Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamic Effects of PQR309 in Glioblastoma Patients

Inclusion Criteria:

1. Patients with histologically confirmed glioblastoma at first progression following or during standard temozolomide chemoradiotherapy (TMZ/RTTMZ)
2. older than 18 years of age
3. Radiographic demonstration of disease progression by RANO criteria
4. Only for patients of the surgical cohort:

   * Eligible for open resection of progressive tumor according to standard practice of the study center
   * Availability of adequate surgical tissue sample for the evaluation of concentration of PQR309 in the tumor and its PD effect
   * Patients treated with PQR309 after incomplete surgical resection may still have measurable disease according to RANO criteria and may therefore be evaluable for evaluation of response to treatment with PQR309 according to RANO criteria. The best response in patients treated with PQR309 after complete surgical resection is stable disease. All patients can be assessed for PFS6.
5. Only for patients of the non-surgical cohort:

   \- Presence of at least one lesion of bi-dimensionally measurable disease by MRI with a contrast-enhancing tumor of at least 1 cm (10 mm) in the longest diameter on baseline MRI is required for patients who do not undergo surgery at relapse. For patients who undergo surgery for recurrence but do not participate in the presurgical PQR309 dosing cohort, the same rules regarding response assessment as in the surgical cohort apply. All patients can be assessed for PFS6.
6. 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.
7. 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.
8. 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.
9. Karnofsky Performance Score (KPS) \>70%.
10. More than 12 weeks from radiotherapy (RT)
11. More than 4 weeks from last administration of TMZ
12. More than 4 weeks from any investigational agent (at the judgment of the investigator and in agreement with lead investigator and PIQUR)
13. 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
14. Able and willing to swallow and retain oral medication
15. Female and male patients of reproductive potential must agree to use effective contraception from screening until 90 days after discontinuing study treatment\*
16. Willing and able to sign the informed consent and to comply with the protocol for the duration of the study

Exclusion Criteria:

1. Second or later glioblastoma relapse
2. Received more than one systemic treatment regimen for glioblastoma
3. Patients receiving enzyme-inducing anti-epileptic drug (EIAED) within 7 days of the first dose of PQR309
4. Patient is taking a drug with known risk to promote QT prolongation and Torsades de Pointes.
5. 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
6. Patients with glioblastoma known to contain IDH1 or 2 mutation
7. Other concomitant anti-tumor therapy as determined by the study team
8. Prior treatment with intracerebral agents, e.g. prolifeprospan 20 with carmustine wafer
9. Patients unable to undergo contrast-enhanced MRI
10. Fasting glucose \> 7.0 mmol/L or HbA1c \> 6.4%.
11. 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.
12. Anxiety ≥CTC AE grade 3
13. 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
14. Presence of gastrointestinal disease or any other condition that could interfere significantly with the absorption of the study drug.
15. 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,
16. 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.

      * Child-bearing potential for the sake of this study is defined as sexually mature women who have not undergone a hysterectomy, have not been naturally postmenopausal for at least 12 consecutive months or have a serum FSH \< 40 mIU/ml.