Status and phase
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About
PQR309 is an oral, dual pan-PI3K (phosphatidylinositol 3-kinase phosphoinositide 3-kinase) and mTOR (mammilian target of rapamycin) inhibitor that penetrates the blood-brain barrier at pharmacodynamically active concentrations. This study plans to evaluate PQR309 in treatment of patients with first progression of glioblastoma.
Full description
Open-label, non-randomized, two-stage, multi-center study evaluating clinical efficacy, safety, pharmacokinetics and pharmacodynamic effects of PQR309 in patients with progressive glioblastoma during or after standard temozolomide chemoradiotherapy.
The first stage of the study will enroll a minimum of 18 patients with glioblastoma at first progression during or after temozolomide chemoradiotherapy or temozolomide only. Following the completion of recruitment of patients in the first stage of the study, the decision will be made by the study team (study investigators and the sponsor), based on the continuous evaluation of safety and efficacy data, whether to continue recruitment of patients in the second stage while awaiting the data analyses. 17 additional patients may be enrolled for the second stage of the study, for a minimum of 35 patients in total. All patients evaluable for the primary endpoint will be followed until disease progression or death.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Patients with histologically confirmed glioblastoma at first progression following or during standard temozolomide chemoradiotherapy (TMZ/RTTMZ)
older than 18 years of age
Radiographic demonstration of disease progression by RANO criteria
Only for patients of the surgical cohort:
Only for patients of the non-surgical cohort:
Patient must have at least 1 formalin-fixed paraffin-embedded archival tumor tissue block representative of glioblastoma available from the first surgical resection of glioblastoma.
One prior systemic therapy regimen: patients must have received at least one dose of TMZ in the first line therapy. More than 6 cycles and alternative dosing regiments of TMZ are allowed.
If receiving corticosteroids, patients must have been on a stable or decreasing dose of corticosteroids and no more than 8 mg dexamethasone equivalent for ≥ 5 days prior to baseline MRI.
Karnofsky Performance Score (KPS) >70%.
More than 12 weeks from radiotherapy (RT)
More than 4 weeks from last administration of TMZ
More than 4 weeks from any investigational agent (at the judgment of the investigator and in agreement with lead investigator and PIQUR)
Adequate hematological, liver and renal function defined as follows:
Absolute neutrophil count (ANC) ≥1.5x109/l, platelets ≥ 100x109/l, hemoglobin ≥ 100g/L. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN Serum Creatinine ≤ 1.5 times ULN
Able and willing to swallow and retain oral medication
Female and male patients of reproductive potential must agree to use effective contraception from screening until 90 days after discontinuing study treatment*
Willing and able to sign the informed consent and to comply with the protocol for the duration of the study
Exclusion criteria
Second or later glioblastoma relapse
Received more than one systemic treatment regimen for glioblastoma
Patients receiving enzyme-inducing anti-epileptic drug (EIAED) within 7 days of the first dose of PQR309
Patient is taking a drug with known risk to promote QT prolongation and Torsades de Pointes.
Patient is currently using herbal preparations or medications. Patient should stop using herbal medications 7 days prior to the first dose of the study drug
Patients with glioblastoma known to contain IDH1 or 2 mutation
Other concomitant anti-tumor therapy as determined by the study team
Prior treatment with intracerebral agents, e.g. prolifeprospan 20 with carmustine wafer
Patients unable to undergo contrast-enhanced MRI
Fasting glucose > 7.0 mmol/L or HbA1c > 6.4%.
Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders.
Anxiety ≥CTC AE grade 3
Patient has an uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, known HIV infection, chronic liver disease, chronic renal disease, pancreatitis, chronic pulmonary disease, active cardiac disease or cardiac dysfunction, interstitial lung disease, active autoimmune disease, uncontrolled diabetes, neuropsychiatric or social situations that would limit compliance with the study requirements
Presence of gastrointestinal disease or any other condition that could interfere significantly with the absorption of the study drug.
Concomitant treatment with medicinal products that increase the pH (reduce acidity) of the upper gastrointestinal tract, including, but not limited to, proton-pump inhibitors (e.g. omeprazole), H2-antagonists (e.g. ranitidine) and antacids. Patients may be enrolled in the study after a wash-out period sufficient to terminate their effect (See section 11.2.2.8).Women who are pregnant or breast feeding,
Women able to conceive and unwilling to practice an effective method of birth control* from screening until 90 days after discontinuing study treatment (women of childbearing potential** must have a negative urine or serum pregnancy test within 7 days prior to first dose of PQR309
Adequate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), or double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Male patients must agree to use condoms as contraception method.
Primary purpose
Allocation
Interventional model
Masking
10 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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