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

Phase 2TerminatedNCT02850744

PIQUR Therapeutics AG10 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Glioblastoma Multiforme

Interventions

PQR309DRUG

80mg capsules p.o. once daily and possibly Standard Treatment with temozolomide

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (1)

University Hospital Zurich, Neurology

Zurich, Switzerland

Outcomes

Primary Outcomes

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

Time frame: 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

Time frame: 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 Outcomes

Number of Adverse Events and Serious Adverse Events as related to the study medication

Non surgical cohort

Time frame: 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

Time frame: 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

Time frame: Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery

Data from ClinicalTrials.gov

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Changes in pulse rate

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery

Changes in hematology

Non-surgical cohort

Time frame: 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

Time frame: Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery

Changes of urinalysis

Non-surgical cohort

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Determination of AUC0-24

Non-surgical cohort

Determination of tmax

Non-surgical cohort

Determination of AUClast

Non-surgical cohort

Determination of tmax

Surgical cohort

Determination of AUClast

Surgical cohort

Determination of AUC0-∞

Surgical cohort

Determination of AUC0-∞

Non-surgical cohort

Determination of t½

Surgical cohort

Determination of t½

Non-surgical cohort

Assessment of tumor concentration,

Surgical cohort only

Time frame: 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

Time frame: On day of surgery (day 3)

Assessment of PQR309 Skin concentration

Surgical cohort only

Time frame: On day of surgery (day 3)

Overall Response Rate (ORR) including complete and partial Response based on RANO criteria

Surgical and Non-surgical Cohort

Duration of response (DOR) based on RANO criteria

Surgical and non-surgical cohort

Time frame: 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