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Pre-operative RT and TMZ in Patients With Newly Diagnosed GBM Diagnosed Glioblastoma. A Phase I Study. (PARADIGMA) (PARADIGMA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. 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Recruitment Status : Withdrawn (competing study was opened by the surgeon after this trial was opened)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
Information provided by (Responsible Party):
Valerie Panet-Raymond, McGill University Health Centre/Research Institute of the McGill University Health Centre

Tracking Information
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
 (submitted: March 21, 2018)
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
Current Secondary Outcome Measures  ICMJE
 (submitted: March 21, 2018)
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
Descriptive Information
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)
Brief 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.

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 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
Intervention  ICMJE
  • Drug: Temozolomide
    Experimental: Registered one arm study Seven days of pre-operative Radiation+Temozolomide followed by surgery plus TMZ, as adjuvant component.for six cycles.
    Other Name: Surgery
  • Radiation: Pre-Operative Radiation
    Radiation is given with Temozolomide for 7 days before surgery
Study Arms  ICMJE Experimental: Pre-operative RT and TMZ
  • Single Arm: Pre-operative Radiation +Temozolomide followed by Surgery plus six cycles of Temozolomide
  • Drug: Temozolomide
  • Radiation: Pre-Operative Radiation
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Withdrawn
Actual Enrollment  ICMJE
 (submitted: August 12, 2019)
Original Estimated Enrollment  ICMJE
 (submitted: March 21, 2018)
Estimated Study Completion Date  ICMJE November 2023
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • 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)
  • 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.

Exclusion Criteria:

  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
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  
Administrative Information
NCT Number  ICMJE NCT03480867
Other Study ID Numbers  ICMJE MUHC-2016-1524
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description: Upon official request approved by the Research Ethics Board (REB), some data may be shared depending on what needs to be shared.
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
Investigators  ICMJE
Principal Investigator: Valerie Panet-Raymond, M.D. McGill University Health Centre/Research Institute of the McGill University Health Centre
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