A Prospective Cohort to Study the Effect of Temozolomide on IDH Mutational Low Grade Gliomas

February 20, 2019 updated by: Jinsong Wu, Huashan Hospital

A Prospective Cohort to Study the Effect of Postoperative Upfront Temozolomide Chemotherapy on IDH Mutational Low Grade Gliomas in Eloquent Areas

Low grade gliomas (LGGs) are the most common primary central nervous system malignancies. Brain surgeries with the most possible extent of resection are endeavored to achieve longer survivals in LGG patients. For patients with tumor located in eloquent areas so that gross total resection is not applicable, National Comprehensive Cancer Network (NCCN) 2013 guidelines assigned both radiotherapy or chemotherapy as adjuvant treatments of low grade glioma following surgeries. Retrospective studies have suggested that temozolomide (an oral chemotherapeutics) chemotherapy have good effects on the control of tumor progression or recurrence in LGG patients after surgeries, especially in those with isocitrate dehydrogenase (IDH) gene mutations.

Therefore, our prospective cohort study is to provide a higher level(IIb) of evidence for the correlation between IDH mutation and the responsiveness to up-front adjuvant metronomic temozolomide chemotherapy in young patients with LGG located in eloquent brain areas. And hopefully justify future RCTs with comparison between effects of adjuvant radiotherapy and chemotherapy in these patients.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Low grade gliomas, according to the 2007 WHO classification of tumors of the central nervous system, include astrocytomas, oligodendrogliomas, and oligoastrocytomas. It contributes to 25% of diffuse gliomas and 15% of all gliomas in adults. The majority of age group that is the most vulnerable to this neoplasm is from 30-45 years old. Median survival is usually 5-12 years, but can be prolonged up to 20 years under optimal treatment strategies. National Comprehensive Cancer Network (NCCN) and Chinese Guideline for Gliomas 2012 both point out that for LGG patients in low-risk group (oligodendrogliomas or oligoastrocytomas; no more than 40 years old; KPS 80 and higher; tumor size less than 6cm; no or minor neurological deficits), "wait and see" strategy could be considered after gross total resection; but when the tumors are in eloquent areas so that gross total resections are not applicable, the standard strategies for this specific group of patients are maximum safely resection with adjuvant treatments (radiotherapy and/or chemotherapy). Conventionally, radiotherapy is used as adjuvant treatment after surgeries. However, a recent phase III randomized trial comparing early versus later irradiation has demonstrated that early adjuvant radiotherapy had no significant impact on overall survival. Moreover, radiotherapy brings as much side effects as its control of tumor recurrence. It inevitably jeopardizes patients, especially young ones, with post-radiation cognitive deficits, which impair their social functions. On the other hand, chemotherapy could be a safer adjuvant treatment for LGG. Several phase II and III studies demonstrated that single chemotherapy is effective for treating LGG, with 50-75% response rate (including minor response), and 24-48 months of median duration of response.PCV regimen (procarbazine-CCNU-vincristine), which is administrated intravenously, used to be considered standard for LGG (oligodendrogliomas and oligoastrocytomas) chemotherapy, but now temozolomide (TMZ), an oral alkylating agent, with relatively less side effects than PCV regimen, is gaining gradual acceptance. Now we propose up-front adjuvant chemotherapy to achieve the effect of early tumor control as well as avoidance or postponement of adverse effects caused by premature adjuvant radiotherapy.

As for different schedules of temozolomide, a systematic review suggested an indication that metronomic regimens of TMZ (75 mg/m2/day for 21 days repeated every 4 weeks) result in better PFS and response rate when compared to the conventional standard 5 day regimen (200 mg/m2/day for 5 days, repeated every 4 weeks), despite of insufficient available data and study heterogeneity, thus justifying future well designed trials to verify the efficacy of the metronomic regimen. More frequent administration of TMZ will lead to MGMT (O6-methylguanine DNA methyl transferase) depletion and render higher levels of O6-methylated DNA adducts, thus reducing the chemotherapeutic resistance.

The spontaneous behavior of LGGs, as well as their response to therapy, is difficult to predict, and their outcome is highly variable. These clinical features are closely relevant to their genetic characteristics, including IDH (isocitrate dehydrogenase) gene, with 2 subtypes, IDH1 and IDH2 (less common). These genetic mutations occur in more than 70% primary LGGs. And its prognostic significance of gliomas has been reported in the New England Journal of Medicine, Journal of Clinical Oncology, and Neuro-oncology. A retrospective study suggested its predictive value of high LGGs sensitivity to TMZ. Basic research provided us the rationale that overexpression of wild IDH1 gene resulted in chemotherapy resistance to a high dose of TMZ in vivo and in vitro, while IDH1 mutation caused cell cycle arrest in G1 stage, with a compromised ability of proliferation and invasion, raising sensitivity to chemotherapy.

During our previous clinical practice, it is interesting to reveal the consistence of IDH mutation, MGMT methylation and 1p19q co-deletion in WHO Grade II and Grade III gliomas. It theoretically acknowledged potential higher sensitivity of TMZ chemotherapy in LGGs.

In order to verify the predictive significance of IDH mutation for a higher sensitivity of LGGs in eloquent areas which entail gross total resection inapplicable, higher level of evidence should be provided. And recent RANO (response assessment in neuro-oncology) revised guidelines for evaluations of objective response rate, cognitive functions, and quality of life have better facilitated standard trials.

Study Type

Interventional

Enrollment (Actual)

54

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Shanghai
      • Shanghai, Shanghai, China, 200040
        • Huashan Hospital affiliated to Fudan University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 18 years < age ≤ 40 years, both genders.
  • No neurologic cognitive deficits (MMSE ≥ 27), no psychiatric abnormalities before surgery, pre-operative KPS ≥ 80.
  • Tumors located in eloquent areas or deeply located nuclei, rendering radiological complete resection inapplicable, according to updated standards of extent of resection: as for non-enhancing LGG, postoperative MRI within 72h shows absence of any preoperative T2/FLAIR signal changes - complete resection; and for enhancing LGG, postoperative MRI shows total removal of preoperative enhancing tissue - complete resection of enhancing tumor; and total removal of enhancing and non-enhancing tissues (T2/FLAIR) - complete resection of detectable tumor.
  • Post-operative histological pathology confirms LGGs (astrocytomas, oligodendrogliomas, or oligoastrocytomas, 2007 WHO classification Grade II).
  • No contraindications to TMZ chemotherapy.
  • Informed consent to TMZ chemotherapy.

Exclusion Criteria:

  • Tumor involves more than 3 cerebral lobes (gliomatosis or multiple gliomas).
  • Tumor is complicated with other intracranial neoplasms (e.g. metastatic tumors or meningiomas).
  • Tumor is complicated with systematic malignancies.
  • Dysfunctions of other vital organs: liver and kidney (ALT﹥40U/L, AST > 40U/L, creatinine > 97-106μmol/L, urea nitrogen > 7.1mmol/L, or other lab abnormalities); Heart (NYHA II-IV); Lungs (hypoxemia).
  • Physiological pregnancy.
  • Participate in other clinical trials at meantime.
  • History of severe anaphylaxis.
  • Voluntarily quit or decline chemotherapy.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: IDH wild type
Patients with IDH wild type, according to the result of genetic sequencing of their surgical resected specimens. Intervention: oral temozolomide, 75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.
Drug: Temozolomide
75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.
Other Names:
  • Temodar
  • Temodal
Experimental: IDH mutation
Patients with IDH mutations, according to the result of genetic sequencing of their surgical resected specimens. Intervention: oral temozolomide, 75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.
Drug: Temozolomide
75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.
Other Names:
  • Temodar
  • Temodal

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective Response Rate, ORR
Time Frame: Within 72 hours after surgery, at the beginning of chemotherapy, every 2 months thereafter up to a year, every 3-6 months after a year, until the first documented progression or date of death from any cause, whichever came first, up to 2 years.

According to the revised RANO criteria (M J van den Bent, et al. 2011), compared to residual tumor volume calculated with iMRI T2/Flair right after surgery and before up-front adjuvant chemotherapy (Baseline tumor volume):

Complete response (CR): disappearance of abnormality Partial response (PR): no less than 50% reduction Minimal response (MR): no less than 25% but less than 50% reduction Stable disease (SD): less than 25% reduction also less than 25% increase Progressive disease (PD): no less than 25% increase

Enhanced T1-weighted imaging, magnetic resonance spectroscopy (MRS), Diffusion tensor imaging (DTI) and perfusion-weighted imaging (PWI) will also be utilized to detect progressions.
Within 72 hours after surgery, at the beginning of chemotherapy, every 2 months thereafter up to a year, every 3-6 months after a year, until the first documented progression or date of death from any cause, whichever came first, up to 2 years.
Velocity of Diameter Evolution, VDE
Time Frame: Within 72 hours after surgery, at the beginning of chemotherapy, every 2 months thereafter up to a year, every 3-6 months after a year, until the first documented progression or date of death from any cause, whichever came first, up to 2 years.

According to the Definition of New Endpoints by E. Mandonnet et al, 2013, VDE is calculated with formula D = (2 × V)^1/3, (V= tumor volume).

Uncontrolled: unchanged or increased VDE compared to baseline VDE. Slowed down: decreased VDE compared to baseline VDE, but still positive. Stabilized: VDE is close to 0 mm/year. Reversed: negative VDE. Treatment escape and relapse: re-growth of the tumor greater than 2 mm, during the course of chemotherapy and after the end of chemotherapy, respectively.

Intensity of response (IOR): how much the diameter has been reduced by the therapy.

Duration of response (DOR): the time period between treatment onset and treatment escape or relapse. If Replapse (25% increase/VDE>2mm/Maligmant enhancement), start 2° treatment: Second surgery or radiotherapy or salvage chemotherapy
Within 72 hours after surgery, at the beginning of chemotherapy, every 2 months thereafter up to a year, every 3-6 months after a year, until the first documented progression or date of death from any cause, whichever came first, up to 2 years.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression free survival (PFS)-6, -12, -24
Time Frame: 6, 12 and 24 months after the 1st cycle of chemotherapy
The survival rate of followed patients without progressive disease (PD) 6, 12, and 24 months after the 1st cycle of chemotherapy
6, 12 and 24 months after the 1st cycle of chemotherapy
Cognitive functions
Time Frame: At the beginning of chemotherapy, every 2 months thereafter up to a year, and every 3-6 months after a year of follow-up, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.

Test battery:

Measured with Minimal Mental State Examination (MMSE); Hopkins verbal learning test-revised; Trail making test, part A and B; Multilingual aphasia examination controlled oral word association
At the beginning of chemotherapy, every 2 months thereafter up to a year, and every 3-6 months after a year of follow-up, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.
Quality of life (QoL)
Time Frame: At the beginnning of chemotherapy, every 2 months thereafter up to a year, and every 3-6 months after a year of follow-up, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.
Measured with EORTC QLQ-C30 and EORTC-BN20. Duration of response with good quality of life is defined as Time with good quality of life (TQL).
At the beginnning of chemotherapy, every 2 months thereafter up to a year, and every 3-6 months after a year of follow-up, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.
Adverse effect of chemotherapy
Time Frame: At the beginning of chemotherapy, every 2 months thereafter up to a year, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.
Blood routine and kidney/liver functions
At the beginning of chemotherapy, every 2 months thereafter up to a year, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.
Malignant progression-free survival (MPFS) -6, -12, -24
Time Frame: 6, 12 and 24 months after the 1st cycle of chemotherapy
The survival rate of followed patients without any MRI T1 enhancing signals in 6, 12, and 24 months after the 1st cycle of chemotherapy
6, 12 and 24 months after the 1st cycle of chemotherapy
Symptom Burden
Time Frame: At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years
Measured with M.D. Anderson Symptom Inventory Brain Tumor Module, MDASI-BT.
At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years
Seizure activity
Time Frame: At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years
Measured by one neurologist, number and type of seizure and medication in the past month before each follow-up visit are recorded.
At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Huashan Hospital

Investigators

  • Principal Investigator: Jinsong Wu, Professor, Huashan Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2014

Primary Completion (Anticipated)

April 1, 2019

Study Completion (Anticipated)

May 1, 2019

Study Registration Dates

First Submitted

July 30, 2014

First Submitted That Met QC Criteria

August 3, 2014

First Posted (Estimate)

August 5, 2014

Study Record Updates

Last Update Posted (Actual)

February 21, 2019

Last Update Submitted That Met QC Criteria

February 20, 2019

Last Verified

February 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KY2014-182

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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