Clinical trial NCT04209790: Neoadjuvant Chemoradiation for Resectable Glioblastoma
Official title: Phase II Study of Neoadjuvant Chemoradiation for Resectable Glioblastoma (NeoGlio)
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Glioblastoma
Surgery
High Grade Glioma
Keywords: Glioblastoma
Lead sponsor: Geisinger Clinic
Sponsor class: OTHER
First posted: 2019-12-24
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: After standard treatment of Glioblastoma multiforme (GBM) with resection and adjuvant therapy, local failure the dominant pattern of failure. Neo adjuvant therapy consistently provides the potential for improved local control and removal of residual stem cell niches. The hypothesis is that earlier institution of neo adjuvant chemo radiation therapy in GBM would improve local control and potentially overall survival.

Involved field radiation is often employed to treat unresectable or sub totally resected GBM. Radiating native GBM is not uncommon as many tumors are not safely resectable due to its location in eloquent brain. Planned neoadjuvant chemo radiation prior to immediate surgical resection in glioblastoma is a novel approach in resectable tumors.
Primary purpose: TREATMENT

Brief summary: Preoperative therapy has not been well studied in resectable glioblastoma. This study attempts to prospectively assess the feasibility and efficacy of preoperative chemo radiation in improving local control, as this is the predominant mode of failure in these patients leading to poor outcomes.

This Phase II study design would be used to proceed with the study treatment after meeting pre-specified events in the initial phase, with goal being to determine whether the new treatment paradigm is sufficiently promising to warrant a major controlled clinical evaluation against the standard therapy.

Detailed description: Neo adjuvant, preoperative chemo radiation has consistently shown improvements in local disease control or organ preservation in many cancers including head and neck, esophageal, rectal, bladder cancers and sarcomas, leading to improvements in overall survival and limb or organ preservation.

This interventional study will be done in two phases using the Simon two-stage Phase II study design. The median progression-free survival of these patients with current standard of care therapy is in the range of 6-8 months (6.9 months in the standard of care). With the proposed trial of surgical resection of the tumor after chemotherapy and radiation the median progression free survival is anticipated to be approximately 11-12 months from subset analysis of available literature and based on prior data on other disease sites. In other words, the 7-month local progression rates is anticipated to decrease from 50% to 25%, or progression free survival improve from 50-75%

Eligibility criteria: Inclusion Criteria:

1. Newly diagnosed GBM with histopathological confirmation.
2. Surgically suitable for subtotal or gross total resection as determined by central review.
3. Karnofsky Performance Status (KPS)\>70
4. No contraindication for chemoradiation.
5. Complete blood count (CBC)/differential obtained within 28 days prior to registration, with adequate bone marrow function defined as follows:

   1. Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;
   2. Platelets ≥ 100,000 cells/mm3;
   3. Hemoglobin ≥ 8.0 g/dl (Note: the use of transfusion or other intervention to achieve Hgb ≥8.0 g/dl is acceptable)
6. Adequate hepatic function within 28 days prior to registration, as defined below:

   1. Alanine Aminotransferase (ALT) and Aspartate transaminase (AST) ≤ 3 x ULN
   2. Bilirubin ≤ 1.5 upper limit of normal (ULN)
7. Negative serum pregnancy test obtained for females of child-bearing potential within 28 days prior to step 2 registration.
8. Ability to get multiplanar contrast enhanced Magnetic Resonance Imaging (MRI)

Exclusion Criteria:

1. Recurrent, unresectable or multifocal malignant gliomas.
2. Any site of distant disease (for example, drop metastases from the GBM tumor site)
3. Prior radiation or chemotherapy or radiosensitizers for cancers of the brain and head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide).
4. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
5. Patents treated on any other therapeutic clinical protocols within 30 days prior to registration.
6. Inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker, or severe claustrophobia).
7. Severe, active co-morbidity, defined as follows:

   1. Transmural myocardial infarction within the last 6 months prior to registration
   2. History of recent myocardial infarction 1month prior
   3. New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 3 months prior to registration.
   4. Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to registration, with the exception of the craniotomy for surgical resection
   5. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
   6. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol.
   7. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
   8. Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is because the treatments involved in this protocol may be significantly immunosuppressive with potentially fatal outcomes in patients already immunosuppressed.
   9. Any other severe immuno-compromised condition.
   10. Active connective tissue disorders, such as lupus or scleroderma that in the opinion of the treating physician may put the patient at high risk for radiation toxicity.
   11. End-stage renal disease (i.e. on dialysis or dialysis has been recommended).
   12. Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy.

Primary outcomes:
measure: No study related undue toxicity or progression in >6 of 11 patients.
timeFrame: 7 months for each patient from registration.
measure: Progression Free Survival
timeFrame: 7 months after completion of therapy
Secondary outcomes:
Other outcomes:
Locations:
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Geisinger Wyoming Valley Medical Center
state: Pennsylvania
Study officials:
affiliation: Geisinger Clinic
name: Michel Lacroix, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Milano MT, Okunieff P, Donatello RS, Mohile NA, Sul J, Walter KA, Korones DN. Patterns and timing of recurrence after temozolomide-based chemoradiation for glioblastoma. Int J Radiat Oncol Biol Phys. 2010 Nov 15;78(4):1147-55. doi: 10.1016/j.ijrobp.2009.09.018. Epub 2010 Mar 6.
citation: 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.
citation: Yarbro JW. Future potential of adjuvant and neoadjuvant therapy. Semin Oncol. 1991 Dec;18(6):613-9. No abstract available.
citation: Filatova A, Acker T, Garvalov BK. The cancer stem cell niche(s): the crosstalk between glioma stem cells and their microenvironment. Biochim Biophys Acta. 2013 Feb;1830(2):2496-508. doi: 10.1016/j.bbagen.2012.10.008. Epub 2012 Oct 16.
citation: Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat Biol. 2014 Aug;90(8):615-21. doi: 10.3109/09553002.2014.892227. Epub 2014 Mar 7.