WEE1 Inhibitor MK-1775, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma Multiforme
Conditions
Adult Giant Cell Glioblastoma - Adult Glioblastoma - Adult Gliosarcoma - Recurrent Adult Brain Neoplasm
Conditions: official terms
Brain Neoplasms - Glioblastoma - Gliosarcoma
Study Type
Interventional
Study Phase
Phase 1
Study Design
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Intervention
Name: Laboratory Biomarker Analysis Type: Other
Name: Pharmacological Study Type: Other
Name: Radiation Therapy Type: Radiation
Name: Temozolomide Type: Drug
Name: WEE1 Inhibitor MK-1775 Type: Drug
Overall Status
Recruiting
Summary
This phase I trial studies the side effects and best dose of WEE1 inhibitor MK-1775 when given together with radiation therapy and temozolomide in treating patients with newly diagnosed or glioblastoma multiforme that has come back. WEE1 inhibitor MK-1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving WEE1 inhibitor MK-1775 together with radiation therapy and temozolomide may work better in treating glioblastoma multiforme.
Detailed Description
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated doses (MTD) of AZD1775 (MK-1775) (WEE1 inhibitor MK-1775) in combination with the current standard of care (radiotherapy/temozolomide for concomitant therapy and temozolomide for adjuvant therapy) for treating patients with newly diagnosed glioblastoma.

II. To define the MTD of AZD1775 (MK-1775) in combination with 6 weeks of daily (Monday-Friday [M-F]) radiotherapy (RT) and concomitant temozolomide (TMZ) administered at 75 mg/m^2/day in patients with newly diagnosed glioblastoma. (Arm 1) III. To define the MTD of AZD1775 (MK-1775) in combination with adjuvant TMZ administered at 150 mg/m^2/day-200 mg/m^2/day for 5 days every 28 days in patients with glioblastoma after concurrent RT/TMZ. (Arm 2)

SECONDARY OBJECTIVES:

I. To characterize the safety profile of AZD1775 (MK-1775) in combination with RT and concomitant TMZ (Arm 1) and AZD1775 (MK-1775) with adjuvant TMZ (Arm 2) in patients with newly diagnosed glioblastoma.

II. To assess the pharmacokinetic (PK) profile of AZD1775 (MK-1775) in combination with upfront radiation/TMZ and adjuvant TMZ in patients with newly diagnosed glioblastoma.

TERTIARY OBJECTIVES:

I. To determine the intratumoral concentration of AZD1775 (MK-1775) achieved in patients treated with the putative MTD.

II. To characterize the time course of AZD1775 (MK-1775) in extracellular fluid within brain tumors following a single oral dose of drug by microdialysis.

III. To characterize O6-methylguanine deoxyribonucleic acid (DNA)-methyltransferase (MGMT) methylation and tumor protein p53 (P53) pathway status, also P-glycoprotein (P-gp) and wee1 expression levels in patients with newly diagnosed glioblastoma treated with standard therapy in combination with AZD1775 (MK-1775).

OUTLINE: This is a dose-escalation study of WEE1 inhibitor MK-1775. Patients are assigned to 1 of 2 treatment arms.

ARM I:

INITIATION COURSE: Patients receive WEE1 inhibitor MK-1775 orally (PO) on days 1, 3, and 5 or 1-5 weekly and temozolomide PO once daily (QD) for 6 weeks. Patients also undergo concurrent radiation therapy 5 days per week for 6 weeks.

MAINTENANCE COURSES: Beginning in week 10, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive WEE1 inhibitor MK-1775 PO QD on days 1, 3, and 5 or 1-5, and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 2 years and then every 6 months thereafter.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: Inclusion Criteria:

- Patients must have a tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of glioblastoma completed and signed by a pathologist

- 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)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal; if above the institutional upper limit of normal but =< 3 times institutional upper limit of normal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient

- Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60 ml/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Activated partial thromboplastin time (APTT)/partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal

- Patients must be able to provide written informed consent

- Patients must have magnetic resonance imaging (MRI) within 21 days of starting treatment

- Women of childbearing potential must have a negative serum pregnancy test prior to study entry; women of childbearing potential and men must agree to use two birth control methods (either two barrier methods or a barrier method plus a hormonal method) or abstinence prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

- Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; patients with prior malignancies must be disease-free for >= five years

- Patients must be maintained on a stable corticosteroid regimen (no increase for 5 days) prior to the start of treatment

- Patients must be able to swallow whole capsules

- PHASE I PATIENTS:

- Must have histologically proven glioblastoma

- Must have recovered from the immediate post-operative period

- Patients going on Arm 1 or combination dose cohort must not have received prior radiation therapy, chemotherapy, immunotherapy or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, tumor infiltrating lymphocytes [TIL], lymphokine-activated killer [LAK] or gene therapy), or hormonal therapy for their brain tumor; glucocorticoid therapy is allowed

- Patients going on Arm 2 must have received planned treatment with radiation therapy and concomitant temozolomide at least 28 days but no more than 49 days prior to starting treatment on this study; patients must have received at least 80% of planned temozolomide and radiation therapy with no grade 3 or grade 4 toxicity (except lymphopenia) attributed to the temozolomide; Arm 2 patients may not have received any other prior chemotherapy, immunotherapy or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, TIL, LAK or gene therapy), or hormonal therapy for their brain tumor; prior Gliadel wafers are allowed; glucocorticoid therapy is allowed

- INTRATUMORAL DRUG DISTRIBUTION STUDY PATIENTS:

- Patients must have prior histologically proven glioblastoma that is progressive or recurrent following radiation therapy +/- chemotherapy

- Patients must be undergoing repeat surgery that is clinically indicated as determined by their care providers

- Patients must have measurable contrast-enhancing progressive or recurrent glioblastoma by MRI within 21 days of starting treatment; patient must be able to tolerate MRIs

- Patients may have an unlimited number of prior therapy regimens

- Patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible:

- 12 weeks from the completion of radiation

- 6 weeks from a nitrosourea chemotherapy

- 3 weeks from a non-nitrosourea chemotherapy

- 4 weeks from any investigational (not Food and Drug Administration [FDA]-approved) agents

- 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., Tarceva, hydroxychloroquine, bevacizumab, etc.)

Exclusion Criteria:

- Patients receiving any other investigational agents are ineligible

- Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or AZD1775 (MK-1775) are ineligible; the AZD1775 (MK-1775) Investigator brochure and the temozolomide package insert can be referenced for more information

- Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for treatment on this protocol; patients may be on non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs; patients previously treated with EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of AZD1775 (MK-1775)

- Patients may not be on drugs known to be moderate or potent inhibitors/inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4), sensitive substrates of CYP3A4, or substrates of CYP3A4 with narrow therapeutic windows

- Patients may not be on anti-coagulants (warfarin, etc.) other than low-molecular weight heparin (LMWH)

- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible

- Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with AZD1775 (MK-1775)

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
Locations
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Status: Recruiting
Contact: Louis B. Nabors - 205-934-0309
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
Status: Recruiting
Contact: Timothy F. Cloughesy - 888-798-0719
UCSF Medical Center-Parnassus
San Francisco, California, United States
Status: Recruiting
Contact: Jennifer L. Clarke - 877-827-3222
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
Status: Recruiting
Contact: Stuart A. Grossman - 410-955-8804 - jhcccro@jhmi.edu
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Status: Recruiting
Contact: Brian M. Alexander - 617-724-5200
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States
Status: Recruiting
Contact: Brian M. Alexander - 617-724-5200
Henry Ford Hospital
Detroit, Michigan, United States
Status: Recruiting
Contact: Tom Mikkelsen - 313-916-1784
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
Status: Recruiting
Contact: Thomas J. Kaley - 212-639-7202
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States
Status: Recruiting
Contact: Glenn J. Lesser - 336-713-6771
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Status: Recruiting
Contact: David M. Peereboom - 866-223-8100
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, United States
Status: Recruiting
Contact: Arati Desai - 800-474-9892
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
Status: Recruiting
Contact: Frank S. Lieberman - 412-647-8073
Start Date
August 2013
Sponsors
National Cancer Institute (NCI)
Source
National Cancer Institute (NCI)
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page