Glioblastoma Multiforme, AdultPhase 1PARADIGMANCT03480867
Pre-operative RT and TMZ in Patients With Newly Diagnosed GBM Diagnosed Glioblastoma. A Phase I Study. (PARADIGMA)
A Phase 1 study testing Temozolomide and Pre-Operative Radiation in people with Glioblastoma Multiforme, Adult, run by McGill University Health Centre/Research Institute of the McGill University Health Centre at 1 site in Canada.
Trial summary
Glioblastoma (GBM) is the most common primary brain cancer in adults. Despite surgery, conventional radiotherapy, and chemotherapy, the average survival for GBM is 15-16 months. Although additional chemoradiotherapy has been shown to increase survival, the majority recur at the original location. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Glioblastoma Multiforme, Adult
- What is being tested?
- Temozolomide and Pre-Operative Radiation
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteCanada
- Study dates
- Mar 2017to Nov 2023
- Phase
- Phase 1
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Newly diagnosed (MR image-based) GBM - Must be able to undergo gadolinium-enhanced MRI.
- Must be a candidate for radical surgical resection in the opinion of the neurosurgeon.
- The tumor must measure less than 6 cm in maximum diameter. The tumor diameter will be the greatest diameter as measured on the contrast-enhanced MRI.
- A neurosurgical oncologist, radiation oncologist and neuro-oncologist will assess each patient in advance of enrollment.
- The estimated post-surgical radiation field must be compatible with the proposed radiation scheme - ie, to ensure a safe radiation margin from structures such as the optic apparatus and brain stem.
- The GBM tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed)
Show all 12Show fewer
- Age>18years
- Karnofsky Performance Status (KPS) 70.
- History and physical examination within 14 days from start of therapy, including documentation of steroid dose.
- Adequate complete blood counts (Absolute neutrophil count (ANC) .:! 1,800. cells/mm3; Platelets.:! 100,000 cells/mm3; Hemoglobin.:! 10.0 g/dl), renal and liver function within 14 days prior to therapy with values< 3x (upper limit normal) ULN.
- For females of child-bearing potential, negative serum pregnancy test within 14 days prior to therapy and use of contraception.
- Signed consent form.
Who cannot join
- Tumors within 1 cm from critical structures (brainstem, optic apparatus), or with massive edema, or with the possibility of herniation, or any tumor that in the neurosurgeon's opinion would be considered unsafe to delay surgery or is not grossly resectable.
- Prior invasive malignancy (except for non-melanomatous skin cancer, non- invasive bladder cancer, and non-invasive cervix cancer) unless disease free for 2:5 years.
- Recurrent or multifocal GBM.
- Any site of metastatic disease (drop metastases).
- Prior chemotherapy or radiation therapy to the head or neck (except for T1 glottic tumor
- Severe active co-morbid medical condition as assessed by medical team.
- Patients enrolled in any other protocol.
- Inability to undergo MRI.
Trial locations and contacts
1 site in 1 country.
Canada1 site
McGill University Health Centre-Cedars Cancer Centre
Montreal, Québec, Canada, H4A 3J1
About this study
Official title: Pre-operative Radiation Therapy (RT) and Temozolomide (TMZ) in Patients With Newly Diagnosed Glioblastoma. A Phase I Study. (PARADIGMA)
Glioblastoma (GBM) is the most common primary brain cancer in adults. Despite surgery, conventional radiotherapy, and chemotherapy, the average survival for GBM is 15-16 months. Although additional chemoradiotherapy has been shown to increase survival, the majority recur at the original location.
Despite many efforts to improve the local control by improving surgical techniques, increasing the radiotherapy dose or adding newer chemotherapy agents, these attempts have failed to show a survival benefit or an improved cancer control. People who are not participating in a study are usually treated with surgery followed by radiation (6 weeks duration) together with temozolomide (chemotherapy drug) followed by temozolomide alone. For patients who receive this usual treatment approach for this cancer, about 4 out of 100 are free of cancer growth five years later. Because GBM invades the surrounding normal brain, this study is looking into the possibility of minimizing invasion by starting treatment using the combination of radiotherapy and chemotherapy prior to surgery. This approach is an experimental form of treatment and the diagnosis is based exclusively on imaging and not on histology of the tumour tissue, and there is a possibility that your tumor may not be a GB but of other origins.
Read the detailed description
One of the deadly properties of GBM is its capacity to diffusely infiltrate the surrounding normal brain tissue. Unlikely many malignancies, in GBM local disease progression, rather than metastatic disease, is the leading cause of death. Extent of resection plays a key role in the treatment of these patients with complete surgical resection improving outcome. In a prospective, non- interventional, multi-institutional study of over 140 patients with GBM and minimal or no residual tumor on post-operative MRI, Stummer et al.have shown that extent of resection is indeed associated with improved survival. However, despite evidence of complete resection on post-operative imaging studies, surgery is rarely truly complete. GBMs are invasive tumors and, at time of surgery, a clear boundary is not clearly identifiable, either on pre- or intra- operative imaging. Even when sophisticated imaging'techniques are used, they are unable to detect invasive brain cancer cell for proper pre-operative surgical planning to optimally delineate the tumor boundaries for a truly complete resection. Even if they were, brain eloquence would preclude a complete resection of most GBMs.
Despite extensive and complete surgical tumor removal coupled with radiation and chemotherapy, even in high doses, 90% of patients still fail at the border or within a few centimeters from the surgical cavity. Glioma cell migration outside the original tumor site may be responsible for this recurrence pattern. Cell migration is a complex, dynamic process and is well-documented in GBM. It involves, at least, 3 independent but coordinated biologic processes: 1) cell adhesion to components of the extracellular matrix, 2) cell's own motility and 3) invasion. Giese et al.) reported that cell migration is established by several independent mechanisms, facilitating the spread of tumor astrocytes, but with cell motility being the possible common denominator for this biologic behavior.
Invasion of tumor glioma cells is a multi-factorial process. To migrate, the cell needs a change in morphology and to interact with the extracellular matrix. It is possible that the surgical insult at the time of tumor removal may facilitate such an environment. Also, Wild-Bode et al.(6) have shown, in animal models, that sub-lethal doses of irradiation promote the migration and invasiveness of glioma cells. It is conceivable that the use of conventionally fractionated radiation therapy (2 Gy per day), even in doses above 60 Gy, leads to only sub-lethal damage potentially promoting cell migration.
In a recently completed Phase 2 study for patients with newly diagnosed GBM, our group has shown that the use of concurrent temozolomide and hypofractionated radiation therapy to a dose of 60 Gy given in 20 fractions (daily dose of 3 Gy) preceded by 2 weeks of temozolomide given in the post-operative setting was associated with 2-year survival rates of 63% and 29% for MGMT methylated and unmethylated tumors, respectively (Dr. G. Shenouda, personal information. Manuscript submitted for publication). These promising results may be possibly due to a dual effect of the use of neoadjuvant temozolomide (prior to radiation therapy) and the use of a hypofractionated radiotherapy regimen. The upfront use of temozolomide may have affected tumor control by interfering with the upstream signaling event triggered by the RT preventing cell migration and also by promoting inhibition of glioma cell invasion.
GBMs are one of the most rapidly growing tumors. Primary GBMs typically develop and grow to be greater than 3 cm in less than 4 months. Under the current standard treatment approach, patients undergo surgery and, rather than starting adjuvant therapy immediately at a moment when there is the least amount of residual tumor burden, they wait 3-4 weeks, for practical reasons, to start adjuvant treatment with RT and TMZ. In addition, the combined treatment takes an additional 6 weeks to complete. Thus it takes 9-10 weeks for patients to complete maximum local treatment. In other words, one of the most aggressive tumors has been given another 9-10 weeks to proliferate, repopulate and invade. It is conceivable that this delay in adjuvant treatment gives the residual brain cancer cells the opportunity to regrow and invade prior to completion of RT and TMZ thus contributing to 85% of all failures occurring at or within 2 cm of the original resection cavity margin.
The use of pre-operative RT, either alone or in combination with chemotherapy, has been successfully used in other pathologies. In patients with soft tissue sarcoma, localized . rectal cancer, locally advanced breast cancer, and esophageal cancer the use of pre-operative RT has been associated with improved local control (8-11). Recently, the use of neoadjuvant radiosurgery has been explored in patients harboring resectable metastatic brain lesions (12). A total of 47 patients underwent radiosurgery prior to the surgical procedure (total of 51 lesions) and the authors report high rates of local control with limited toxicity. The use of pre-operative RT has several theoretical advantages in patients with GBM. Neoadjuvant RT is delivered prior to the surgical procedure minimizing, theoretically, the risk of local cell migration at the time of the surgical intervention. It has also the advantage of treating a target that has an intact blood supply and, most importantly, RT will be delivered to a better defined target. It also allows a definitive portion of the treatment paradigm to be delivered in a timely manner with no prolonged delay.
- Conditions
- Glioblastoma Multiforme, Adult
- Being tested
- Temozolomide, Pre-Operative Radiation
- Medical subject headings
- Glioblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TemozolomideDrug
Also called Surgery
Experimental: Registered one arm study Seven days of pre-operative Radiation+Temozolomide followed by surgery plus TMZ, as adjuvant component.for six cycles.
Pre-Operative RadiationRadiation
Radiation is given with Temozolomide for 7 days before surgery
| Study group | Role | What they receive |
|---|---|---|
| Pre-operative RT and TMZ | Experimental | * Single Arm: Pre-operative Radiation +Temozolomide followed by Surgery plus six cycles of Temozolomide Receives: Drug: Temozolomide; Radiation: Pre-Operative Radiation |
What is being measured
The primary outcome is the main question the study is designed to answer.
To assess toxicity of the regimen
Toxicity will be assessed and graded using CTCAE V. 4.03
Measured: one year
Secondary outcomes (1)
Number of patients completing the study treatment
To determine the overall survival
Measured: one year.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Mar 2018
- Study startMar 2017 (estimated)
- Primary completionJun 2021 (estimated)
- Study completionNov 2023 (estimated)
Why it stopped: competing study was opened by the surgeon after this trial was opened
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (20)Papers the sponsor has linked to this study.
- Other trials for Glioblastoma Multiforme, AdultStudies of the same condition, open and under way.
- More trials run by McGill University Health Centre/Research Institute of the McGill University Health CentreThe 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 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- RT 28Gy in 7 fractions with a concomitant boost of 42Gy in 7 fractions+ Temozolomide (75mg/m2) followed by surgery then Temozolomide (150-200mg/m2) q 5 days every 28 days.
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- McGill University Health Centre/Research Institute of the McGill University Health Centre
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Valerie Panet-Raymond, McGill University Health Centre/Research Institute of the McGill University Health Centre
- Investigators
- Valerie Panet-Raymond, M.D., Principal investigator, McGill University Health Centre/Research Institute of the McGill University Health Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03480867
- Sponsor's protocol ID
- MUHC-2016-1524
- Acronym
- PARADIGMA
- Status last verified
- Aug 2019
- First submitted
- 21 Mar 2018
- Last updated
- 14 Aug 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: Upon official request approved by the Research Ethics Board (REB), some data may be shared depending on what needs to be shared.
Publications
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.
PubMed 15758009Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009 May;10(5):459-66. doi: 10.1016/S1470-2045(09)70025-7. Epub 2009 Mar 9.
PubMed 19269895Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573.
PubMed 24552317Stummer W, Meinel T, Ewelt C, Martus P, Jakobs O, Felsberg J, Reifenberger G. Prospective cohort study of radiotherapy with concomitant and adjuvant temozolomide chemotherapy for glioblastoma patients with no or minimal residual enhancing tumor load after surgery. J Neurooncol. 2012 May;108(1):89-97. doi: 10.1007/s11060-012-0798-3. Epub 2012 Feb 4.
PubMed 22307805Giese A, Bjerkvig R, Berens ME, Westphal M. Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol. 2003 Apr 15;21(8):1624-36. doi: 10.1200/JCO.2003.05.063.
PubMed 12697889Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W. Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. Cancer Res. 2001 Mar 15;61(6):2744-50.
PubMed 11289157Wick W, Wick A, Schulz JB, Dichgans J, Rodemann HP, Weller M. Prevention of irradiation-induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase. Cancer Res. 2002 Mar 15;62(6):1915-9.
PubMed 11912174O'Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, Wunder J, Kandel R, Goddard K, Sadura A, Pater J, Zee B. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002 Jun 29;359(9325):2235-41. doi: 10.1016/S0140-6736(02)09292-9.
PubMed 12103287Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004 Oct 21;351(17):1731-40. doi: 10.1056/NEJMoa040694.
PubMed 15496622Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg. 2003 Jun;185(6):538-43. doi: 10.1016/s0002-9610(03)00066-7.
PubMed 12781882Matuschek C, Bolke E, Roth SL, Orth K, Lang I, Bojar H, Janni JW, Audretsch W, Nestle-Kraemling C, Lammering G, Speer V, Gripp S, Gerber PA, Buhren BA, Sauer R, Peiper M, Schauer M, Dommach M, Struse-Soll K, Budach W. Long-term outcome after neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer and predictive factors for a pathologic complete remission : results of a multivariate analysis. Strahlenther Onkol. 2012 Sep;188(9):777-81. doi: 10.1007/s00066-012-0162-8. Epub 2012 Aug 11.
PubMed 22878547Asher AL, Burri SH, Wiggins WF, Kelly RP, Boltes MO, Mehrlich M, Norton HJ, Fraser RW. A new treatment paradigm: neoadjuvant radiosurgery before surgical resection of brain metastases with analysis of local tumor recurrence. Int J Radiat Oncol Biol Phys. 2014 Mar 15;88(4):899-906. doi: 10.1016/j.ijrobp.2013.12.013.
PubMed 24606851Law M, Yang S, Wang H, Babb JS, Johnson G, Cha S, Knopp EA, Zagzag D. Glioma grading: sensitivity, specificity, and predictive values of perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR imaging. AJNR Am J Neuroradiol. 2003 Nov-Dec;24(10):1989-98.
PubMed 14625221Warren KE, Patronas N, Aikin AA, Albert PS, Balis FM. Comparison of one-, two-, and three-dimensional measurements of childhood brain tumors. J Natl Cancer Inst. 2001 Sep 19;93(18):1401-5. doi: 10.1093/jnci/93.18.1401.
PubMed 11562391Boxerman JL, Ellingson BM, Jeyapalan S, Elinzano H, Harris RJ, Rogg JM, Pope WB, Safran H. Longitudinal DSC-MRI for Distinguishing Tumor Recurrence From Pseudoprogression in Patients With a High-grade Glioma. Am J Clin Oncol. 2017 Jun;40(3):228-234. doi: 10.1097/COC.0000000000000156.
PubMed 25436828
Study at a glance
From the registry record, last updated by the sponsor on 14 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pre-operative Radiation Therapy (RT) and Temozolomide (TMZ) in Patients With Newly Diagnosed Glioblastoma. A Phase I Study. (PARADIGMA)
- ClinicalTrials.gov ID
- NCT03480867
- Acronym / sponsor ID
- PARADIGMA / MUHC-2016-1524
- Conditions
- Glioblastoma Multiforme, Adult
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: competing study was opened by the surgeon after this trial was opened
- Enrolment
- 0 participants (actual)
- Lead sponsor
- McGill University Health Centre/Research Institute of the McGill University Health CentreUniversity, hospital or other
- Study start
- Mar 2017 (estimated)
- Primary completion
- Jun 2021 (estimated)
- Study completion
- Nov 2023 (estimated)
- First posted
- 29 Mar 2018 (actual)
- 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.
Glioblastoma (GBM) is the most common primary brain cancer in adults. Despite surgery, conventional radiotherapy, and chemotherapy, the average survival for GBM is 15-16 months. Although additional chemoradiotherapy has been shown to increase survival, the majority recur at the original location.
Despite many efforts to improve the local control by improving surgical techniques, increasing the radiotherapy dose or adding newer chemotherapy agents, these attempts have failed to show a survival benefit or an improved cancer control. People who are not participating in a study are usually treated with surgery followed by radiation (6 weeks duration) together with temozolomide (chemotherapy drug) followed by temozolomide alone. For patients who receive this usual treatment approach for this cancer, about 4 out of 100 are free of cancer growth five years later. Because GBM invades the surrounding normal brain, this study is looking into the possibility of minimizing invasion by starting treatment using the combination of radiotherapy and chemotherapy prior to surgery. This approach is an experimental form of treatment and the diagnosis is based exclusively on imaging and not on histology of the tumour tissue, and there is a possibility that your tumor may not be a GB but of other origins.
Detailed description
One of the deadly properties of GBM is its capacity to diffusely infiltrate the surrounding normal brain tissue. Unlikely many malignancies, in GBM local disease progression, rather than metastatic disease, is the leading cause of death. Extent of resection plays a key role in the treatment of these patients with complete surgical resection improving outcome. In a prospective, non- interventional, multi-institutional study of over 140 patients with GBM and minimal or no residual tumor on post-operative MRI, Stummer et al.have shown that extent of resection is indeed associated with improved survival. However, despite evidence of complete resection on post-operative imaging studies, surgery is rarely truly complete. GBMs are invasive tumors and, at time of surgery, a clear boundary is not clearly identifiable, either on pre- or intra- operative imaging. Even when sophisticated imaging'techniques are used, they are unable to detect invasive brain cancer cell for proper pre-operative surgical planning to optimally delineate the tumor boundaries for a truly complete resection. Even if they were, brain eloquence would preclude a complete resection of most GBMs.
Despite extensive and complete surgical tumor removal coupled with radiation and chemotherapy, even in high doses, 90% of patients still fail at the border or within a few centimeters from the surgical cavity. Glioma cell migration outside the original tumor site may be responsible for this recurrence pattern. Cell migration is a complex, dynamic process and is well-documented in GBM. It involves, at least, 3 independent but coordinated biologic processes: 1) cell adhesion to components of the extracellular matrix, 2) cell's own motility and 3) invasion. Giese et al.) reported that cell migration is established by several independent mechanisms, facilitating the spread of tumor astrocytes, but with cell motility being the possible common denominator for this biologic behavior.
Invasion of tumor glioma cells is a multi-factorial process. To migrate, the cell needs a change in morphology and to interact with the extracellular matrix. It is possible that the surgical insult at the time of tumor removal may facilitate such an environment. Also, Wild-Bode et al.(6) have shown, in animal models, that sub-lethal doses of irradiation promote the migration and invasiveness of glioma cells. It is conceivable that the use of conventionally fractionated radiation therapy (2 Gy per day), even in doses above 60 Gy, leads to only sub-lethal damage potentially promoting cell migration.
In a recently completed Phase 2 study for patients with newly diagnosed GBM, our group has shown that the use of concurrent temozolomide and hypofractionated radiation therapy to a dose of 60 Gy given in 20 fractions (daily dose of 3 Gy) preceded by 2 weeks of temozolomide given in the post-operative setting was associated with 2-year survival rates of 63% and 29% for MGMT methylated and unmethylated tumors, respectively (Dr. G. Shenouda, personal information. Manuscript submitted for publication). These promising results may be possibly due to a dual effect of the use of neoadjuvant temozolomide (prior to radiation therapy) and the use of a hypofractionated radiotherapy regimen. The upfront use of temozolomide may have affected tumor control by interfering with the upstream signaling event triggered by the RT preventing cell migration and also by promoting inhibition of glioma cell invasion.
GBMs are one of the most rapidly growing tumors. Primary GBMs typically develop and grow to be greater than 3 cm in less than 4 months. Under the current standard treatment approach, patients undergo surgery and, rather than starting adjuvant therapy immediately at a moment when there is the least amount of residual tumor burden, they wait 3-4 weeks, for practical reasons, to start adjuvant treatment with RT and TMZ. In addition, the combined treatment takes an additional 6 weeks to complete. Thus it takes 9-10 weeks for patients to complete maximum local treatment. In other words, one of the most aggressive tumors has been given another 9-10 weeks to proliferate, repopulate and invade. It is conceivable that this delay in adjuvant treatment gives the residual brain cancer cells the opportunity to regrow and invade prior to completion of RT and TMZ thus contributing to 85% of all failures occurring at or within 2 cm of the original resection cavity margin.
The use of pre-operative RT, either alone or in combination with chemotherapy, has been successfully used in other pathologies. In patients with soft tissue sarcoma, localized . rectal cancer, locally advanced breast cancer, and esophageal cancer the use of pre-operative RT has been associated with improved local control (8-11). Recently, the use of neoadjuvant radiosurgery has been explored in patients harboring resectable metastatic brain lesions (12). A total of 47 patients underwent radiosurgery prior to the surgical procedure (total of 51 lesions) and the authors report high rates of local control with limited toxicity. The use of pre-operative RT has several theoretical advantages in patients with GBM. Neoadjuvant RT is delivered prior to the surgical procedure minimizing, theoretically, the risk of local cell migration at the time of the surgical intervention. It has also the advantage of treating a target that has an intact blood supply and, most importantly, RT will be delivered to a better defined target. It also allows a definitive portion of the treatment paradigm to be delivered in a timely manner with no prolonged delay.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- RT 28Gy in 7 fractions with a concomitant boost of 42Gy in 7 fractions+ Temozolomide (75mg/m2) followed by surgery then Temozolomide (150-200mg/m2) q 5 days every 28 days.
| Arm | Type | Receives |
|---|---|---|
| Pre-operative RT and TMZ | Experimental | Drug: Temozolomide, Radiation: Pre-Operative Radiation* Single Arm: Pre-operative Radiation +Temozolomide followed by Surgery plus six cycles of Temozolomide |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Newly diagnosed (MR image-based) GBM - Must be able to undergo gadolinium-enhanced MRI.
- Must be a candidate for radical surgical resection in the opinion of the neurosurgeon.
- The tumor must measure less than 6 cm in maximum diameter. The tumor diameter will be the greatest diameter as measured on the contrast-enhanced MRI.
- A neurosurgical oncologist, radiation oncologist and neuro-oncologist will assess each patient in advance of enrollment.
- The estimated post-surgical radiation field must be compatible with the proposed radiation scheme - ie, to ensure a safe radiation margin from structures such as the optic apparatus and brain stem.
Key exclusion criteria (8 listed)
- Tumors within 1 cm from critical structures (brainstem, optic apparatus), or with massive edema, or with the possibility of herniation, or any tumor that in the neurosurgeon's opinion would be considered unsafe to delay surgery or is not grossly resectable.
- Prior invasive malignancy (except for non-melanomatous skin cancer, non- invasive bladder cancer, and non-invasive cervix cancer) unless disease free for 2:5 years.
- Recurrent or multifocal GBM.
- Any site of metastatic disease (drop metastases).
- Prior chemotherapy or radiation therapy to the head or neck (except for T1 glottic tumor
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: SurgeryExperimental: Registered one arm study Seven days of pre-operative Radiation+Temozolomide followed by surgery plus TMZ, as adjuvant component.for six cycles. | Drug | Pre-operative RT and TMZ |
| Pre-Operative RadiationRadiation is given with Temozolomide for 7 days before surgery | Radiation | Pre-operative RT and TMZ |
Primary outcome
To assess toxicity of the regimen
Time frame: one year
Toxicity will be assessed and graded using CTCAE V. 4.03
1 secondary outcome
Number of patients completing the study treatment
Time frame: one year.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Aug 2019.
- Background: PubMed 15758009Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.
- Background: PubMed 19269895Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009 May;10(5):459-66. doi: 10.1016/S1470-2045(09)70025-7. Epub 2009 Mar 9.
- Background: PubMed 24552317Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573.
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- Individual participant dataSharing planned: Undecided. Upon official request approved by the Research Ethics Board (REB), some data may be shared depending on what needs to be shared.
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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.
Valerie Panet-Raymond, M.D. principal investigator
McGill University Health Centre/Research Institute of the McGill University Health Centre
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Temozolomide and Pre-Operative Radiation in people with Glioblastoma Multiforme, Adult, run by McGill University Health Centre/Research Institute of the McGill University Health Centre at 1 site in Canada.
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 12 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: withdrawn, as of the sponsor's last update on 14 Aug 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 Canada. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
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?
To assess toxicity of the regimen (time frame: one year). 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 NCT03480867, which also lists 20 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 14 Aug 2019.