Hydroxychloroquine, Radiation, and Temozolomide Treating Patients With Newly Diagnosed Glioblastoma Multiforme
Study Details
Study Description
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 |
|---|---|---|
|
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.
Study Design
Arms and Interventions
| 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:
Drug: temozolomide
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Other Names:
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:
Radiation: Radiation
Radiation during the first six weeks of treatment Monday-Friday
Other Names:
|
| 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:
Drug: temozolomide
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Other Names:
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:
Radiation: Radiation
Radiation during the first six weeks of treatment Monday-Friday
Other Names:
|
| 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:
Drug: temozolomide
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Other Names:
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:
Radiation: Radiation
Radiation during the first six weeks of treatment Monday-Friday
Other Names:
|
| 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:
Drug: temozolomide
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Other Names:
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:
Radiation: Radiation
Radiation during the first six weeks of treatment Monday-Friday
Other Names:
|
| 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:
Drug: temozolomide
TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)
Other Names:
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:
Radiation: Radiation
Radiation during the first six weeks of treatment Monday-Friday
Other Names:
|
Outcome Measures
Primary Outcome Measures
- (Phase I) Maximum Tolerated Dose (MTD) of Hydroxychloroquine (HCQ) [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) [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 [2 years]
Number of months alive after end of study participation
Secondary Outcome Measures
- (Phase II) Number of Participants With Grade 3 and 4 Toxicity [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
- Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition [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.
- Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition in Relation to Maximal Concentration (Cmax) of HCQ [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.
- Pharmacokinetics (PK) of Hydroxychloroquine as Measured by Lag Time (Tlag) [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.
- PK of Hydroxychloroquine as Measured by Oral Clearance (Liters/Hour) From Central Compartment (CL/F) [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.
- PK of Hydroxychloroquine as Measured by Volume of Distribution of Central Compartment (V/F) [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.
- PK of Hydroxychloroquine as Measured by Distribution Volume of Peripheral Compartment (V2/F) [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.
- PK of Hydroxychloroquine as Measured by First-order Absorption Rate Constant (Ka) [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.
Eligibility Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alabama at Birmingham Comprehensive Cancer Center | Birmingham | Alabama | United States | 35294 |
| 2 | H. Lee Moffitt Cancer Center and Research Institute at University of South Florida | Tampa | Florida | United States | 33612-9497 |
| 3 | Winship Cancer Institute of Emory University | Atlanta | Georgia | United States | 30322 |
| 4 | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore | Maryland | United States | 21231-2410 |
| 5 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
| 6 | Josephine Ford Cancer Center at Henry Ford Hospital | Detroit | Michigan | United States | 48202 |
| 7 | Wake Forest University Comprehensive Cancer Center | Winston-Salem | North Carolina | United States | 27157-1096 |
| 8 | Case Comprehensive Cancer Center | Cleveland | Ohio | United States | 44106-5065 |
| 9 | 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
- Study Chair: Myrna Rosenfeld, MD, PhD, New Approaches to Brain Tumor Therapy/Adult Brain Tumor Consortium
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NABTT-0603
- U01CA062475
- ABTC-0603
- CDR0000549734
- NA_00012420
Study Results
Participant Flow
| Recruitment Details | This study was conducted by the Adult Brain Tumor Consortium (ABTC) and patients were recruited from the consortium members outpatient centers. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | RT+TMZ+HCQ Phase 1 - 200 mg | RT+TMZ+HCQ Phase 1 - 400 mg | RT+TMZ+HCQ Phase 1 - 600 mg | RT+TMZ+HCQ Phase 1 - 800 mg | RT+TMZ+HCQ Phase 2 - MTD 600 mg |
|---|---|---|---|---|---|
| Arm/Group Description | 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 | 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 | 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 | 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 | 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 |
| Period Title: Overall Study | |||||
| STARTED | 3 | 7 | 3 | 3 | 76 |
| COMPLETED | 2 | 6 | 3 | 3 | 76 |
| NOT COMPLETED | 1 | 1 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | RT+TMZ+HCQ Phase 1 | RT+TMZ+HCQ Phase 2 | Total |
|---|---|---|---|
| Arm/Group Description | 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 | 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. | Total of all reporting groups |
| Overall Participants | 16 | 76 | 92 |
| Age (years) [Median (Full Range) ] | |||
| Median (Full Range) [years] |
55
|
59
|
58
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
4
25%
|
30
39.5%
|
34
37%
|
| Male |
12
75%
|
46
60.5%
|
58
63%
|
| Karnofsky Performance Status (Count of Participants) | |||
| 100 |
5
31.3%
|
15
19.7%
|
20
21.7%
|
| 90 |
7
43.8%
|
31
40.8%
|
38
41.3%
|
| 80 |
3
18.8%
|
18
23.7%
|
21
22.8%
|
| 70 |
1
6.3%
|
10
13.2%
|
11
12%
|
| 60 |
0
0%
|
2
2.6%
|
2
2.2%
|
| Surgical Procedure (Count of Participants) | |||
| Biopsy |
6
37.5%
|
18
23.7%
|
24
26.1%
|
| Craniotomy |
10
62.5%
|
58
76.3%
|
68
73.9%
|
Outcome Measures
| Title | (Phase I) Maximum Tolerated Dose (MTD) of Hydroxychloroquine (HCQ) |
|---|---|
| Description | 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. |
| Time Frame | 10 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Cohort 200mg - 3 subjects ; cohort 400mg - 7 subjects; 600mg - 3 subjects; 800mg - 3 subjects |
| Arm/Group Title | Phase 1 - Dose Finding |
|---|---|
| Arm/Group Description | 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. 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, 600mg 800mg. NO dose escalation beyond 800mg. temozolomide: TMZ daily 75mg/m2 for 6weeks with RT+HCQ TMZ Maintenance cycle 1-6 150-200mg/m2 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 (C2W4), Cycle3 Week4 (C3W4), Cycle6 Week4 (C6W4) Radiation 6weeks during initation cycle Monday - Friday |
| Measure Participants | 16 |
| 200mg |
3
18.8%
|
| 400mg |
7
43.8%
|
| 600mg |
3
18.8%
|
| 800mg |
0
0%
|
| Title | (Phase I) Number of Participants Who Experienced Dose Limiting Toxicity (DLT) |
|---|---|
| Description | 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) |
| Time Frame | 10 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| 1/7 subjects from the 400mg cohort only received 70% of expected dose, therefore this subject was not used for toxicity analysis |
| Arm/Group Title | Phase 1: RT+TMZ+HCQ - 200mg | Phase 1: RT+TMZ+HCQ - 400mg | Phase 1: RT+TMZ+HCQ - 600mg | Phase 1: RT+TMZ+HCQ - 800mg |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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 | 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 | 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 |
| Measure Participants | 3 | 6 | 3 | 3 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
3
NaN
|
| Title | (Phase II) Overall Survival |
|---|---|
| Description | Number of months alive after end of study participation |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only Phase 2 participants were assessed for this outcome measure. |
| Arm/Group Title | Phase 2: RT + TMZ + HCQ |
|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 76 |
| Median (95% Confidence Interval) [months] |
15.6
|
| Title | (Phase II) Number of Participants With Grade 3 and 4 Toxicity |
|---|---|
| Description | 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 |
| Time Frame | up to 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only participants from Phase II were assessed for this outcome measure. |
| Arm/Group Title | Phase 2: RT + TMZ + HCQ |
|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 76 |
| Count of Participants [Participants] |
22
137.5%
|
| Title | Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition |
|---|---|
| Description | 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. |
| Time Frame | up to 9 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only 40 participants had at least 2 PBMC samples that were amenable to EM, which was required to assess this outcome measure. |
| Arm/Group Title | Phase 2: RT + TMZ + HCQ |
|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 40 |
| AV increase |
22
137.5%
|
| No AV increase |
18
112.5%
|
| Title | Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition in Relation to Maximal Concentration (Cmax) of HCQ |
|---|---|
| Description | 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. |
| Time Frame | up to 9 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only participants who had at least 2 PBMC samples that were amenable to EM were assessed for this outcome measure |
| Arm/Group Title | HCQ Cmax <= 1785 ng/mL | HCQ Cmax>1785 ng/mL |
|---|---|---|
| Arm/Group Description | Participants from Phase I and II with a HCQ Cmax <= 1785 ng/mL Cmax calculated based on 7 samples collected (baseline, initiation Cycle(C) W3-4, W9-10, Maintenance C1W4, C2W4, C3W4, C6W4) | Participants from Phase I and II with a HCQ Cmax>1785 ng/mL Cmax calculated based on 7 samples collected (baseline, initiation Cycle(C) W3-4, W9-10, Maintenance C1W4, C2W4, C3W4, C6W4) |
| Measure Participants | 22 | 18 |
| AV Increase |
10
62.5%
|
12
15.8%
|
| No AV Increase |
12
75%
|
6
7.9%
|
| Title | Pharmacokinetics (PK) of Hydroxychloroquine as Measured by Lag Time (Tlag) |
|---|---|
| Description | 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. |
| Time Frame | up to 276 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only participants from Phase II were assessed for this outcome measure. Data was not collected from 4/76 participants. |
| Arm/Group Title | Phase 2: RT + TMZ + HCQ |
|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 72 |
| Mean (Full Range) [hour] |
1.06
|
| Title | PK of Hydroxychloroquine as Measured by Oral Clearance (Liters/Hour) From Central Compartment (CL/F) |
|---|---|
| Description | 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. |
| Time Frame | up to 276 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only participants from Phase II were assessed for this outcome measure. Data was not collected from 4/76 participants. |
| Arm/Group Title | Phase 2: RT + TMZ + HCQ |
|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 72 |
| Mean (Full Range) [L/hr] |
11.85
|
| Title | PK of Hydroxychloroquine as Measured by Volume of Distribution of Central Compartment (V/F) |
|---|---|
| Description | 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. |
| Time Frame | up to 276 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only participants from Phase II were assessed for this outcome measure. Data was not collected from 4/76 participants. |
| Arm/Group Title | Phase 2: RT + TMZ + HCQ |
|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 72 |
| Mean (Full Range) [Liters] |
483.96
|
| Title | PK of Hydroxychloroquine as Measured by Distribution Volume of Peripheral Compartment (V2/F) |
|---|---|
| Description | 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. |
| Time Frame | up to 276 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only participants from Phase II were assessed for this outcome measure. Data was not collected from 4/76 participants. |
| Arm/Group Title | Phase 2: RT + TMZ + HCQ |
|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 72 |
| Mean (Full Range) [Liters] |
963
|
| Title | PK of Hydroxychloroquine as Measured by First-order Absorption Rate Constant (Ka) |
|---|---|
| Description | 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. |
| Time Frame | up to 276 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only participants from Phase II were assessed for this outcome measure. Data was not collected from 4/76 participants. |
| Arm/Group Title | Phase 2: RT + TMZ + HCQ |
|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 72 |
| Mean (Full Range) [hours] |
0.51
|
Adverse Events
| Time Frame | 3 years | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse events not serious are defined as having Grade 1 and Grade 2 severity | |||||||||
| Arm/Group Title | Phase 1: RT+TMZ+HCQ - 200mg | Phase 1: RT+TMZ+HCQ - 400mg | Phase 1: RT+TMZ+HCQ - 600mg | Phase 1: RT+TMZ+HCQ - 800mg | Phase 2: RT+TMZ+HCQ - MTD 600mg | |||||
| Arm/Group Description | 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 | 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 | 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 | 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 | 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 | |||||
All Cause Mortality |
||||||||||
| Phase 1: RT+TMZ+HCQ - 200mg | Phase 1: RT+TMZ+HCQ - 400mg | Phase 1: RT+TMZ+HCQ - 600mg | Phase 1: RT+TMZ+HCQ - 800mg | Phase 2: RT+TMZ+HCQ - MTD 600mg | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/3 (0%) | 0/7 (0%) | 0/3 (0%) | 0/3 (0%) | 0/76 (0%) | |||||
Serious Adverse Events |
||||||||||
| Phase 1: RT+TMZ+HCQ - 200mg | Phase 1: RT+TMZ+HCQ - 400mg | Phase 1: RT+TMZ+HCQ - 600mg | Phase 1: RT+TMZ+HCQ - 800mg | Phase 2: RT+TMZ+HCQ - MTD 600mg | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/3 (33.3%) | 7/7 (100%) | 3/3 (100%) | 3/3 (100%) | 53/76 (69.7%) | |||||
| Blood and lymphatic system disorders | ||||||||||
| anemia | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 1/3 (33.3%) | 1 | 3/3 (100%) | 4 | 3/76 (3.9%) | 3 |
| febrile neutropenia | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 1/3 (33.3%) | 1 | 0/76 (0%) | 0 |
| hemolysis | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| Eye disorders | ||||||||||
| decreased depth perception | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| Gastrointestinal disorders | ||||||||||
| abdominal pain | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| constipation | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| nausea | 1/3 (33.3%) | 1 | 1/7 (14.3%) | 1 | 1/3 (33.3%) | 1 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| General disorders | ||||||||||
| fatigue | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| Infections and infestations | ||||||||||
| other | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/3 (33.3%) | 1 | 0/76 (0%) | 0 |
| Investigations | ||||||||||
| alanine aminotransferase increased | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 2/76 (2.6%) | 2 |
| alkaline phosphatase increased | 0/3 (0%) | 0 | 2/7 (28.6%) | 2 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 6/76 (7.9%) | 6 |
| blood bilirubin increased | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| lymphocyte count decreased | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| neutrophil count decreased | 0/3 (0%) | 0 | 2/7 (28.6%) | 3 | 1/3 (33.3%) | 2 | 2/3 (66.7%) | 2 | 8/76 (10.5%) | 10 |
| platelet count decreased | 0/3 (0%) | 0 | 1/7 (14.3%) | 2 | 0/3 (0%) | 0 | 3/3 (100%) | 4 | 9/76 (11.8%) | 11 |
| Metabolism and nutrition disorders | ||||||||||
| anorexia | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| hyperkalemia | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| hyperuricemia | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| white blood cell count decreased | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 1/3 (33.3%) | 1 | 2/3 (66.7%) | 2 | 8/76 (10.5%) | 8 |
| Musculoskeletal and connective tissue disorders | ||||||||||
| generalized muscle weakness | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||||
| rash maculo-papular | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 9/76 (11.8%) | 9 |
Other (Not Including Serious) Adverse Events |
||||||||||
| Phase 1: RT+TMZ+HCQ - 200mg | Phase 1: RT+TMZ+HCQ - 400mg | Phase 1: RT+TMZ+HCQ - 600mg | Phase 1: RT+TMZ+HCQ - 800mg | Phase 2: RT+TMZ+HCQ - MTD 600mg | ||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/3 (100%) | 7/7 (100%) | 3/3 (100%) | 3/3 (100%) | 76/76 (100%) | |||||
| Blood and lymphatic system disorders | ||||||||||
| anemia | 3/3 (100%) | 3 | 3/7 (42.9%) | 4 | 1/3 (33.3%) | 1 | 3/3 (100%) | 4 | 37/76 (48.7%) | 38 |
| Eye disorders | ||||||||||
| blurred vision | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 2/76 (2.6%) | 2 |
| other | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| Gastrointestinal disorders | ||||||||||
| abdominal distension | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| bloating | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| constipation | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 1/3 (33.3%) | 1 | 1/3 (33.3%) | 1 | 12/76 (15.8%) | 12 |
| diarrhea | 0/3 (0%) | 0 | 2/7 (28.6%) | 2 | 0/3 (0%) | 0 | 2/3 (66.7%) | 2 | 14/76 (18.4%) | 14 |
| dyspepsia | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 5/76 (6.6%) | 5 |
| esophageal pain | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| gastric hemorrhage | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| gastroesophageal reflux disease | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 2/76 (2.6%) | 2 |
| mucositis oral | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 2/76 (2.6%) | 2 |
| nausea | 1/3 (33.3%) | 1 | 5/7 (71.4%) | 6 | 1/3 (33.3%) | 1 | 0/3 (0%) | 0 | 35/76 (46.1%) | 38 |
| stomach pain | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 2/76 (2.6%) | 2 |
| vomiting | 0/3 (0%) | 0 | 2/7 (28.6%) | 2 | 1/3 (33.3%) | 1 | 2/3 (66.7%) | 2 | 13/76 (17.1%) | 13 |
| General disorders | ||||||||||
| chills | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/3 (0%) | 0 | 2/76 (2.6%) | 2 |
| edema limbs | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| fatigue | 0/3 (0%) | 0 | 5/7 (71.4%) | 6 | 2/3 (66.7%) | 2 | 2/3 (66.7%) | 2 | 44/76 (57.9%) | 47 |
| feber | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| malaise | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| pain | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| Infections and infestations | ||||||||||
| other | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| Injury, poisoning and procedural complications | ||||||||||
| bruising | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| Investigations | ||||||||||
| alanine aminotransferase increased | 0/3 (0%) | 0 | 2/7 (28.6%) | 2 | 1/3 (33.3%) | 1 | 0/3 (0%) | 0 | 14/76 (18.4%) | 14 |
| alkaline phosphatase increased | 0/3 (0%) | 0 | 2/7 (28.6%) | 2 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 6/76 (7.9%) | 6 |
| aspartate aminotransferase increased | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 11/76 (14.5%) | 11 |
| blood bilirubin increased | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 4/76 (5.3%) | 4 |
| creatinine increased | 1/3 (33.3%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 2/76 (2.6%) | 2 |
| other | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 2/76 (2.6%) | 2 |
| lipase increased | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| lymphocyte count decreased | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 2 |
| neutrophil count decreased | 1/3 (33.3%) | 1 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 10/76 (13.2%) | 10 |
| platelet count decreased | 1/3 (33.3%) | 1 | 3/7 (42.9%) | 3 | 2/3 (66.7%) | 2 | 2/3 (66.7%) | 2 | 30/76 (39.5%) | 32 |
| serum amylase increased | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| Metabolism and nutrition disorders | ||||||||||
| anorexia | 2/3 (66.7%) | 2 | 2/7 (28.6%) | 2 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 15/76 (19.7%) | 15 |
| hyperkalemia | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| hyperuricemia | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| hypocalcemia | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/3 (33.3%) | 1 | 3/76 (3.9%) | 3 |
| hypokalemia | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| hypomagnesemia | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| hyponatremia | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 3/76 (3.9%) | 3 |
| weight loss | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 2/76 (2.6%) | 2 |
| white blood cell count decreased | 1/3 (33.3%) | 1 | 2/7 (28.6%) | 4 | 2/3 (66.7%) | 2 | 2/3 (66.7%) | 3 | 27/76 (35.5%) | 27 |
| Musculoskeletal and connective tissue disorders | ||||||||||
| generalized muscle weakness | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| muscle weakness lower limb | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| pain in extremity | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| Nervous system disorders | ||||||||||
| ataxia | 1/3 (33.3%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| dysarthria | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| dizziness | 2/3 (66.7%) | 2 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| dysgeusia | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 5/76 (6.6%) | 5 |
| headache | 2/3 (66.7%) | 2 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 2/76 (2.6%) | 2 |
| memory impairment | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| peripheral sensory neuropathy | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| Psychiatric disorders | ||||||||||
| mood alteration | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| anxiety | 1/3 (33.3%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| depression | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| insomnia | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| irritability | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||
| dyspnea | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| epistaxis | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/3 (33.3%) | 1 | 0/76 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||||
| alopecia | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| dry skin | 1/3 (33.3%) | 1 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| erythema multiforme | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| photosensitivity | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| Pruritus | 1/3 (33.3%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 7/76 (9.2%) | 7 |
| purpura | 1/3 (33.3%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 0/76 (0%) | 0 |
| rash acneiform | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
| rash maculo-papular | 0/3 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 1/3 (33.3%) | 1 | 9/76 (11.8%) | 10 |
| Vascular disorders | ||||||||||
| hypotension | 0/3 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/3 (0%) | 0 | 1/76 (1.3%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Director of ABTC |
|---|---|
| Organization | Adult Brain Tumor Consortium |
| Phone | 410-955-3657 |
| jfisher@jhmi.edu |
- NABTT-0603
- U01CA062475
- ABTC-0603
- CDR0000549734
- NA_00012420