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

NCT01849146

Description:

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: WEE1 Inhibitor AZD1775, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2013-00858
  • SECONDARY ID: NCI-2013-00858
  • SECONDARY ID: ABTC 1202
  • SECONDARY ID: ABTC-1202
  • SECONDARY ID: ABTC-1202
  • SECONDARY ID: ABTC-1202
  • SECONDARY ID: UM1CA137443
  • NCT ID: NCT01849146

Conditions

  • Adult Glioblastoma
  • Recurrent Glioblastoma

Interventions

DrugSynonymsArms
TemozolomideCCRG-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, TemomedacArm I (WEE1 inhibitor AZD1775, temozolomide, radiation)
WEE1 Inhibitor AZD1775AZD-1775, AZD1775, MK-1775, MK1775Arm I (WEE1 inhibitor AZD1775, temozolomide, radiation)

Purpose

This phase I trial studies the side effects and best dose of WEE1 inhibitor AZD1775 when given together with radiation therapy and temozolomide in treating patients with newly diagnosed or glioblastoma that has come back. WEE1 inhibitor AZD1775 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 WEE1 inhibitor AZD1775, radiation therapy, and temozolomide may work better in treating patients with newly diagnosed or recurrent glioblastoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated doses (MTD) of AZD1775 (MK-1775) (WEE1 inhibitor
      AZD1775) 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 WEE1 inhibitor AZD1775. Patients are assigned to
      1 of 2 treatment arms.

      ARM I:

      INITIATION COURSE: Patients receive WEE1 inhibitor AZD1775 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 AZD1775 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 at 30 days, every 2 months for
      2 years, and then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (WEE1 inhibitor AZD1775, temozolomide, radiation)ExperimentalINITIATION COURSE: Patients receive WEE1 inhibitor AZD1775 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.
  • Temozolomide
  • WEE1 Inhibitor AZD1775
Arm II (WEE1 inhibitor AZD1775, temozolomide)ExperimentalPatients receive WEE1 inhibitor AZD1775 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.
  • Temozolomide
  • WEE1 Inhibitor AZD1775

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of toxicities, graded according to the NCI CTCAE v4.0
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description: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

Measure:Overall survival
Time Frame:The time from the date of initial diagnosis to the date of death, assessed up to 2 years
Safety Issue:
Description:Calculated using the Kaplan-Meier method.
Measure: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
Safety Issue:
Description:Calculated using the Kaplan-Meier method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 4, 2017