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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Open-label, Non-randomized, Two-stage Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamic Effects of PQR309 in Patients With Progressive Glioblastoma

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: PQR309


Participation Criteria
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Eligibility Criteria
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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: 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. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single-arm<br>Open label, single arm including patients with progressive glioblastoma during or after temozolomide chemotherapy obtaining PQR309 80mg capsules. | Drug: PQR309<br>* 80mg capsules p.o. once daily and possibly Standard Treatment with temozolomide<br>* Other names: temozolomide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival rate at 6 months (PFS6) based on RANO criteria [30]glioblastoma, using progression-free survival rate at 6 months (PFS6) based on RANO criteria [30] | Non Surgical Cohort, Tumor response evaluation according to RANO criteria | Change to base line of contrast MRI scans and incorporated clinical signs will be assessed on Day 1 of Cycle 1 and on Day 1 of every following cycle and at the end of treatment which can be up to 24 months after | 
| Progression-free survival rate at 6 months (PFS6) based on RANO criteria [30]glioblastoma, using progression-free survival rate at 6 months (PFS6) based on RANO criteria [30] | Surgical Cohort, Tumor response evaluation according to RANO criteria | Change to base line of contrast MRI scans and incorporated clinical signs will be assessed on Day1 pre-surgery, Day 4 post-surgery and 30 days after surgery and thereafter every 8 weeks (+/-7 days) until end of treatment up to 24mths | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events and Serious Adverse Events as related to the study medication | Non surgical cohort | Cycle 1 on Day 1,2,8 and 15, on Cycle 2 and following cycles on Day 1 and 15 und 30 days after end of treatmen which can up to 24 months | 
| Number of Adverse Events and Serious Adverse Events as related to the study medication | Surgical cohort | Assessment on Day 1,2 pre-surgery, Day3 surgery, Day4 post -surgery and 30 days after surgery, Cycle 2 on Day 1 and 15 and 30 days after end of treatment which can be up to 24 months | 
| Changes in pulse rate | Surgical Cohort | Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Changes in pulse rate | Non-surgical cohort | Assessment will during Cycle 1 on day 1,8,15, Cycle 2 day 1, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment and 30 days after last treatment | 
| Changes in blood pressure | Surgical cohort | Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Changes in blood pressure | Non-surgical cohort | Assessment will during Cycle 1 on day 1,8,15, Cycle 2 day 1, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment and 30 days after last treatment | 
| Changes in body weight | Surgical cohort | Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Changes in body weight | Non-surgical cohort | Assessment will during Cycle 1 on day 1,8,15, Cycle 2 day 1, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment and 30 days after last treatment | 
| Changes in temperature | Surgical Cohort | Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Changes in temperature | Non-surgical cohort | Assessment will during Cycle 1 on day 1,8,15, Cycle 2 day 1, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment and 30 days after last treatment | 
| Changes in ECG | Surgical Cohort | Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Changes in ECG | Non-surgical cohort | Assessment will during Cycle 1 on day 1,8,15, Cycle 2 day 1, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment and 30 days after last treatment | 
| Physical examination according to Karnofsky Performance Status | Surgical cohort | Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Physical examination according to Karnofsky Performance Status | Non-surgical cohort | Assessment will during Cycle 1 on day 1,8,15, Cycle 2 day 1, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment and 30 days after last treatment | 
| Depression Test (PHQ-9) | Surgical cohort | Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Depression test PHQ-9 | Non-surgical cohort | CAssessment will during Cycle 1 on day 1,8,15, Cycle 2 day 1, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment and 30 days after last treatment | 
| Generalized Anxiety Disorder mood scale score (GAD7) | Surgical Cohort | Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Generalized Anxiety Disorder mood scale score (GAD) | Non-surgical cohort | Cycle 1Assessment will during Cycle 1 on day 1,8,15, Cycle 2 day 1, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment and 30 days after last treatment | 
| Changes in routine blood chemistry | Surgical cohort | Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Changes in routine blood chemistry | Non-surgical cohort | Cycle 1 on day 1,8,15, Cycle 2 day 1& 15, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment & 30 days after last treatment | 
| Changes in hematology | Surgical cohort | Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Changes in hematology | Non-surgical cohort | Cycle 1 on day 1,8,15, Cycle 2 day 1& 15, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment & 30 days after last treatment | 
| Changes of urinalysis | Surgical cohort | Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery | 
| Changes of urinalysis | Non-surgical cohort | Cycle 1 on day 1,8,15, Cycle 2 day 1& 15, Cycle 3 und follow up cycles on day 1 up to 24 weeks, end of treatment & 30 days after last treatment | 
| Change of Insulin/Glucose/C-Peptide | Surgical cohort | Day 1: at pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose (± 5 minutes) Day 2: at pre-dose (= 24 hour post first dose on Day 1) (± 5 minutes)& 3 - Pre-dose, and 1hr post dose. Day 4 - 24hr post last dose on Day 3 | 
| Change of Insulin/Glucose/C-Peptide | Non- surgical cohort | Cycle 1 Day 1 - Pre-dose, 1hr post dose. Day 2 - 24hr post-dose. Cycle 2 Day 1 - pre-dose. | 
| Change of Haemostasis | Non- surgical cohort | Cycle 1 Day 1 - Pre-dose, 1hr post dose. Day 2 - 24hr post-dose. Cycle 2 Day 1 - pre-dose. | 
| Change of Haemostasis | Surgical cohort | Cycle 1 Day 1 - Pre-dose, 1hr post dose. Day 2 - 24hr post-dose. Cycle 2 Day 1 pre-dose. | 
| Determination of cmax | Surgical cohort | Day 1: at pre-dose ,0.5, 1, 2, 4, 6, 8 hours post-dose ;Day 2: at pre-dose (= 24 hour post first dose on Day 1);Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose; Day 4: at 24h after the last dose | 
| Determination of cmax | Surgical cohort | Day 1: at pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose; Day 2: at pre-dose (= 24 hour post first dose on Day 1), Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose, Day 4: at 24h after the last dose | 
| Determination of AUC0-24 | Non-surgical cohort | Day 1: at pre-dose ,0.5, 1, 2, 4, 6, 8 hours post-dose ;Day 2: at pre-dose (= 24 hour post first dose on Day 1);Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose; Day 4: at 24h after the last dose | 
| Determination of AUC0-24 | Non-surgical cohort | Day 1: at pre-dose ,0.5, 1, 2, 4, 6, 8 hours post-dose ;Day 2: at pre-dose (= 24 hour post first dose on Day 1);Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose; Day 4: at 24h after the | 
| Determination of tmax | Non-surgical cohort | Day 1: at pre-dose ,0.5, 1, 2, 4, 6, 8 hours post-dose ;Day 2: at pre-dose (= 24 hour post first dose on Day 1);Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose; Day 4: at 24h after the | 
| Determination of AUClast | Non-surgical cohort | Day 1: at pre-dose ,0.5, 1, 2, 4, 6, 8 hours post-dose ;Day 2: at pre-dose (= 24 hour post first dose on Day 1);Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose; Day 4: at 24h after the | 
| Determination of tmax | Surgical cohort | Day 1: at pre-dose ,0.5, 1, 2, 4, 6, 8 hours post-dose ;Day 2: at pre-dose (= 24 hour post first dose on Day 1);Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose; Day 4: at 24h after the last dose | 
| Determination of AUClast | Surgical cohort | Day 1: at pre-dose and 0.5, 1, 2, 4, 6, 8 hours post-dose; Day 2: at pre-dose (= 24 hour post first dose on Day 1), Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose, Day 4: at 24h after the last dose | 
| Determination of AUC0-∞ | Surgical cohort | Day 1: at pre-dose ,0.5, 1, 2, 4, 6, 8 hours post-dose ;Day 2: at pre-dose (= 24 hour post first dose on Day 1);Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose; Day 4: at 24h after the last dose | 
| Determination of AUC0-∞ | Non-surgical cohort | Day 1: at pre-dose ,0.5, 1, 2, 4, 6, 8 hours post-dose ;Day 2: at pre-dose (= 24 hour post first dose on Day 1);Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose; Day 4: at 24h after the | 
| Determination of t½ | Surgical cohort | Day 1: at pre-dose ,0.5, 1, 2, 4, 6, 8 hours post-dose ;Day 2: at pre-dose (= 24 hour post first dose on Day 1);Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose; Day 4: at 24h after the last dose | 
| Determination of t½ | Non-surgical cohort | Day 1: at pre-dose ,0.5, 1, 2, 4, 6, 8 hours post-dose ;Day 2: at pre-dose (= 24 hour post first dose on Day 1);Day 3:at pre-dose, 0.5h, 1.0h, 2h, 4h, 6h, 8h post-dose; Day 4: at 24h after the | 
| Assessment of tumor concentration, | Surgical cohort only | On day of surgery (day 3) | 
| Assessment of PQR309 concentration in cerebrospinal fluid Day 3,pre-dose,0.5h, 1h, 2h, 4h, 6h, 8h post-dose Day 4 24h after the last dose given | Surgical cohort only | On day of surgery (day 3) | 
| Assessment of PQR309 Skin concentration | Surgical cohort only | On day of surgery (day 3) | 
| Overall Response Rate (ORR) including complete and partial Response based on RANO criteria | Surgical and Non-surgical Cohort | Change to base line of contrast MRI scans and incorporated clinical signs will be assessed on Day 1 of Cycle 1 and on Day 1 of every following cycle and at the end of treatment which can be up to 24 months after | 
| Duration of response (DOR) based on RANO criteria | Surgical and non-surgical cohort | of contrast MRI scans and incorporated clinical signs will be assessed on Day 1 of Cycle 1 and on Day 1 of every following cycle and at the end of treatment which can be up to 24 months after | 
| Progression-free survival at 3 months (PFS3) based on RANO criteria | Surgical and non surgical cohort | of contrast MRI scans and incorporated clinical signs will be assessed on Day 1 of Cycle 1 and on Day 1 of every following cycle and at the end of treatment which can be up to 24 months after |