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

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ClinicalTrials.gov Identifier: NCT01849146
Recruitment Status : Recruiting
First Posted : May 8, 2013
Last Update Posted : August 13, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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 glioblastoma that is newly diagnosed or 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 compared to radiation therapy and temozolomide alone.

Condition or disease Intervention/treatment Phase
Glioblastoma Recurrent Glioblastoma Drug: Adavosertib Radiation: Radiation Therapy Drug: Temozolomide Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 114 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of AZD1775 (Adavosertib) With Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma and Evaluation of Intratumoral Drug Distribution in Patients With Recurrent Glioblastoma
Actual Study Start Date : August 19, 2013
Estimated Primary Completion Date : February 28, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm I (adavosertib, temozolomide, radiation)

INITIATION CYCLE: Patients receive adavosertib 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 CYCLES: Beginning in week 10, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Adavosertib
Given PO
Other Names:
  • AZD-1775
  • AZD1775
  • MK-1775
  • MK1775

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • RADIOTHERAPY
  • RT
  • Therapy, Radiation

Drug: Temozolomide
Given PO
Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temcad
  • Temodal
  • Temodar
  • Temomedac
  • TMZ

Experimental: Arm II (adavosertib, temozolomide)
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 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Adavosertib
Given PO
Other Names:
  • AZD-1775
  • AZD1775
  • MK-1775
  • MK1775

Drug: Temozolomide
Given PO
Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temcad
  • Temodal
  • Temodar
  • Temomedac
  • TMZ




Primary Outcome Measures :
  1. Maximum tolerated dose of adavosertib with 6 weeks of radiotherapy and temozolomide (Arm I) [ Time Frame: Up to 6 weeks ]
    Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. 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.

  2. Maximum tolerated dose of adavosertib with adjuvant temozolomide (Arm II) [ Time Frame: Up to 28 days ]
    Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. 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.

  3. Incidence of toxicities [ Time Frame: Up to 30 days post-treatment ]
    Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. 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.


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: The time from the date of initial diagnosis to the date of death, assessed up to 2 years ]
    Calculated using the Kaplan-Meier method.

  2. 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 ]
    Calculated using the Kaplan-Meier method.


Other Outcome Measures:
  1. Pharmacokinetic profile of adavosertib in combination with radiation and temozolomide and adjuvant temozolomide [ Time Frame: Baseline, at 0.5, 1, 2, 4, 6, 8 and 24 hours of weeks 1 and 4 of cycle 1 (Arm I) and at baseline, 0.5, 1, 2, 4, 6, 8, and 24 hours of cycle 1 (Arm II) ]
    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, North Carolina). The geometric mean +/- standard deviation of the estimated values of the pharmacokinetic parameter for groups of subjects evaluated at maximum tolerated 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.

  2. Intratumoral adavosertib concentration [ Time Frame: Up to the day of surgery ]
    Will be summarized using descriptive statistics.

  3. pRb (S807/811) expression levels [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.

  4. Proliferation (Ki-67) expression levels [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.

  5. pCDC2 expression levels [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.

  6. Apoptosis (cleaved caspase 3) levels [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.

  7. Genotyping data [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.

  8. MGMT methylation status [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.

  9. P53 mutation status [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.

  10. P-gp expression level [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.

  11. Wee1 expression level [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 (adavosertib) are ineligible; the AZD1775 (adavosertib) 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 (adavosertib)
  • 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 because AZD1775 (adavosertib) has potential for teratogenic or abortifacients effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD1775 (adavosertib), breastfeeding should be discontinued if the mother is treated with AZD1775 (adavosertib)
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD1775 (adavosertib); in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01849146


Locations
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United States, Alabama
University of Alabama at Birmingham Cancer Center Suspended
Birmingham, Alabama, United States, 35233
United States, California
UCLA / Jonsson Comprehensive Cancer Center Active, not recruiting
Los Angeles, California, United States, 90095
UCSF Medical Center-Parnassus Suspended
San Francisco, California, United States, 94143
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Suspended
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Site Public Contact    877-726-5130      
Principal Investigator: Eudocia Q. Lee         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    877-442-3324      
Principal Investigator: Eudocia Q. Lee         
United States, Michigan
Henry Ford Hospital Recruiting
Detroit, Michigan, United States, 48202
Contact: Site Public Contact    313-916-3721    CTOResearch@hfhs.org   
Principal Investigator: Tobias Walbert         
United States, New York
Memorial Sloan Kettering Cancer Center Suspended
New York, New York, United States, 10065
United States, North Carolina
Wake Forest University Health Sciences Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Site Public Contact    336-713-6771      
Principal Investigator: Glenn J. Lesser         
United States, Ohio
Cleveland Clinic Foundation Active, not recruiting
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
University of Pennsylvania/Abramson Cancer Center Suspended
Philadelphia, Pennsylvania, United States, 19104
University of Pittsburgh Cancer Institute (UPCI) Suspended
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Eudocia Q Lee National Cancer Institute (NCI)

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01849146     History of Changes
Other Study ID Numbers: NCI-2013-00858
NCI-2013-00858 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ABTC 1202
ABTC-1202 ( Other Identifier: Adult Brain Tumor Consortium )
ABTC-1202 ( Other Identifier: CTEP )
UM1CA137443 ( U.S. NIH Grant/Contract )
First Posted: May 8, 2013    Key Record Dates
Last Update Posted: August 13, 2019
Last Verified: April 2019

Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
MK-1775
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors