Clinical trial NCT02209428: A Prospective Cohort to Study the Effect of Temozolomide on IDH Mutational Low Grade Gliomas
Official title: A Prospective Cohort to Study the Effect of Postoperative Upfront Temozolomide Chemotherapy on IDH Mutational Low Grade Gliomas in Eloquent Areas
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Astrocytoma
Oligodendroglioma
Oligoastrocytoma
Keywords: Temozolomide
IDH mutation
Low grade glioma
Lead sponsor: Huashan Hospital
Sponsor class: OTHER
First posted: 2014-08-05
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Objective Response Rate, ORR
timeFrame: 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.
measure: Velocity of Diameter Evolution, VDE
timeFrame: 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 outcomes:
measure: Progression free survival (PFS)-6, -12, -24
timeFrame: 6, 12 and 24 months after the 1st cycle of chemotherapy
measure: Cognitive functions
timeFrame: 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.
measure: Quality of life (QoL)
timeFrame: 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.
measure: Adverse effect of chemotherapy
timeFrame: 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.
measure: Malignant progression-free survival (MPFS) -6, -12, -24
timeFrame: 6, 12 and 24 months after the 1st cycle of chemotherapy
measure: Symptom Burden
timeFrame: At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years
measure: Seizure activity
timeFrame: At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Huashan Hospital Affiliated to Fudan University
state: Shanghai
Study officials:
affiliation: Huashan Hospital
name: Jinsong Wu, Professor
role: PRINCIPAL_INVESTIGATOR
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