Rate Constant (Ka)
Time frame: up to 276 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jul 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 24991840Rosenfeld MR, Ye X, Supko JG, Desideri S, Grossman SA, Brem S, Mikkelson T, Wang D, Chang YC, Hu J, McAfee Q, Fisher J, Troxel AB, Piao S, Heitjan DF, Tan KS, Pontiggia L, O'Dwyer PJ, Davis LE, Amaravadi RK. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy. 2014 Aug;10(8):1359-68. doi: 10.4161/auto.28984. Epub 2014 May 20.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Myrna Rosenfeld, MD, PhD study chair
New Approaches to Brain Tumor Therapy/Adult Brain Tumor Consortium
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing hydroxychloroquine, temozolomide and pharmacological study in people with Brain and Central Nervous System Tumors, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 9 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Jul 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
(Phase I) Maximum Tolerated Dose (MTD) of Hydroxychloroquine (HCQ) (time frame: 10 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00486603, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2019.