None listed
Conditions
Brief summary
The purpose of this study is to determine the safety of BMS-986504 in participants diagnosed with glioblastoma (GBM) that has progressed after previous treatment. The study will evaluate the safety prior to and after surgical removal of GBM. BMS-986504 works by attaching to and blocking a molecule called Protein Arginine Methyltransferase 5 (PRMT5). PRMT5 is a protein that has a crucial role in gene expression and repairing damage to deoxyribonucleic acid (DNA). Cancer cells overexpress PRMT5 which allow these cells to survive and multiply. Medicines that block PRMT5 help to selectively destroy the cancer cells and allow normal cells to remain unharmed. Who is it for? You may be eligible for this study if you are aged 18 years or older, you have recurrent MTAP-deleted GBM, and you meet additional criteria relating to your wellbeing and ability to tolerate surgical procedures. Study details Participants who choose to enrol in this study will undergo two brain surgeries; the purpose of the first surgery is to perform a biopsy. A biopsy is a procedure that involves removing a sample of the cancer to be analysed. The purpose of the second surgery is to remove as much of the GBM cancer as safely as possible. Participants will receive BMS-986504 after the biopsy and prior to surgical removal of your GBM. Treatment given prior to surgery is referred to as ‘neoadjuvant treatment’. Following surgery, participants will receive BMS-986504 (treatment given after surgery is referred to as ‘adjuvant treatment’). Blood tests and other assessments will be performed regularly to monitor safety and response to treatment. It is hoped that this study will show that BMS-986504 is safe to deliver to patients with GBM cancer, and that BMS-986504 works to shrink GBM cancers making them easier to remove surgically.
Interventions
Participants will receive the drug BMS-986504 prior to and following surgical resection of the glioblastoma cancer. Treatment given prior to surgery is referred to as ‘neoadjuvant treatment’. Treatment given after surgery is referred to as ‘adjuvant treatment’.
BMS-986504 Neoadjuvant treatment: oral tablet, 600mg once daily, administered continuously from Day 1 to 21 of Cycle 1 or from Day 1 to the day of surgical resection. Participants will be given a medication diary to record when doses ar
Participants will receive the drug BMS-986504 prior to and following surgical resection of the glioblastoma cancer. Treatment given prior to surgery is referred to as ‘neoadjuvant treatment’. Treatment given after surgery is referred to as ‘adjuvant treatment’. BMS-986504 Neoadjuvant treatment: oral tablet, 600mg once daily, administered continuously from Day 1 to 21 of Cycle 1 or from Day 1 to the day of surgical resection. Participants will be given a medication diary to record when doses are taken. Surgical Resection: The treating neurosurgeon will perform surgery to remove the glioblastoma cancer. Surgical adjuncts (such as 5-aminolevulenic acid, intraoperative MRI, or awake surgery with cortical mapping) will be utilised. After the surgery participants will be monitored in the neurosurgery ward for a minimum of two days. BMS-986504 Adjuvant treatment: oral tablet, 600mg once daily, administered continuously until disease progression, commencement of new anti-glioblastoma therapy or unacceptable toxicity. Participants will be evaluated at 3-weekly intervals to determine cessation or continuation of BMS-986504 adjuvant treatment. Participants will be given a medication diary to record when doses are taken.
Sponsors
Peter MacCallum Cancer Centre
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient has provided written informed consent using the PRIME Patient Information and Consent Form (PICF) 2. Histologically confirmed intracranial GBM per 2021 WHO classification guidelines 3. MTAP deficient tumours defined as evidence of homozygous deletion of one or more exons of the MTAP gene in tumour tissue AND/OR loss of MTAP expression in the tumour tissue 4. Adults greater than or equal to 18 years of age at the time of signing consent 5. Evidence of recurrent disease demonstrated by radiological progression 6. Patients must have received standard first line treatment for GBM, including Temozolomide (TMZ) and radiation therapy. Patients who are MGMT unmethylated do not need to have receive TMZ to be eligible, radiation alone is sufficient 7. Patients who in the opinion of the treating neurosurgeon require resection and suitable for two surgical procedures 8. Patient is willing to undergo planned surgical procedures 9. Eastern Co-operative Oncology Group (ECOG) performance status of 0-1 10. Minimum life expectancy of 6 months as per investigator judgement 11. Be able to understand and comply with the requirements of the study, as judged by the Investigator 12. Able to swallow and retain orally administered study treatment and willing to record daily adherence to study treatment 13. Haematological function as follows: • Absolute neutrophil count greater than or equal to 1.5 x 109/L • Platelet count greater than or equal to 100 x 109/L • Haemoglobin (Hb) > 90 g/L • Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of normal (ULN) 14. Renal function as follows: Serum creatinine less than or equal to 1.5 x ULN or calculated creatinine clearance greater than or equal to 40 ml/min using the Cockcroft-Gault formula 15. Hepatic function as follows: • Total bilirubin less than or equal to 1.5 x ULN (Exception: Patient has known or suspected Gilbert’s Syndrome for which additional lab testing of direct and/or indirect bilirubin supports this diagnosis. In these instances, a total bilirubin of less than or equal to 3.0 x ULN is acceptable) • Alkaline phosphatase (ALP) less than or equal to 2.5 x ULN • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x ULN • Serum albumin greater than or equal to 25 g/L 16. Adequate cardiac function, as follows: Mean resting QTcF interval <470 msec, obtained from triplicate ECGs performed at Screening 17. Negative human immunodeficiency virus (HIV) test at Screening 18. Negative hepatitis B surface antigen (HbsAg) test at Screening Note: Patients who are HbsAg positive due to prior hepatitis B vaccination and have no evidence of active infection are eligible 19. Negative hepatitis C antibody (anti-HCV) test at Screening 20. Women of childbearing potential (WCBP) must agree to use a combination of a hormonal and a non-hormonal contraceptive method or a non-hormonal contraception method alone that is highly effective (with a failure rate of < 1% per year) during study treatment and for at least 1 month following the last dose of study drug and agree not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period. Note: WCBP are not permitted to use hormonal contraceptive methods alone as a highly effective method of contraception 21. Sexually active male patients must use a condom during intercourse and must agree to refrain from sperm donation, from registration on the study until 1 month after the last dose of treatment 22. Women of childbearing potential must have a negative highly sensitive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 72 hours prior to registration
Exclusion criteria
1. Multicentric / multifocal tumour in which safe maximal resection is not feasible 2. Tumour involves cerebellum, brainstem, or deep basal ganglia 3. Contraindication to surgery 4. Prior neurosurgical biopsy or resection within 28 days prior to registration 5. Patients who require urgent resection for mass effect, cerebral oedema, or hydrocephalus in the opinion of the treating neurosurgeon 6. Evidence of acute intracranial/intra-tumoural haemorrhage, which requires urgent intervention 7. History of CNS bleeding as defined by stroke or arterial thrombosis (e.g., stroke or transient ischaemic attack) within 6 months prior to registration 8. Patients with contraindications to MRI or unwilling to undergo MRI 9. Prior treatment with MATA2 inhibitor or a PRMT5 inhibitor 10. Prior treatment with bevacizumab or immunotherapy. Note: Patients who have received lomustine are eligible 11. Administration of any non-cytotoxic potential anti-tumour agent and or herbal preparation/medications within 7 days of planned biopsy 12. Use of therapeutic anticoagulation. Note: Prophylactic low molecular weight heparins and low dose aspirin is allowed 13. Treatment with immunosuppressive medications. Note: Low-dose corticosteroids (less than or equal to 2 mg/day dexamethasone or equivalent) for tumour-associated oedema is permitted. Patients who require corticosteroids > 2 mg/day dexamethasone (or equivalent) for acute emergencies during the screening window will be eligible if the corticosteroid dosing reduces to less than or equal to 2 mg/day dexamethasone (or equivalent) at least one day prior to the initial trial-mandated biopsy 14. Ongoing need for a medication known as a strong inhibitor or strong inducer of CYP3A4 and/or P-glycoprotein (P-gp) or a proton-pump inhibitor that cannot be switched to alternative treatment prior to registration. The following drug interaction databases and other literature can be utilised to determine the CYP3A4/P-gp inhibitors and inducers: https://www.fda.gov/drugs/drug-interactions-labeling/drugdevelopment-and-druginteractions-table-substratesinhibitors-and-inducers; https://druginteractions.medicine.iu.edu/MainTable.aspxhttps://druginteractions.medicine.iu.edu/MainTable.aspx. 15. Ongoing need for a medication with a known risk of Torsades de Pointes that cannot be switched to alternative treatment prior to registration 16. Significant cardiac dysfunction defined as: • Unstable angina pectoris or myocardial infarction within 6 months prior to registration • Congestive heart failure greater than or equal to New York Heart Association Class 3 within 6 months prior to registration • Left ventricular ejection fraction (LVEF) < 50% • Prolonged QTc > 470 milliseconds or medical or immediate family history of congenital Long QT Syndrome • Symptomatic or uncontrolled atrial fibrillation or other arrhythmia within 6 months prior to registration 17. Gastrointestinal tract disease causing inability to take oral medication, malabsorption syndrome, gastric/jejunal tube feeds, uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis) 18. Active tuberculosis 19. Severe infection within 4 weeks prior to registration. A severe infection is defined as an infection that leads to septic shock, organ dysfunction, or admission to intensive care within four weeks of a patient's registration. It also includes any active, uncontrolled infection, such as fungemia or bacteraemia 20. Treatment with a live, attenuated vaccine within 4 weeks prior to registration, or anticipation of need for such a vaccine during the study 21. Patients are excluded if they have had another malignancy or received treatment for another malignancy within two years of enrolment. The only exceptions are patients with adequately treated cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin. Patients with a history of other malignancies are eligible if they have been treated with curative intent or continuously disease free for at least 2 years after definitive primary treatment 22. Major surgical procedure, within 4 weeks prior to registration 23. History of idiopathic pulmonary fibrosis, organising pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis 24. Patient is pregnant or breast-feeding 25. Known severe hypersensitivity to study treatment and/or any of its excipients 26. Prior allogeneic stem cell or solid organ transplantation 27. Presence of any psychological, social, geographical, or other condition for which, in the opinion of the site Investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
Outcome results
None listed