AstrocytomaPhase 2NCT02209428
A Prospective Cohort to Study the Effect of Temozolomide on IDH Mutational Low Grade Gliomas
A Phase 2 study testing Temozolomide in people with Astrocytoma and Oligodendroglioma, run by Huashan Hospital at 1 site in China.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 years
- Conditions the study is for
- Astrocytoma, Oligodendroglioma, Oligoastrocytoma
- What is being tested?
- Temozolomide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 54 participants
- Where
- 1 siteChina
- Study dates
- Jun 2014to May 2019
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
China1 site
Huashan Hospital Affiliated to Fudan University
Shanghai, Shanghai Municipality, 200040
About this study
Official title: 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.
Read the 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.
- Conditions
- Astrocytoma, Oligodendroglioma, Oligoastrocytoma
- Being tested
- Temozolomide
- Keywords
- Temozolomide, IDH mutation, Low grade glioma
- Medical subject headings
- Astrocytoma, Oligodendroglioma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TemozolomideDrug
Also called Temodar, Temodal
75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Temozolomide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 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
The survival rate of followed patients without progressive disease (PD) 6, 12, and 24 months after the 1st cycle of chemotherapy
Measured: 6, 12 and 24 months after the 1st cycle of chemotherapy
Cognitive functions
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
Measured: 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)
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).
Measured: 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
Blood routine and kidney/liver functions
Measured: 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
The survival rate of followed patients without any MRI T1 enhancing signals in 6, 12, and 24 months after the 1st cycle of chemotherapy
Measured: 6, 12 and 24 months after the 1st cycle of chemotherapy
Symptom Burden
Measured with M.D. Anderson Symptom Inventory Brain Tumor Module, MDASI-BT.
Measured: At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years
Seizure activity
Measured by one neurologist, number and type of seizure and medication in the past month before each follow-up visit are recorded.
Measured: At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Aug 2014 (estimated)
- Study startJun 2014
- Primary completionApr 2019 (estimated)
- Study completionMay 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (16)Papers the sponsor has linked to this study.
- Other trials for AstrocytomaStudies of the same condition, open and under way.
- More trials run by Huashan HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 54 participants (actual)
Sponsor and investigators
- Lead sponsor
- Huashan Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jinsong Wu, Huashan Hospital
- Investigators
- Jinsong Wu, Professor, Principal investigator, Huashan Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02209428
- Sponsor's protocol ID
- KY2014-182
- Status last verified
- Feb 2019
- First submitted
- 30 Jul 2014
- Last updated
- 21 Feb 2019
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007 Aug;114(2):97-109. doi: 10.1007/s00401-007-0243-4. Epub 2007 Jul 6.
PubMed 17618441Viaccoz A, Lekoubou A, Ducray F. Chemotherapy in low-grade gliomas. Curr Opin Oncol. 2012 Nov;24(6):694-701. doi: 10.1097/CCO.0b013e328357f503.
PubMed 22913972Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, Paris S, Boisselier B, Idbaih A, Laigle-Donadey F, Hoang-Xuan K, Sanson M, Delattre JY. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010 Oct 26;75(17):1560-6. doi: 10.1212/WNL.0b013e3181f96282.
PubMed 20975057Vogelbaum MA, Jost S, Aghi MK, Heimberger AB, Sampson JH, Wen PY, Macdonald DR, Van den Bent MJ, Chang SM. Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. Neurosurgery. 2012 Jan;70(1):234-43; discussion 243-4. doi: 10.1227/NEU.0b013e318223f5a7.
PubMed 21593697Wang JB, Dong DF, Wang MD, Gao K. IDH1 overexpression induced chemotherapy resistance and IDH1 mutation enhanced chemotherapy sensitivity in Glioma cells in vitro and in vivo. Asian Pac J Cancer Prev. 2014;15(1):427-32. doi: 10.7314/apjcp.2014.15.1.427.
PubMed 24528069Nabors LB, Portnow J, Ahluwalia M, Baehring J, Brem H, Brem S, Butowski N, Campian JL, Clark SW, Fabiano AJ, Forsyth P, Hattangadi-Gluth J, Holdhoff M, Horbinski C, Junck L, Kaley T, Kumthekar P, Loeffler JS, Mrugala MM, Nagpal S, Pandey M, Parney I, Peters K, Puduvalli VK, Robins I, Rockhill J, Rusthoven C, Shonka N, Shrieve DC, Swinnen LJ, Weiss S, Wen PY, Willmarth NE, Bergman MA, Darlow SD. Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020 Nov 2;18(11):1537-1570. doi: 10.6004/jnccn.2020.0052.
PubMed 33152694van den Bent MJ, Taphoorn MJ, Brandes AA, Menten J, Stupp R, Frenay M, Chinot O, Kros JM, van der Rijt CC, Vecht ChJ, Allgeier A, Gorlia T; European Organization for Research and Treatment of Cancer Brain Tumor Group. Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol. 2003 Jul 1;21(13):2525-8. doi: 10.1200/JCO.2003.12.015.
PubMed 12829671Brada M, Viviers L, Abson C, Hines F, Britton J, Ashley S, Sardell S, Traish D, Gonsalves A, Wilkins P, Westbury C. Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas. Ann Oncol. 2003 Dec;14(12):1715-21. doi: 10.1093/annonc/mdg371.
PubMed 14630674Lashkari 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.
PubMed 21748491Yan 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.
PubMed 19228619Sanson 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.
PubMed 19636000Ichimura 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.
PubMed 19435942van 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.
PubMed 21474379E. 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
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.
PubMed 24929994
Study at a glance
From the registry record, last updated by the sponsor on 21 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Prospective Cohort to Study the Effect of Postoperative Upfront Temozolomide Chemotherapy on IDH Mutational Low Grade Gliomas in Eloquent Areas
- ClinicalTrials.gov ID
- NCT02209428
- Acronym / sponsor ID
- KY2014-182
- Conditions
- Astrocytoma, Oligodendroglioma, Oligoastrocytoma
- Keywords
- Temozolomide, IDH mutation, Low grade glioma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 54 participants (actual)
- Lead sponsor
- Huashan HospitalUniversity, hospital or other
- Study start
- Jun 2014
- Primary completion
- Apr 2019 (estimated)
- Study completion
- May 2019 (estimated)
- First posted
- 5 Aug 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| IDH wild type | Active comparator | Drug: TemozolomidePatients 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. |
| IDH mutation | Experimental | Drug: TemozolomidePatients 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. |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TemozolomideAlso: Temodar, Temodal75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles. | Drug | IDH mutation, IDH wild type |
Primary outcome
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.
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
7 secondary outcomes
Progression free survival (PFS)-6, -12, -24
Time frame: 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.
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.
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.
Malignant progression-free survival (MPFS) -6, -12, -24
Time frame: 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
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
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Feb 2019.
- Background: PubMed 17618441Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007 Aug;114(2):97-109. doi: 10.1007/s00401-007-0243-4. Epub 2007 Jul 6.
- Background: PubMed 22913972Viaccoz A, Lekoubou A, Ducray F. Chemotherapy in low-grade gliomas. Curr Opin Oncol. 2012 Nov;24(6):694-701. doi: 10.1097/CCO.0b013e328357f503.
- Background: PubMed 20975057Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, Paris S, Boisselier B, Idbaih A, Laigle-Donadey F, Hoang-Xuan K, Sanson M, Delattre JY. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010 Oct 26;75(17):1560-6. doi: 10.1212/WNL.0b013e3181f96282.
- Background: PubMed 21593697Vogelbaum MA, Jost S, Aghi MK, Heimberger AB, Sampson JH, Wen PY, Macdonald DR, Van den Bent MJ, Chang SM. Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. Neurosurgery. 2012 Jan;70(1):234-43; discussion 243-4. doi: 10.1227/NEU.0b013e318223f5a7.
- Background: PubMed 24528069Wang JB, Dong DF, Wang MD, Gao K. IDH1 overexpression induced chemotherapy resistance and IDH1 mutation enhanced chemotherapy sensitivity in Glioma cells in vitro and in vivo. Asian Pac J Cancer Prev. 2014;15(1):427-32. doi: 10.7314/apjcp.2014.15.1.427.
- Background: PubMed 33152694Nabors LB, Portnow J, Ahluwalia M, Baehring J, Brem H, Brem S, Butowski N, Campian JL, Clark SW, Fabiano AJ, Forsyth P, Hattangadi-Gluth J, Holdhoff M, Horbinski C, Junck L, Kaley T, Kumthekar P, Loeffler JS, Mrugala MM, Nagpal S, Pandey M, Parney I, Peters K, Puduvalli VK, Robins I, Rockhill J, Rusthoven C, Shonka N, Shrieve DC, Swinnen LJ, Weiss S, Wen PY, Willmarth NE, Bergman MA, Darlow SD. Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020 Nov 2;18(11):1537-1570. doi: 10.6004/jnccn.2020.0052.
- Background: PubMed 12829671van den Bent MJ, Taphoorn MJ, Brandes AA, Menten J, Stupp R, Frenay M, Chinot O, Kros JM, van der Rijt CC, Vecht ChJ, Allgeier A, Gorlia T; European Organization for Research and Treatment of Cancer Brain Tumor Group. Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol. 2003 Jul 1;21(13):2525-8. doi: 10.1200/JCO.2003.12.015.
- Background: PubMed 14630674Brada M, Viviers L, Abson C, Hines F, Britton J, Ashley S, Sardell S, Traish D, Gonsalves A, Wilkins P, Westbury C. Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas. Ann Oncol. 2003 Dec;14(12):1715-21. doi: 10.1093/annonc/mdg371.
- Background: PubMed 21748491Lashkari 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.
- Background: PubMed 19228619Yan 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.
- Background: PubMed 19636000Sanson 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jinsong Wu, Professor principal investigator
Huashan Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Temozolomide in people with Astrocytoma and Oligodendroglioma, run by Huashan Hospital at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 21 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02209428, which also lists 16 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Feb 2019.