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

Glioblastoma Clinical Trial

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

Status Active, not recruiting

Clinical Trial 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.

Clinical Trial Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated doses (MTD) of AZD1775 (adavosertib) 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 (adavosertib) 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 (adavosertib) 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 (adavosertib) in combination with RT and concomitant TMZ (Arm 1) and AZD1775 (adavosertib) with adjuvant TMZ (Arm 2) in patients with newly diagnosed glioblastoma.

II. To assess the pharmacokinetic (PK) profile of AZD1775 (adavosertib) in combination with upfront radiation/TMZ and adjuvant TMZ in patients with newly diagnosed glioblastoma.

INTRATUMORAL CORRELATIVES/PHARMACOKINETICS OBJECTIVES:

I. To determine the intratumoral concentration of AZD1775 (adavosertib) achieved in patients treated with the putative MTD.

II. To characterize the time course of AZD1775 (adavosertib) 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 (adavosertib).

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 CYCLE: 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 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.

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 cycles 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. ;

Related Conditions & MeSH terms

• Glioblastoma
• Recurrence
• Recurrent Glioblastoma

• NCT number: NCT01849146
• Study type: Interventional
• Source: National Cancer Institute (NCI)
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: August 19, 2013
• Completion date: March 4, 2025