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

Glioblastoma Multiforme Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02850744
• Other study ID #: PQR309-004
• Status: Terminated
• Phase: Phase 2
• Start date: July 2015
• Est. completion date: November 2017

Study information

• Verified date: October 2018
• Source: PIQUR Therapeutics AG
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: November 2017
• Est. primary completion date: November 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Glioblastoma
• Glioblastoma Multiforme

Intervention

Drug:
• PQR309
80mg capsules p.o. once daily and possibly Standard Treatment with temozolomide

Locations

Country	Name	City	State
Switzerland	University Hospital Zurich, Neurology	Zurich

Sponsors (4)

Lead Sponsor	Collaborator
PIQUR Therapeutics AG	University Hospital Inselspital, Berne, University Hospital, Basel, Switzerland, University Hospital, Zürich

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Changes in temperature	Surgical Cohort	Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery
Secondary	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
Secondary	Changes in ECG	Surgical Cohort	Assessment on Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Changes in routine blood chemistry	Surgical cohort	Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery
Secondary	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
Secondary	Changes in hematology	Surgical cohort	Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery
Secondary	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
Secondary	Changes of urinalysis	Surgical cohort	Day1,2 pre-surgery, Day 3 surgery and Day 4 post-surgery and 30 days after surgery
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Determination of AUC0-8	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
Secondary	Determination of AUC0-8	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
Secondary	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
Secondary	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
Secondary	Assessment of tumor concentration,	Surgical cohort only	On day of surgery (day 3)
Secondary	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)
Secondary	Assessment of PQR309 Skin concentration	Surgical cohort only	On day of surgery (day 3)
Secondary	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
Secondary	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
Secondary	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