CCRT With Temozolomide Versus RT Alone in Patients With IDH Wild-type/TERT Promoter Mutation Grade II/III Gliomas

Sponsor

Beijing Tiantan Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT02766270

Collaborator

Beijing Neurosurgical Institute (Other), Beijing Shijitan Hospital, Capital Medical University (Other)

Enrollment

Location

Arms

26.2

Anticipated Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The management of lower-grade gliomas (Diffuse low-grade and intermediate-grade gliomas, WHO II and III) is largely based on surgery followed by radiotherapy. Recent studies showed that lower-grade glioma patients with IDH wild-type (IDH-wt) and TERT promoter mutation (TERTp-mut) had dismal clinical outcomes. These results suggested that current treatment strategies are not adequate for this subtype of lower-grade glioma.

The present study aims to examine the efficacy and safety of concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide for lower- grade glioma patients with IDH-wt and TERTp-mut.

Condition or Disease	Intervention/Treatment	Phase
Grade II/III Glioma	Drug: Temozolomide Radiation: Radiotherapy	Early Phase 1

Detailed Description

Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) are infiltrative neoplasms that arise most often in the cerebral hemispheres of adults and include astrocytomas, oligodendrogliomas, and oligoastrocytomas. The management of lower-grade gliomas is largely based on surgery followed by radiotherapy.

Lower-grade gliomas have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Consequently, clinicians increasingly rely on genetic classification to guide clinical decision making. Mutations in IDH1 and IDH2 characterize the majority of lower-grade gliomas in adults and define a subtype that is associated with a favorable prognosis. Mutations of the telomerase reverse transcriptase (TERT) promoter, which result in enhanced telomerase activity and lengthened telomeres, have been observed in several human cancers including glioma. Accumulating evidence suggest that TERT promoter mutation is another molecular marker which can stratify lower-grade gliomas into prognostic subgroups in combination with IDH mutation. In our previous study, patients(28/377, 7.4%) who had lower-grade gliomas with IDH wild-type (IDH-wt) and TERT promoter mutation (TERTp-mut) had the poorest clinical outcomes (median OS, 27.7mo; 5-year OS, 29%). These results were accordant with the recent studies and suggested that current treatment strategies are not adequate for this subtype of lower-grade glioma.

Radiotherapy plus temozolomide has emerged as a new standard of care for patients with good PS non-elderly glioblastoma. There are some data that support temozolomide as adjuvant therapy for lower-grade glioma. Given that the IDH-wt/TERTp-mut subgroup of lower-grade gliomas has dismal prognosis, a more aggressive therapy such as concurrent chemoradiotherapy seems to be reasonable. The present study aims to examine the efficacy and safety of concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide for lower-grade glioma patients with IDH-wt and TERTp-mut. Half the patients will be randomly assigned to receive concurrent chemoradiotherapy (surgery + concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide) and half the patients will be randomly assigned to receive conventional therapy (surgery + radiotherapy only).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Prospective Study of Concurrent Chemoradiotherapy With Temozolomide Versus Radiation Therapy Alone in Patients With IDH Wild-type/TERT Promoter Mutation Grade II/III Gliomas

Actual Study Start Date :

Sep 26, 2016

Anticipated Primary Completion Date :

Dec 1, 2017

Anticipated Study Completion Date :

Dec 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Chemoradiotherapy with Temozolomide Patients undergo intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy 5 days a week for 6 weeks (for a total of 60 Gy) and receive temozolomide PO QD (75 mg/m2/day, 7 days/week) for up to 7 weeks. Beginning 4 weeks after completion of chemotherapy and radiation therapy, patients receive temozolomide PO QD on days 1-5 (150-200 mg/m2). Treatment with temozolomide repeats every 28 days for up to 12 courses	Drug: Temozolomide RT with daily temozolomide (75 mg/m2/day, 7 days/week for up to 7 weeks) and adjuvant temozolomide (150-200 mg/m2 PO QD for 5 days, repeats every 28 days for up to 12 courses). Radiation: Radiotherapy
Active Comparator: Radiotherapy alone Patients undergo intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy 5 days a week for 6 weeks (for a total of 60 Gy)	Radiation: Radiotherapy

Arm

Intervention/Treatment

Experimental: Chemoradiotherapy with Temozolomide

Patients undergo intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy 5 days a week for 6 weeks (for a total of 60 Gy) and receive temozolomide PO QD (75 mg/m2/day, 7 days/week) for up to 7 weeks. Beginning 4 weeks after completion of chemotherapy and radiation therapy, patients receive temozolomide PO QD on days 1-5 (150-200 mg/m2). Treatment with temozolomide repeats every 28 days for up to 12 courses

Drug: Temozolomide

RT with daily temozolomide (75 mg/m2/day, 7 days/week for up to 7 weeks) and adjuvant temozolomide (150-200 mg/m2 PO QD for 5 days, repeats every 28 days for up to 12 courses).

Radiation: Radiotherapy

Active Comparator: Radiotherapy alone

Patients undergo intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy 5 days a week for 6 weeks (for a total of 60 Gy)

Radiation: Radiotherapy

Outcome Measures

Primary Outcome Measures

Overall survival (OS) [Up to 2 years]
Overall survival is defined as the time from randomization to death.

Secondary Outcome Measures

Progression free survival(PFS) [Up to 2 years]
Progression free survival(PFS) is defined as the time from randomization to progressive disease or death. A combination of neurological examination and MRI brain scan used to define progression.
The incidence and severity of adverse events associated with treatment with RT alone and combined with temozolomide chemotherapy; according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. [Up to 2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed supratentorial Diffuse low-grade and intermediate-grade gliomas (World Health Organization grades II and III )
IDH wild-type and TERT promoter mutation
Age > 18
Karnofsky performance score > 60
Neutrophilic granulocyte count > 1500/µl
Platelet count > 100 000/µl
Hemoglobin > 10 g/dl
Serum creatinine < 1.5 times the lab's upper normal limit
AST or ALT < 1.5 times the lab's upper normal limit
Adequate medical health to participate in this study
No previous systemic chemotherapy
No previous radiotherapy to the brain
Written informed consent

Exclusion Criteria:

Serious medical or neurological condition with a poor prognosis
Contraindications to radiotherapy or temozolomide chemotherapy
Patient unable to follow procedures, visits, examinations described in the study
Second cancer requiring radiotherapy or chemotherapy
Inability to undergo gadolinium-contrasted MRIs
Pregnant women or nursing mothers can not participate in the study