WEE1 Inhibitor MK-1775, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma Multiforme

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01849146
First received: May 6, 2013
Last updated: September 16, 2014
Last verified: August 2014

May 6, 2013
September 16, 2014
August 2013
December 2014   (final data collection date for primary outcome measure)
  • MTD of WEE1 inhibitor MK-1775 with 6 weeks of RT and temozolomide, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 (Arm I) [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: Yes ]
    Severity and frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experience grade 3 or above toxicities will be estimated, along with 95% confidence intervals by each type of toxicity.
  • MTD of WEE1 inhibitor MK-1775 with adjuvant temozolomide, graded according to the NCI CTCAE v4.0 (Arm II) [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
    Severity and frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experience grade 3 or above toxicities will be estimated, along with 95% confidence intervals by each type of toxicity.
  • Incidence of toxicities, graded according to the NCI CTCAE v4.0 [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: Yes ]
    Severity and frequency of toxicity will be tabulated by the tested dose or doses using descriptive statistics. The proportion of subjects who experience grade 3 or above toxicities will be estimated, along with 95% confidence intervals by each type of toxicity.
Same as current
Complete list of historical versions of study NCT01849146 on ClinicalTrials.gov Archive Site
  • Overall survival [ Time Frame: The time from the date of initial diagnosis to the date of death, assessed up to 2 years ] [ Designated as safety issue: No ]
    Calculated using the Kaplan-Meier method.
  • Progression-free survival [ Time Frame: The time from the date of initial diagnosis to the date progressive disease was defined and also patient was alive, assessed up to 2 years ] [ Designated as safety issue: No ]
    Calculated using the Kaplan-Meier method.
  • Overall survival [ Time Frame: The time from the date of initial diagnosis to the date of death, assessed up to 1 year ] [ Designated as safety issue: No ]
    Calculated using the Kaplan-Meier method.
  • Progression-free survival [ Time Frame: The time from the date of initial diagnosis to the date progressive disease was defined and also patient was alive, assessed up to 1 year ] [ Designated as safety issue: No ]
    Calculated using the Kaplan-Meier method.
  • PK profile of AZD1775 (MK-1775) in combination with radiation and temozolomide and adjuvant TMZ [ Time Frame: Baseline, at 0.5, 1, 2, 4, 6, 8 and 24 hours of weeks 1 and 4 of course 1 (Arm I) and at baseline, 0.5, 1, 2, 4, 6, 8, and 24 hours of course 1 (Arm II) ] [ Designated as safety issue: No ]
    Individual subject plasma concentration-time curves will be analyzed by non-compartmental methods using routines supplied in the WinNonlin Professional Version 5.0 software package (Pharsight Corp., Cary, NC). The geometric mean ± standard deviation of the estimated values of the pharmacokinetic parameter for groups of subjects evaluated at MTD dose level will be calculated. Parametric statistical tests (i.e., single factor analysis of variance, Student's t-test) of pharmacokinetic variables will be performed after logarithmic transformation of the data.
  • Intratumoral AZD1775 (MK-1775) concentration [ Time Frame: Up to the day of surgery ] [ Designated as safety issue: No ]
    Will be summarized using descriptive statistics.
  • MGMT methylation status [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Will be summarized using descriptive statistics.
  • P53 mutation status [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Will be summarized using descriptive statistics.
  • P-gp expression level [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Will be summarized using descriptive statistics.
  • Wee1 expression level [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Will be summarized using descriptive statistics.
Not Provided
 
WEE1 Inhibitor MK-1775, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma Multiforme
Phase I Study of AZD1775 (MK-1775) With Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma and Evaluation of Intratumoral Drug Distribution in Patients With Recurrent Glioblastoma

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.

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.

Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Recurrent Adult Brain Tumor
  • Drug: WEE1 inhibitor MK-1775
    Given PO
    Other Names:
    • AZD1775
    • MK-1775
  • Radiation: radiation therapy
    Undergo radiation therapy
    Other Names:
    • irradiation
    • radiotherapy
    • therapy, radiation
  • Drug: temozolomide
    Given PO
    Other Names:
    • SCH 52365
    • Temodal
    • Temodar
    • TMZ
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Arm I (WEE1 inhibitor MK-1775, temozolomide, radiation)

    INITIATION COURSE: Patients receive WEE1 inhibitor MK-1775 PO on days 1, 3, and 5 or 1-5 weekly and temozolomide PO 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.

    Interventions:
    • Drug: WEE1 inhibitor MK-1775
    • Radiation: radiation therapy
    • Drug: temozolomide
    • Other: pharmacological study
    • Other: laboratory biomarker analysis
  • Experimental: Arm II (WEE1 inhibitor MK-1775, temozolomide)
    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.
    Interventions:
    • Drug: WEE1 inhibitor MK-1775
    • Drug: temozolomide
    • Other: pharmacological study
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
114
Not Provided
December 2014   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
United States
 
NCT01849146
NCI-2013-00858, NCI-2013-00858, ABTC 1202, ABTC # 1202, ABTC-1202, UM1CA137443
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Brian Alexander National Cancer Institute (NCI)
National Cancer Institute (NCI)
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP