Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| U01CA062475 | U.S. NIH Grant/Contract | View source | |
| ABTC-0603 | Other Identifier | Adult Brain Tumor Consortium | |
| CDR0000549734 | Other Identifier | NCI PDQ | |
| NA_00012420 | Other Identifier | JHM IRB |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| National Cancer Institute (NCI) | NIH |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a multicenter, open-label, phase I, dose-escalation study of hydroxychloroquine followed by a phase II study.
Phase I:
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.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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) |
|
| 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) |
|
| 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) |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| hydroxychloroquine | Drug | 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 |
|
| Measure | Description | Time Frame |
|---|---|---|
| (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. | 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) | 10 weeks |
| (Phase II) Overall Survival | Number of months alive after end of study participation | 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| (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 | up to 2 years |
| Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition |
Not provided
DISEASE CHARACTERISTICS:
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:
EXCLUSION CRITERIA:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Myrna Rosenfeld, MD, PhD | New Approaches to Brain Tumor Therapy/Adult Brain Tumor Consortium | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham Comprehensive Cancer Center | Birmingham | Alabama | 35294 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24991840 | Result | 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. |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
This study was conducted by the Adult Brain Tumor Consortium (ABTC) and patients were recruited from the consortium members outpatient centers.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | RT+TMZ+HCQ Phase 1 - 200 mg | Daily Hydroxchloroquine (HCQ) on 1st day of RT and TMZ for 6wks during RT. 200mg. After 6 wks, 4 wkd 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. Phse 2: same schema as above but at the prescribed MTD from Phse 1. PKs - correlatives will be collected in Phse 1 and Phse 2 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 temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) pharmacological study/Correlative study: Seven samples in total will be collected baseline, initiation cycle -wk3-4, wk9-10, Maintenance Cycle 1Week 4 (C1W4), C2W4, C3W4, C6W4 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| 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) |
|
| 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) |
|
|
| temozolomide | Drug | TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) |
|
|
| pharmacological study | Other | 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 | Radiation | Radiation during the first six weeks of treatment Monday-Friday |
|
|
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. |
| 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. | 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. | 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. | 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. | 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. | 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. | up to 276 days |
| H. Lee Moffitt Cancer Center and Research Institute at University of South Florida |
| Tampa |
| Florida |
| 33612-9497 |
| United States |
| Winship Cancer Institute of Emory University | Atlanta | Georgia | 30322 | United States |
| Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore | Maryland | 21231-2410 | United States |
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
| Josephine Ford Cancer Center at Henry Ford Hospital | Detroit | Michigan | 48202 | United States |
| Wake Forest University Comprehensive Cancer Center | Winston-Salem | North Carolina | 27157-1096 | United States |
| Case Comprehensive Cancer Center | Cleveland | Ohio | 44106-5065 | United States |
| Abramson Cancer Center of the University of Pennsylvania | Philadelphia | Pennsylvania | 19104-4283 | United States |
| FG001 | RT+TMZ+HCQ Phase 1 - 400 mg | Daily Hydroxchloroquine (HCQ) on 1st day of RT and TMZ for 6wks during RT. 400mg. After 6 wks, 4 wkd 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. Phse 2: same schema as above but at the prescribed MTD from Phse 1. PKs - correlatives will be collected in Phse 1 and Phse 2 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 temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) pharmacological study/Correlative study: Seven samples in total will be collected baseline, initiation cycle -wk3-4, wk9-10, Maintenance Cycle 1Week 4 (C1W4), C2W4, C3W4, C6W4 |
| FG002 | RT+TMZ+HCQ Phase 1 - 600 mg | Daily Hydroxchloroquine (HCQ) on 1st day of RT and TMZ for 6wks during RT. 600mg. After 6 wks, 4 wkd 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. Phse 2: same schema as above but at the prescribed MTD from Phse 1. PKs - correlatives will be collected in Phse 1 and Phse 2 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 temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) pharmacological study/Correlative study: Seven samples in total will be collected baseline, initiation cycle -wk3-4, wk9-10, Maintenance Cycle 1Week 4 (C1W4), C2W4, C3W4, C6W4 |
| FG003 | RT+TMZ+HCQ Phase 1 - 800 mg | Daily Hydroxchloroquine (HCQ) on 1st day of RT and TMZ for 6wks during RT. 800mg. After 6 wks, 4 wkd 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. Phse 2: same schema as above but at the prescribed MTD from Phse 1. PKs - correlatives will be collected in Phse 1 and Phse 2 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 temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) pharmacological study/Correlative study: Seven samples in total will be collected baseline, initiation cycle -wk3-4, wk9-10, Maintenance Cycle 1Week 4 (C1W4), C2W4, C3W4, C6W4 |
| FG004 | RT+TMZ+HCQ Phase 2 - MTD 600 mg | Phse 2: daily hydroxychloroquine (HCQ) (MTD 600mg) on 1st day of RT and concomitant temozolomide for 6wks during RT. After 6 wks, 4 wkd of HCQ alone daily. After 6 wks, 4 wkd 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. Pts will continue on treatment unitl tumor progression. PKs - correlatives will be collected in Phse 2 Radiation |
| COMPLETED |
|
| NOT COMPLETED |
|
|
Baseline characteristics for all participants from Phase 1 were analyzed as a group.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | RT+TMZ+HCQ Phase 1 | Phse I: daily Hydroxychloroquine (HCQ) on 1st day of RT and concomitant TMZ 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. then every 4 weeks will be cycle of mono therapy of HCQ daily. cohorts of three pts: dose levels: 200, 400, 600, 800mg. NO dose escalation beyond 800mg. 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 temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ TMZ days 1-5 150-20mg/m2 cycles 1-6 pharmacological study/Correlative 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 Radiation 6weeks during initiation cycle Monday - Friday |
| BG001 | RT+TMZ+HCQ Phase 2 | Daily hydroxychloroquine (HCQ) (MTD 600mg) on 1st day of RT and temozolomide for 6wks during RT. After 6 wks, 4 wkd of HCQ alone daily. this will 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. temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ TMZ D1-5 150-20mg/m2 cycles 1-6 pharmacological study/Correlative study: Seven samples in total collected baseline, initiation cycle -week3-4, week9-10, Maintenance Cycle 1 Week 4 (C1W4), Cycle2 Week4, Cycle3 Week4, Cycle6 Week4 Radiation 6weeks during initiation cycle Monday - Friday Pts will continue on treatment unti/tumor progression. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Full Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Karnofsky Performance Status | The Karnofsky Performance Score (KPS) measures individual's functional impairment to assess prognosis. Score ranges from 0-100 with a lower score reflecting a worse prognosis. KPS is categorized as follows: 0-40= Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly; 50-70= unable to work; able to live at home and care for most personal needs; varying amount of assistance needed; 80-100= able to carry on normal activity and to work; no special care needed. KPS >=60 is part of eligibility criteria for this study. | Count of Participants | Participants |
| |||||||||||||||
| Surgical Procedure | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | (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. | Cohort 200mg - 3 subjects ; cohort 400mg - 7 subjects; 600mg - 3 subjects; 800mg - 3 subjects | Posted | Count of Participants | Participants | 10 weeks |
|
|
| ||||||||||||||||||||||||||||
| Primary | (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) | 1/7 subjects from the 400mg cohort only received 70% of expected dose, therefore this subject was not used for toxicity analysis | Posted | Count of Participants | Participants | 10 weeks |
| ||||||||||||||||||||||||||||||
| Primary | (Phase II) Overall Survival | Number of months alive after end of study participation | Only Phase 2 participants were assessed for this outcome measure. | Posted | Median | 95% Confidence Interval | months | 2 years |
|
| ||||||||||||||||||||||||||||
| Secondary | (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 | Only participants from Phase II were assessed for this outcome measure. | Posted | Count of Participants | Participants | up to 2 years |
|
| |||||||||||||||||||||||||||||
| Secondary | 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. | Only 40 participants had at least 2 PBMC samples that were amenable to EM, which was required to assess this outcome measure. | Posted | Count of Participants | Participants | up to 9 weeks |
|
| |||||||||||||||||||||||||||||
| Secondary | 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. | Only participants who had at least 2 PBMC samples that were amenable to EM were assessed for this outcome measure | Posted | Count of Participants | Participants | up to 9 weeks |
|
| |||||||||||||||||||||||||||||
| Secondary | 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. | Only participants from Phase II were assessed for this outcome measure. Data was not collected from 4/76 participants. | Posted | Mean | Full Range | hour | up to 276 days |
| |||||||||||||||||||||||||||||
| Secondary | 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. | Only participants from Phase II were assessed for this outcome measure. Data was not collected from 4/76 participants. | Posted | Mean | Full Range | L/hr | up to 276 days |
| |||||||||||||||||||||||||||||
| Secondary | 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. | Only participants from Phase II were assessed for this outcome measure. Data was not collected from 4/76 participants. | Posted | Mean | Full Range | Liters | up to 276 days |
| |||||||||||||||||||||||||||||
| Secondary | 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. | Only participants from Phase II were assessed for this outcome measure. Data was not collected from 4/76 participants. | Posted | Mean | Full Range | Liters | up to 276 days |
| |||||||||||||||||||||||||||||
| Secondary | 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. | Only participants from Phase II were assessed for this outcome measure. Data was not collected from 4/76 participants. | Posted | Mean | Full Range | hours | up to 276 days |
|
3 years
Adverse events not serious are defined as having Grade 1 and Grade 2 severity
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Phase 1: RT+TMZ+HCQ - 200mg | Daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Dose of HCQ is 200mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. -Initiation Phase temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) 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 Radiation: Radiation during the first six weeks of treatment Monday-Friday | 0 | 3 | 1 | 3 | 3 | 3 |
| EG001 | Phase 1: RT+TMZ+HCQ - 400mg | Daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Dose of HCQ is 400mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. -Initiation Phase temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) 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 Radiation: Radiation during the first six weeks of treatment Monday-Friday | 0 | 7 | 7 | 7 | 7 | 7 |
| EG002 | Phase 1: RT+TMZ+HCQ - 600mg | Daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Dose of HCQ is 600mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. -Initiation Phase temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) 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 Radiation: Radiation during the first six weeks of treatment Monday-Friday | 0 | 3 | 3 | 3 | 3 | 3 |
| EG003 | Phase 1: RT+TMZ+HCQ - 800mg | Daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Dose of HCQ is 800mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. -Initiation Phase temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) 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 Radiation: Radiation during the first six weeks of treatment Monday-Friday | 0 | 3 | 3 | 3 | 3 | 3 |
| EG004 | Phase 2: RT+TMZ+HCQ - MTD 600mg | Daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Dose of HCQ is 600mg MTD. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. -Initiation Phase temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) 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 Radiation: Radiation during the first six weeks of treatment Monday-Friday | 0 | 76 | 53 | 76 | 76 | 76 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| abdominal pain | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| alanine aminotransferase increased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| alkaline phosphatase increased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| anemia | Blood and lymphatic system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| anorexia | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| blood bilirubin increased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| constipation | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| decreased depth perception | Eye disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| fatigue | General disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| febrile neutropenia | Blood and lymphatic system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| generalized muscle weakness | Musculoskeletal and connective tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| hemolysis | Blood and lymphatic system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| hyperkalemia | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| hyperuricemia | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| other | Infections and infestations | CTCAE 3.0 | Non-systematic Assessment | strep bovis (sepsis) |
|
| lymphocyte count decreased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| nausea | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| neutrophil count decreased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| rash maculo-papular | Skin and subcutaneous tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| white blood cell count decreased | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| platelet count decreased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| abdominal distension | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| mood alteration | Psychiatric disorders | CTCAE 3.0 | Non-systematic Assessment | agitation |
|
| alanine aminotransferase increased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| alkaline phosphatase increased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| alopecia | Skin and subcutaneous tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| anemia | Blood and lymphatic system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| anorexia | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| anxiety | Psychiatric disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| aspartate aminotransferase increased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| ataxia | Nervous system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| bloating | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| blood bilirubin increased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| bruising | Injury, poisoning and procedural complications | CTCAE 3.0 | Non-systematic Assessment |
| |
| blurred vision | Eye disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| chills | General disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| constipation | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| creatinine increased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| depression | Psychiatric disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| diarrhea | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| dry skin | Skin and subcutaneous tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| dysarthria | Nervous system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| dizziness | Nervous system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| dysgeusia | Nervous system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| dyspepsia | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| dyspnea | Respiratory, thoracic and mediastinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| edema limbs | General disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| epistaxis | Respiratory, thoracic and mediastinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| erythema multiforme | Skin and subcutaneous tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| esophageal pain | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| other | Eye disorders | CTCAE 3.0 | Non-systematic Assessment | general disorder in right eye |
|
| fatigue | General disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| feber | General disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| gastric hemorrhage | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| gastroesophageal reflux disease | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| generalized muscle weakness | Musculoskeletal and connective tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| headache | Nervous system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| hyperkalemia | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| hyperuricemia | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| hypocalcemia | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| hypokalemia | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| hypomagnesemia | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| hyponatremia | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment | 0 |
|
| hypotension | Vascular disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| other | Investigations | CTCAE 3.0 | Non-systematic Assessment | herpes zoster |
|
| other | Infections and infestations | CTCAE 3.0 | Non-systematic Assessment | thrush |
|
| insomnia | Psychiatric disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| irritability | Psychiatric disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| lipase increased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| lymphocyte count decreased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| malaise | General disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| memory impairment | Nervous system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| mucositis oral | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| muscle weakness lower limb | Musculoskeletal and connective tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| nausea | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| neutrophil count decreased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| pain | General disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| pain in extremity | Musculoskeletal and connective tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| peripheral sensory neuropathy | Nervous system disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| photosensitivity | Skin and subcutaneous tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| purpura | Skin and subcutaneous tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| rash acneiform | Skin and subcutaneous tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| platelet count decreased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| rash maculo-papular | Skin and subcutaneous tissue disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| serum amylase increased | Investigations | CTCAE 3.0 | Non-systematic Assessment |
| |
| stomach pain | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| vomiting | Gastrointestinal disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| weight loss | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
| |
| white blood cell count decreased | Metabolism and nutrition disorders | CTCAE 3.0 | Non-systematic Assessment |
|
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director of ABTC | Adult Brain Tumor Consortium | 410-955-3657 | jfisher@jhmi.edu |
| ID | Term |
|---|---|
| D016543 | Central Nervous System Neoplasms |
| D005909 | Glioblastoma |
| D018316 | Gliosarcoma |
| ID | Term |
|---|---|
| D009423 | Nervous System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D009422 | Nervous System Diseases |
| D001254 | Astrocytoma |
| D005910 | Glioma |
| D018302 | Neoplasms, Neuroepithelial |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009380 | Neoplasms, Nerve Tissue |
Not provided
Not provided
| ID | Term |
|---|---|
| D006886 | Hydroxychloroquine |
| D000077204 | Temozolomide |
| D011827 | Radiation |
| ID | Term |
|---|---|
| D002738 | Chloroquine |
| D000634 | Aminoquinolines |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D003606 | Dacarbazine |
| D014226 | Triazenes |
| D009930 | Organic Chemicals |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D055585 | Physical Phenomena |
Not provided
Not provided
| Male |
|
| 90 |
|
| 80 |
|
| 70 |
|
| 60 |
|
| Craniotomy |
|
|
| 600mg |
|
|
| 800mg |
|
|
| OG002 | Phase 1: RT+TMZ+HCQ - 600mg | Daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Dose of HCQ is 600mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. -Initiation Phase temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) 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 Radiation: Radiation during the first six weeks of treatment Monday-Friday |
| OG003 | Phase 1: RT+TMZ+HCQ - 800mg | Daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Dose of HCQ is 800mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. -Initiation Phase temozolomide: TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle) 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 Radiation: Radiation during the first six weeks of treatment Monday-Friday |
|
|
|
|
|
|
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|
| Units | Counts |
|---|
| Participants |
|
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|