Sulfasalazine and Stereotactic Radiosurgery for Recurrent Glioblastoma

NCT04205357 | Completed Phase 1 DMC

• 1 other identifier: 2019/6834
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Glioma; Glioblastoma; Recurrent Glioblastoma

Outcome Measures

Primary Outcomes (1)

• Toxicity (Common Terminology Criteria for Adverse Event v 4.0)

  Determining the maximum tolerated and recommended dose of sulfasalazine as radiosensitizer.

  1 month

Secondary Outcomes (7)

• Intratumoral Glutathione production

  4 days

• Presence of radiation necrosis

  1 month

• Progression free survival

  1 year

• Overall survival

  2 years

• Quality of life (Functional Assessment of Cancer Therapy-Brain)

  1 year

Study Arms (1)

Sulfasalazine in addition to stereotactic radiosurgery

OTHER

3 + 3 dose escalation The first cohort of 3-6 patients will receive 1.5 g Sulfasalazine daily for 3 days before single fraction stereotactic radiosurgery utilizing 12 Gy prescription dose to the tumor margin. The second, third and fourth cohort will receive 3 days pretreatment with 3 g, 4.5 g and 6 g Sulfasalazine, respectively, before 12 Gy single fraction stereotactic radiosurgery.

Drug: Sulfasalazine

Interventions

Sulfasalazine DRUG

Sulfasalazine combined with stereotactic radiosurgery

Also known as: Stereotactic radiosurgery

Sulfasalazine in addition to stereotactic radiosurgery

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Haukeland University Hospital: lead
• Norwegian Cancer Society: collaborator
• Northwell Health: collaborator
• Weill Medical College of Cornell University: collaborator
• University of Bergen: collaborator
• Helse Stavanger HF: collaborator

Study Sites (1)

Haukeland University Hospital

Bergen, 5021, Norway

Location

Related Publications (10)

• 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.

  PMID: 25798841 BACKGROUND

• Skeie BS, Enger PO, Brogger J, Ganz JC, Thorsen F, Heggdal JI, Pedersen PH. gamma knife surgery versus reoperation for recurrent glioblastoma multiforme. World Neurosurg. 2012 Dec;78(6):658-69. doi: 10.1016/j.wneu.2012.03.024. Epub 2012 Apr 4.

  PMID: 22484078 BACKGROUND

• Dodoo E, Huffmann B, Peredo I, Grinaker H, Sinclair G, Machinis T, Enger PO, Skeie BS, Pedersen PH, Ohlsson M, Orrego A, Kraepelien T, Barsoum P, Benmakhlouf H, Herrman L, Svensson M, Lippitz B. Increased survival using delayed gamma knife radiosurgery for recurrent high-grade glioma: a feasibility study. World Neurosurg. 2014 Nov;82(5):e623-32. doi: 10.1016/j.wneu.2014.06.011. Epub 2014 Jun 13.

  PMID: 24930898 BACKGROUND

• Sontheimer H, Bridges RJ. Sulfasalazine for brain cancer fits. Expert Opin Investig Drugs. 2012 May;21(5):575-8. doi: 10.1517/13543784.2012.670634. Epub 2012 Mar 12.

  PMID: 22404218 BACKGROUND

• Chung WJ, Lyons SA, Nelson GM, Hamza H, Gladson CL, Gillespie GY, Sontheimer H. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J Neurosci. 2005 Aug 3;25(31):7101-10. doi: 10.1523/JNEUROSCI.5258-04.2005.

  PMID: 16079392 BACKGROUND

• Skeie BS, Wang J, Dodoo E, Heggdal JI, Gronli J, Sleire L, Bragstad S, Ganz JC, Chekenya M, Mork S, Pedersen PH, Enger PO. Gamma knife surgery as monotherapy with clinically relevant doses prolongs survival in a human GBM xenograft model. Biomed Res Int. 2013;2013:139674. doi: 10.1155/2013/139674. Epub 2013 Nov 10.

  PMID: 24312904 BACKGROUND

• Takeuchi S, Wada K, Nagatani K, Otani N, Osada H, Nawashiro H. Sulfasalazine and temozolomide with radiation therapy for newly diagnosed glioblastoma. Neurol India. 2014 Jan-Feb;62(1):42-7. doi: 10.4103/0028-3886.128280.

  PMID: 24608453 BACKGROUND

• Robe PA, Martin DH, Nguyen-Khac MT, Artesi M, Deprez M, Albert A, Vanbelle S, Califice S, Bredel M, Bours V. Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults. BMC Cancer. 2009 Oct 19;9:372. doi: 10.1186/1471-2407-9-372.

  PMID: 19840379 BACKGROUND

• Wang F, Oudaert I, Tu C, Maes A, Van der Vreken A, Vlummens P, De Bruyne E, De Veirman K, Wang Y, Fan R, Massie A, Vanderkerken K, Shang P, Menu E. System Xc- inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance. Cancer Lett. 2022 Jun 1;535:215649. doi: 10.1016/j.canlet.2022.215649. Epub 2022 Mar 18.

  PMID: 35315341 DERIVED

• Liu N, Zhang J, Yin M, Liu H, Zhang X, Li J, Yan B, Guo Y, Zhou J, Tao J, Hu S, Chen X, Peng C. Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization. Mol Ther. 2021 Jul 7;29(7):2321-2334. doi: 10.1016/j.ymthe.2021.03.013. Epub 2021 Mar 17.

  PMID: 33744468 DERIVED

MeSH Terms

Conditions

Glioma; Glioblastoma

Interventions

Sulfasalazine; Radiosurgery

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Astrocytoma

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Bente S Skeie

  Haukeland University Hospial

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: November 21, 2019
• First Posted: December 19, 2019
• Study Start: March 1, 2020
• Primary Completion: October 14, 2022
• Study Completion: October 14, 2022
• Last Updated: March 3, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

NO (1)