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Adavosertib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma

Study Purpose

This phase I trial studies the side effects and best dose of adavosertib when given together with radiation therapy and temozolomide in treating patients with newly diagnosed or glioblastoma that has come back. Adavosertib 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 and shrink tumors. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving adavosertib, radiation therapy, and temozolomide may work better in treating patients with newly diagnosed or recurrent glioblastoma.

Recruitment Criteria

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

Accepts Healthy Volunteers
No

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


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Study Type
Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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 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

Trial Details

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

Trial ID:
NCT01849146

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase
Phase 1

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Lead Sponsor
National Cancer Institute (NCI)

The person who is responsible for the scientific and technical direction of the entire clinical study.

Principal Investigator
Brian Alexander
Principal Investigator Affiliation National Cancer Institute (NCI)

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Agency Class
NIH
Overall Status Recruiting
Countries United States

The disease, disorder, syndrome, illness, or injury that is being studied.

Conditions
Adult Glioblastoma, Recurrent Glioblastoma
Additional Details

PRIMARY OBJECTIVES:

  • I. To determine the maximum tolerated doses (MTD) of adavosertib (AZD1775 [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 the pharmacodynamic effects of AZD1775 on tumor through immunohistochemistry (IHC) analysis of pRb (S807/811), proliferation (e.g. Ki-67), pCDC2, Wee1, and apoptosis (e.g. cleaved caspase 3) on resected tumors exposed to drug.
  • IV. To characterize MGMT methylation and P53 pathway status, also P-gp and wee1 expression levels in patients with newly diagnosed glioblastoma treated with standard therapy in combination with AZD1775 (MK-1775).
  • V. To explore and analyze adaptive resistance mechanisms to AZD1775 using proteogenomics, and connect this data to spatially resolved drug distribution through targeted, imaging-based quantification of drug efficacy and tumor response.
OUTLINE: This is a dose-escalation study of adavosertib. Patients are assigned to 1 of 2 treatment arms. ARM I: INITIATION COURSE: Patients receive adavosertib orally (PO) on days 1, 3, and 5 or days 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 adavosertib PO QD on days 1, 3, and 5 or 1-5 weekly, 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.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Birmingham, Alabama

Status

Suspended

Address

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, 35233

Los Angeles, California

Status

Suspended

Address

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095

UCSF Medical Center-Parnassus, San Francisco, California

Status

Suspended

Address

UCSF Medical Center-Parnassus

San Francisco, California, 94143

Baltimore, Maryland

Status

Recruiting

Address

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287

Site Contact

Site Public Contact

jhcccro@jhmi.edu

410-955-8804

Boston, Massachusetts

Status

Recruiting

Address

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114

Site Contact

Site Public Contact

877-726-5130

Dana-Farber Cancer Institute, Boston, Massachusetts

Status

Recruiting

Address

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215

Site Contact

Site Public Contact

877-442-3324

Henry Ford Hospital, Detroit, Michigan

Status

Recruiting

Address

Henry Ford Hospital

Detroit, Michigan, 48202

Site Contact

Site Public Contact

313-916-1784

Memorial Sloan Kettering Cancer Center, New York, New York

Status

Suspended

Address

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

Wake Forest University Health Sciences, Winston-Salem, North Carolina

Status

Suspended

Address

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157

Cleveland Clinic Foundation, Cleveland, Ohio

Status

Suspended

Address

Cleveland Clinic Foundation

Cleveland, Ohio, 44195

Philadelphia, Pennsylvania

Status

Suspended

Address

University of Pennsylvania/Abramson Cancer Center

Philadelphia, Pennsylvania, 19104

Pittsburgh, Pennsylvania

Status

Suspended

Address

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232

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