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

NCT00486603 | Completed Phase 1 Results DMC

• 5 other identifiers: NABTT-0603U01CA062475ABTC-0603CDR0000549734NA_00012420
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 9

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.

Conditions

Brain and Central Nervous System Tumors

Keywords

adult glioblastoma; adult gliosarcoma; adult giant cell glioblastoma

Outcome Measures

Primary Outcomes (3)

• (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

Secondary Outcomes (8)

• (Phase II) Number of Participants With Grade 3 and 4 Toxicity

  up to 2 years

• Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition

  up to 9 weeks

• Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition in Relation to Maximal Concentration (Cmax) of HCQ

  up to 9 weeks

• Pharmacokinetics (PK) of Hydroxychloroquine as Measured by Lag Time (Tlag)

  up to 276 days

• PK of Hydroxychloroquine as Measured by Oral Clearance (Liters/Hour) From Central Compartment (CL/F)

  up to 276 days

Study Arms (5)

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)

Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation

Phase 1: RT+TMZ+HCQ 400 mg

EXPERIMENTAL

Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 400 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days. cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg. Other: pharmacological study (PK) pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1 Radiation (RT)

Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation

Phase 1: RT+TMZ+HCQ 600 mg

EXPERIMENTAL

Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 600 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days. cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg. Other: pharmacological study (PK) pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1 Radiation (RT)

Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation

Phase 1: RT+TMZ+HCQ 800 mg

EXPERIMENTAL

Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 800 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days. cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg. Other: pharmacological study (PK) pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1 Radiation (RT)

Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation

Phase 2: RT + TMZ + HCQ MTD

EXPERIMENTAL

Phse 2: daily hydroxychloroquine (HCQ) (MTD 600mg) on 1st day of RT and concomitant temozolomide for 6wks during RT. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days. Other: pharmacological study (PK) Pts will continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 2 Radiation (RT)

Drug: hydroxychloroquine; Drug: temozolomide; Other: pharmacological study; Radiation: Radiation

Interventions

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

Also known as: Plaquenil, HCQ

Phase 1: RT+TMZ+HCQ 200 mg; Phase 1: RT+TMZ+HCQ 400 mg; Phase 1: RT+TMZ+HCQ 600 mg; Phase 1: RT+TMZ+HCQ 800 mg; Phase 2: RT + TMZ + HCQ MTD

temozolomide DRUG

TMZ daily 75mg/m2 for 6wks with RT+HCQ (TMZ is given only during Initiation cycle)

Also known as: Temodar, TMZ

Phase 1: RT+TMZ+HCQ 200 mg; Phase 1: RT+TMZ+HCQ 400 mg; Phase 1: RT+TMZ+HCQ 600 mg; Phase 1: RT+TMZ+HCQ 800 mg; Phase 2: RT + TMZ + HCQ MTD

pharmacological 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

Also known as: PK, correlative studies

Phase 1: RT+TMZ+HCQ 200 mg; Phase 1: RT+TMZ+HCQ 400 mg; Phase 1: RT+TMZ+HCQ 600 mg; Phase 1: RT+TMZ+HCQ 800 mg; Phase 2: RT + TMZ + HCQ MTD

Radiation RADIATION

Radiation during the first six weeks of treatment Monday-Friday

Also known as: RT

Phase 1: RT+TMZ+HCQ 200 mg; Phase 1: RT+TMZ+HCQ 400 mg; Phase 1: RT+TMZ+HCQ 600 mg; Phase 1: RT+TMZ+HCQ 800 mg; Phase 2: RT + TMZ + HCQ MTD

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• National Cancer Institute (NCI): collaborator

Study Sites (9)

University of Alabama at Birmingham Comprehensive Cancer Center

Birmingham, Alabama, 35294, United States

Location

H. Lee Moffitt Cancer Center and Research Institute at University of South Florida

Tampa, Florida, 33612-9497, United States

Location

Winship Cancer Institute of Emory University

Atlanta, Georgia, 30322, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231-2410, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Josephine Ford Cancer Center at Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Wake Forest University Comprehensive Cancer Center

Winston-Salem, North Carolina, 27157-1096, United States

Location

Case Comprehensive Cancer Center

Cleveland, Ohio, 44106-5065, United States

Location

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104-4283, United States

Location

Related Publications (1)

• 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.

  PMID: 24991840 RESULT

MeSH Terms

Conditions

Central Nervous System Neoplasms; Glioblastoma; Gliosarcoma

Interventions

Hydroxychloroquine; Temozolomide; Radiation

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Physical Phenomena

Results Point of Contact

• Title: Director of ABTC
• Organization: Adult Brain Tumor Consortium

jfisher@jhmi.edu

410-955-3657

Study Officials

• Myrna Rosenfeld, MD, PhD

  New Approaches to Brain Tumor Therapy/Adult Brain Tumor Consortium

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2007
• First Posted: June 14, 2007
• Study Start: October 29, 2007
• Primary Completion: June 1, 2013
• Study Completion: January 1, 2014
• Last Updated: July 10, 2019
• Results First Posted: July 10, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)