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

NCT01849146 | Completed Phase 1

• 4 other identifiers: NCI-2013-00858ABTC 1202ABTC-1202UM1CA137443
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 12

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.

Conditions

Glioblastoma; Recurrent Glioblastoma

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose of adavosertib with 6 weeks of radiotherapy and temozolomide (Arm I)

  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.

  Up to 6 weeks

• Maximum tolerated dose of adavosertib with adjuvant temozolomide (Arm II)

  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.

  Up to 28 days

• Incidence of toxicities

  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.

  Up to 30 days post-treatment

Secondary Outcomes (2)

• Overall survival

  The time from the date of initial diagnosis to the date of death, assessed up to 2 years

• Progression-free survival

  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

Other Outcomes (11)

• Pharmacokinetic profile of adavosertib in combination with radiation and temozolomide and adjuvant temozolomide

  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)

• Intratumoral adavosertib concentration

  Up to the day of surgery

• pRb (S807/811) expression levels

  Up to 2 years

Study Arms (2)

Arm I (adavosertib, temozolomide, radiation)

EXPERIMENTAL

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; Radiation: Radiation Therapy; Drug: Temozolomide

Arm II (adavosertib, temozolomide)

EXPERIMENTAL

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; Drug: Temozolomide

Interventions

Adavosertib DRUG

Given PO

Also known as: AZD 1775, AZD-1775, AZD1775, MK 1775, MK-1775, MK1775

Arm I (adavosertib, temozolomide, radiation); Arm II (adavosertib, temozolomide)

Radiation Therapy RADIATION

Undergo radiation therapy

Also known as: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Arm I (adavosertib, temozolomide, radiation)

Temozolomide DRUG

Given PO

Also known as: CCRG-81045, Gliotem, 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, Temizole, Temodal, Temodar, Temomedac, TMZ

Arm I (adavosertib, temozolomide, radiation); Arm II (adavosertib, temozolomide)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (12)

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, 35233, United States

Location

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

UCSF Medical Center-Parnassus

San Francisco, California, 94143, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

University of Pennsylvania/Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

adavosertib; Radiotherapy; Radiation; Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Therapeutics; Physical Phenomena; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Eudocia Q Lee

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2013
• First Posted: May 8, 2013
• Study Start: October 24, 2013
• Primary Completion: July 29, 2021
• Study Completion: October 30, 2024
• Last Updated: January 9, 2025

Record last verified: 2025-01

Locations

US (12)