Pre-operative RT and TMZ in Patients With Newly Diagnosed GBM Diagnosed Glioblastoma. A Phase I Study. (PARADIGMA) (PARADIGMA)
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|ClinicalTrials.gov Identifier: NCT03480867|
Recruitment Status : Withdrawn (competing study was opened by the surgeon after this trial was opened)
First Posted : March 29, 2018
Last Update Posted : August 14, 2019
|First Submitted Date ICMJE||March 21, 2018|
|First Posted Date ICMJE||March 29, 2018|
|Last Update Posted Date||August 14, 2019|
|Estimated Study Start Date ICMJE||March 2017|
|Estimated Primary Completion Date||June 2021 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||To assess toxicity of the regimen [ Time Frame: one year ]
Toxicity will be assessed and graded using CTCAE V. 4.03
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT03480867 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Number of patients completing the study treatment [ Time Frame: one year. ]
To determine the overall survival
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Pre-operative RT and TMZ in Patients With Newly Diagnosed GBM Diagnosed Glioblastoma. A Phase I Study. (PARADIGMA)|
|Official Title ICMJE||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.
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 Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1|
|Study Design ICMJE||Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment
|Condition ICMJE||Glioblastoma Multiforme, Adult|
|Study Arms ICMJE||Experimental: Pre-operative RT and TMZ
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Withdrawn|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||November 2023|
|Estimated Primary Completion Date||June 2021 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Canada|
|Removed Location Countries|
|NCT Number ICMJE||NCT03480867|
|Other Study ID Numbers ICMJE||MUHC-2016-1524|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Valerie Panet-Raymond, McGill University Health Centre/Research Institute of the McGill University Health Centre|
|Study Sponsor ICMJE||McGill University Health Centre/Research Institute of the McGill University Health Centre|
|Collaborators ICMJE||Not Provided|
|PRS Account||McGill University Health Centre/Research Institute of the McGill University Health Centre|
|Verification Date||August 2019|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP