Clinical trial NCT04205357: Sulfasalazine and Stereotactic Radiosurgery for Recurrent Glioblastoma
Official title: Phase I Trial Combining Sulfasalazine and Gamma Knife Radiosurgery for Recurrent Glioblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Glioma
Glioblastoma
Recurrent Glioblastoma
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
Collaborators: name: Norwegian Cancer Society
name: Northwell Health
name: Weill Medical College of Cornell University
name: University of Bergen
name: Helse Stavanger HF
First posted: 2019-12-19
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: 3 + 3 dose escalation design: Cohort 1 (3-6 patients): 1.5 gr Sulfasalazine x 1 for 3 days Cohort 2 (3-6 patients): 3.0 gr Sulfasalazine x 1 for 3 days Cohort 3 (3-6 patients): 4.5 gr SSulfasalazine x 1 for 3 days Cohort 4 (3-6 patients): 6.0 gr Sulfasalazine x 1 for 3 days
Primary purpose: TREATMENT

Brief summary: This study evaluates the safety associated with the addition of sulfasalazine to stereotactic radiosurgery for recurrent glioblastoma. Sulfasalazine is a potential tumor selective radiosensitizer.

Detailed description: Glioblastoma is the most aggressive and most common type of primary brain cancer. Standard treatment at diagnosis is surgery followed by high dose radiation therapy and chemotherapy. Despite initial treatment nearly all patients will experience recurrence of the tumor with a dismal prognosis. There is no consensus on standard of care at recurrence. Reoperation is associated with a high risk of complications and further conventional radiation therapy is often not possible as the maximum tolerated dose to the normal brain has already been given. In addition most tumors have developed resistance towards chemotherapy. Stereotactic radiosurgery (SRS) may be administered despite prior initial radiation treatment but in order to avoid radiation induced complications only limited doses to limited tumor volumes can be applied.

Developing new strategies to improve the effect of radiation selectively on tumor cells without simultaneously increase the radiation induced damage of normal brain would be valuable.

The investigators have shown in experimental studies that the drug sulfasalazine enhances the number of cancer cells that dies as result of radiation therapy and thereby improves survival in combination with SRS in animals with glioblastoma. Sulfasalazine inhibits the production of an antioxidant that normally protects the tumor against radiation. Hopefully the trial will result in a new and more effective treatment option for patients with recurrent glioblastoma.

Eligibility criteria: Inclusion Criteria:

* Histologically verified glioblastoma multiforme with recurrence (first or second relapse, all subtypes) based on the Response Assessment in Neuro-Oncology criteria.
* Prior standard therapy for newly diagnosed glioblastoma consisting of surgery, standard fractionated radiotherapy to 60 Gy concomitant with Temozolomide
* Has been informed of other treatment options
* Must be eligible to gamma knife treatment
* Tumor size ≤ 3 cm in diameter (≤ 15 cm3 ) on MRI dated no more than 30 days before SRS treatment
* Must be at least 18 years of age
* Must be ambulatory with a Karnofsky performance status of ≥ 70
* Life expectancy \> 12 weeks
* Laboratory parameters for vital functions should be in the normal reference range. Laboratory abnormalities that are not clinically significant are generally permitted, except for the following laboratory parameters, which must be within the ranges specified:

Hematology: White blood cell count: ≥ 3.0 x 109/l, Platelet count:: ≥ 100 x 109/l, Hemoglobin: ≥ 100 g/l, Total bilirubin level: \<1.5 times the upper limit of normal (ULN) (except in patients with Gilbert's Syndrome who must have a total bilirubin less than 51,3 µmol/L), alanine aminotransferase \< 3 times the ULN, Creatinine \< 1.5 times the ULN, Normal prothrombin time / international normalized ratio (PT INR) \< 1.4, Absolute neutrophil count: ≥ 1 x109/L without the support of filgrastim.

* More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less or as specified in the eligibility criteria.
* Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to national/local regulations

Exclusion Criteria:

* Allergy to sulfa drugs
* Adverse reactions to salicylates
* Known hypersensitivity to sulfasalazine, its metabolites or any of the excipients (Povidone; Maize starch; magnesium stearate; colloidal silicon dioxide)
* Eligible to alternative standard treatments with temozolomide
* Treatment with sulfasalazine after glioblastoma diagnosis
* Participation in pharmacokinetic trial within 4 weeks
* Participation in immunotherapy trial within 4 weeks
* History of psychological symptoms affecting ability to consent to and/or fulfill the protocol
* Other malignant diseases and multiple sclerosis
* Pregnant or breast feeding patients.
* Porphyria
* Kidney of liver deficiencies
* Glucose-6-phosphate dehydrogenase deficiency
* Severe allergy or bronchial asthma
* History of erythema multiforme
* Significant heart failure or renal failure
* Intestinal or urinary obstruction
* Any reason why, in the opinion of the investigator, the patient should not participate (e.g. not able to comply with study procedures).

Primary outcomes:
measure: Toxicity (Common Terminology Criteria for Adverse Event v 4.0)
timeFrame: 1 month
Secondary outcomes:
measure: Intratumoral Glutathione production
timeFrame: 4 days
measure: Presence of radiation necrosis
timeFrame: 1 month
measure: Progression free survival
timeFrame: 1 year
measure: Overall survival
timeFrame: 2 years
measure: Quality of life (Functional Assessment of Cancer Therapy-Brain)
timeFrame: 1 year
measure: Karnofsky performance score (KPS)
timeFrame: 1 year
measure: Steroid use in mg over time
timeFrame: 1 year
Other outcomes:
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
Study officials:
affiliation: Haukeland University Hospial
name: Bente S Skeie
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sleire L, Skeie BS, Netland IA, Forde HE, Dodoo E, Selheim F, Leiss L, Heggdal JI, Pedersen PH, Wang J, Enger PO. Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc-, leading to glutathione depletion. Oncogene. 2015 Dec 3;34(49):5951-9. doi: 10.1038/onc.2015.60. Epub 2015 Mar 23.
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