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    Summary
    EudraCT Number:2015-001306-33
    Sponsor's Protocol Code Number:PQR309-005
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-06-14
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-001306-33
    A.3Full title of the trial
    Open-label, non-randomized, phase 2 study evaluating efficacy and safety of PQR309 in patients with relapsed or refractory primary CNS lymphoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 study evaluating efficacy and safety of PQR309 in patients with relapsed or refractory primary CNS lymphoma
    A.4.1Sponsor's protocol code numberPQR309-005
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPIQUR Therapeutics AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPIQUR Therapeutics AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPIQUR Therapeutics AG
    B.5.2Functional name of contact pointSenior Regulatory Affairs Manager
    B.5.3 Address:
    B.5.3.1Street AddressHochbergerstrasse 60C
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4057
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+4161633 29 48
    B.5.6E-mailclaudia.pluess@piqur.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePQR309
    D.3.2Product code PQR309
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available yet
    D.3.9.1CAS number 1225037-39-7
    D.3.9.2Current sponsor codePQR309
    D.3.9.3Other descriptive name5-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)-2-pyridinamine
    D.3.9.4EV Substance CodeSUB172213
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePQR309
    D.3.2Product code PQR309
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot available yet
    D.3.9.1CAS number 1225037-39-7
    D.3.9.2Current sponsor codePQR309
    D.3.9.3Other descriptive name5-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)-2-pyridinamine
    D.3.9.4EV Substance CodeSUB172213
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed or refractory primary CNS lymphoma (PCNSL)
    E.1.1.1Medical condition in easily understood language
    Relapsed or refractory primary central nervous system lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10036685
    E.1.2Term Primary central nervous system lymphoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the clinical efficacy of PQR309 in the treatment of patients with relapsed or refractory primary CNS lymphoma.
    E.2.2Secondary objectives of the trial
    To evaluate:
    - Overall safety and tolerability of PQR309
    - Overall clinical efficacy of PQR309
    - Pharmacokinetics (PK) of PQR309 in plasma
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. ≥ 18 years of age.
    2. Patient with histologically/cytologically confirmed PCNSL at first progression.
    3. Relapsed or refractory PCNSL demonstrated by cranial MRI.
    4. Presence of at least one lesion of bi-dimensionally measurable disease on baseline MRI with a contrast-enhancing tumor of at least 1 cm (10 mm) in the longest diameter.
    5. Maximum two prior systemic therapy regimens excluding myeloablative therapy at first relapse.
    6. If receiving corticosteroids, patients must have been on a stable or decreasing dose of corticosteroids and no more than 8 mg dexamethasone (or equivalent) for at least 5 days prior to date of enrollment.
    7. Karnofsky Performance Score (KPS) ≥ 70%.
    8. More than 4 weeks from any investigational agent (at the judgment of the investigator and in agreement with lead investigator and PIQUR).
    9. Adequate haematological, liver and renal function defined as follows: absolute neutrophil count (ANC) ≥ 1.5x10^9/l, platelets ≥ 100x10^9/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.
    10. Able and willing to swallow and retain oral medication.
    11. Female and male patients of reproductive potential must agree to use effective contraception from screening until 90 days after discontinuing study treatment.
    12. Willing and able to sign the informed consent and to comply with the protocol for the duration of the study.
    E.4Principal exclusion criteria
    1. Secondary CNS lymphoma or chronic immunosuppresion-associated CNS lymphoma.
    2. Previous allogeneic hematopoietic stem cell transplant (HSCT transplant).
    3. Patients with persisting symptoms from previous whole brain radiotherapy (WBRT).
    4. Other concomitant anti-tumor therapy as determined by the study team.
    5. Patients unable to undergo contrast-enhanced MRI.
    6. Prior treatment with a PI3K inhibitor, AKT inhibitor, or mTOR inhibitor.
    7. 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.
    8. 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.
    9. Anxiety ≥CTC AE grade 3.
    10. 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.
    11. Presence of gastrointestinal disease or any other condition that could interfere significantly with the absorption of the study drug.
    12. 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 is restricted. Patients may be enrolled in the study after a washout period sufficient to terminate their effect. Patients who require treatment to increase the pH of the upper GI tract can be treated with 300mg ranitidine given once daily at bed-time. Importantly, in this case PQR309 dosing is switched to the early evening. Patients will take PQR309 on an empty stomach approx 4 hours after lunch and remain fasted for an additional 2 hours prior to the evening meal.
    13. Patient has a history of invasive malignancy other than PCNSL. Patients are eligible if they are disease free for at least 3 years and deemed to be at low risk for recurrence by the Investigator. Patients diagnosed with cervical cancer in situ, basal cell or squamous cell carcinoma of the skin and treated within the past 3 years are eligible.
    14. Women who are pregnant or breast feeding.
    15. 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 serum pregnancy test within 7 days prior to first dose of PQR309).
    16. Fasting glucose > 7.0 mmol/L (126 mg/dL).
    E.5 End points
    E.5.1Primary end point(s)
    ORR including complete response (CR), unconfirmed complete (CRu) and partial response (PR) according to the 2005 Response Criteria of the International Primary CNS Lymphoma Collaborative Group (IPCG)
    E.5.1.1Timepoint(s) of evaluation of this end point
    4 and 8 weeks after first intake of PQR309, subsequently every 8 weeks
    E.5.2Secondary end point(s)
    Safety:
    - Incidence and severity of AEs including SAEs
    - Changes in vital signs (pulse rate, blood pressure, body temperature), Karnofsky performance status (KPS), physical examinations, body weight, ECG, PHQ-9 questionnaire and GAD-7 mood scale score
    - Changes of routine laboratory assessments (haematology, blood chemistry, urinalysis)
    - Changes in Mini-Mental State Examination (MMSE) score

    Additional Clinical Efficacy:
    - Time to response (TTR), duration of response (DOR), time to treatment failure (TTF), progression-free survival (PFS) and survival rate at 1 year

    Pharmacokinetics:
    - PQR309 plasma concentration, PK parameters
    E.5.2.1Timepoint(s) of evaluation of this end point
    AE monitoring: continuously until 30 days after the last dose
    Vital signs, physical examination: at Screening, at Weeks 1, 2, 3, 4 and 7 (and every three weeks later), at the end of treatment and 30 days after the last dose
    PHQ-9 and GAD-7: at Screening, Week 4 and 7 (and every 3 weeks later), and end of treatment
    Haematology & Blood chemistry: at Screening, at Weeks 1, 2, 3, 4, 6 and 7 (and every three weeks later), at the end of treatment, and 30 days after the last dose
    Urinalysis: at Screening, at Weeks 1, 4 and 7 (and every three weeks later), and end of treatment
    MMSE: at Screening and end of treatment
    PK sampling: at Weeks 1 (Day 1 and 2), 2, 3, 4 and 7 until Day 64 (exact timepoints depend on dosing schedule)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    France
    Germany
    Spain
    Switzerland
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 16
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 34
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 42
    F.4.2.2In the whole clinical trial 50
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    All patients enrolled in the study may be treated with PQR309 until unacceptable AE, tumor progression, patient’s request for withdrawal, investigator judgment or death whichever comes first.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-02-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-19
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-03-29
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