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

NCT02209428 | Unknown Phase 2 DMC

• 1 other identifier: KY2014-182
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

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.

Conditions

Astrocytoma; Oligodendroglioma; Oligoastrocytoma

Keywords

Temozolomide; IDH mutation; Low grade glioma

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate, ORR

  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

  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 Outcomes (7)

• Progression free survival (PFS)-6, -12, -24

  6, 12 and 24 months after the 1st cycle of chemotherapy

• Cognitive functions

  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)

  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

  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

  6, 12 and 24 months after the 1st cycle of chemotherapy

Study Arms (2)

IDH wild type

ACTIVE COMPARATOR

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

IDH mutation

EXPERIMENTAL

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

Interventions

Temozolomide DRUG

75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.

Also known as: Temodar, Temodal

IDH mutation; IDH wild type

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Huashan Hospital: lead

Study Sites (1)

Huashan Hospital Affiliated to Fudan University

Shanghai, Shanghai Municipality, 200040, China

Location

Related Publications (16)

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• Lashkari HP, Saso S, Moreno L, Athanasiou T, Zacharoulis S. Using different schedules of Temozolomide to treat low grade gliomas: systematic review of their efficacy and toxicity. J Neurooncol. 2011 Nov;105(2):135-47. doi: 10.1007/s11060-011-0657-7. Epub 2011 Jul 5.

  PMID: 21748491 BACKGROUND

• Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009 Feb 19;360(8):765-73. doi: 10.1056/NEJMoa0808710.

  PMID: 19228619 BACKGROUND

• Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, El Hallani S, Boisselier B, Mokhtari K, Hoang-Xuan K, Delattre JY. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009 Sep 1;27(25):4150-4. doi: 10.1200/JCO.2009.21.9832. Epub 2009 Jul 27.

  PMID: 19636000 BACKGROUND

• Ichimura K, Pearson DM, Kocialkowski S, Backlund LM, Chan R, Jones DT, Collins VP. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol. 2009 Aug;11(4):341-7. doi: 10.1215/15228517-2009-025. Epub 2009 May 12.

  PMID: 19435942 BACKGROUND

• van den Bent MJ, Wefel JS, Schiff D, Taphoorn MJ, Jaeckle K, Junck L, Armstrong T, Choucair A, Waldman AD, Gorlia T, Chamberlain M, Baumert BG, Vogelbaum MA, Macdonald DR, Reardon DA, Wen PY, Chang SM, Jacobs AH. Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol. 2011 Jun;12(6):583-93. doi: 10.1016/S1470-2045(11)70057-2. Epub 2011 Apr 5.

  PMID: 21474379 BACKGROUND

• E. Mandonnet et al. Toward the Definition of New Endpoints. H. Duffau (ed.), Diffuse Low-Grade Gliomas in Adults, DOI 10.1007/978-1-4471-2213-5_29, Springer-Verlag London 2013

  BACKGROUND

• Aibaidula A, Lu JF, Wu JS, Zou HJ, Chen H, Wang YQ, Qin ZY, Yao Y, Gong Y, Che XM, Zhong P, Li SQ, Bao WM, Mao Y, Zhou LF. Establishment and maintenance of a standardized glioma tissue bank: Huashan experience. Cell Tissue Bank. 2015 Jun;16(2):271-81. doi: 10.1007/s10561-014-9459-4. Epub 2014 Jun 15.

  PMID: 24929994 BACKGROUND

• van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, Malmstrom PO, Collette L, Pierart M, Mirimanoff R, Karim AB; EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005 Sep 17-23;366(9490):985-90. doi: 10.1016/S0140-6736(05)67070-5.

  PMID: 16168780 BACKGROUND

MeSH Terms

Conditions

Astrocytoma; Oligodendroglioma

Interventions

Temozolomide

Condition Hierarchy (Ancestors)

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)

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

Study Officials

• Jinsong Wu, Professor

  Huashan Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 30, 2014
• First Posted: August 5, 2014
• Study Start: June 1, 2014
• Primary Completion: April 1, 2019
• Study Completion: May 1, 2019
• Last Updated: February 21, 2019

Record last verified: 2019-02

Locations

CN (1)