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Open-Label, Non Randomized Phase 2 Study With Safety Run-In

Sponsor
PIQUR Therapeutics AG (Industry)
Overall Status
Completed
CT.gov ID
NCT02249429
Collaborator
University College London Hospitals (Other), Churchill Hospital (Other), Royal Marsden NHS Foundation Trust (Other), University of Haifa (Other), Weill Medical College of Cornell University (Other), Institut Curie (Other), University Clinical Center, Sarajevo (Other), Clinical Center Kragujevac (Other), Clinical Center Nis, Nis (Other), Institute for Oncology and Radiology Serbia, Belgrade (Other), University Clinical Centre of Republic of Srpska (Other)
53
Enrollment
12
Locations
1
Arm
40.4
Actual Duration (Months)
4.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main goal of this study is to determine the Maximum Tolerated Dose (MTD) and the Recommended Phase II Dose (RP2D) as well as preliminary antitumor activity of bimiralisib (PQR309) administered orally, as once daily capsules continuously and on intermittent schedule in patients with relapsed or refractory lymphomas.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Open-label, non-randomized, multicentre phase 2 study with a safety run-in evaluating efficacy and safety of bimiralisib (PQR309) in patients with relapsed or refractory lymphoma.

The maximum tolerated dose (MTD) of bimiralisib in patients with advanced solid tumors was defined as 80 mg once daily given continuously (q.d. schedule) in a previous phase 1 study. The safety run-in of this study will follow a modified 3 + 3 design to evaluate the safety of 60 and 80 mg bimiralisib in patients with relapsed or refractory lymphoma administered p.o. once daily during a DLT (dose-limiting toxicity) period of 28 days.

In the safety run-in, three patients will be treated at 60 mg bimiralisib for 28 days. Enrollment and treatment of all three patients may occur simultaneously as 80 mg bimiralisib p.o. qd was established as the MTD in solid tumors. Unless a DLT is observed in any of the three patients during the first 28 days of treatment, the investigators and the sponsor will decide to escalate the dose to 80 mg. Intermittent dosing schedules may be evaluated if, based on the overall evaluation of all the clinical and PK (pharmacokinetic) data from this and other studies with bimiralisib, data emerge during step 1 of the phase 2 expansion in this study, indicating that daily dosing of bimiralisib is not adequately tolerated or inefficacious.

Study Design

Study Type:
Interventional
Actual Enrollment :
53 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Open-Label, Non Randomized Phase 2 Study With Safety Run-In Evaluating Efficacy and Safety of PQR309 in Patients With Relapsed or Refractory Lymphoma
Actual Study Start Date :
May 1, 2015
Actual Primary Completion Date :
Sep 11, 2018
Actual Study Completion Date :
Sep 11, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: bimiralisib (PQR309)

Drug: bimiralisib
60 mg or 80 mg bimiralisib per oral (p.o.) once daily or intermittent dosing (120mg,140mg and 160mg) until unacceptable AE, disease progression, patient's request for withdrawal, investigator judgement or death - whichever comes first.
Other Names:
  • PQR309
  • PI3K Inhibitor (phosphatidylinositol 3-kinase)

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Assessment of Change of Tumor Response Criteria in lymphoma patients During Treatment with PQR309 in patients with relapsed or refractory lymphoma according to Cheston Criteria (5) [28 day prior to first treatment (baseline), during treatment every 8 weeks during 6 months and every 6 months afterwards up to 1 year)]

      Radiological lymphoma Evaluation (CT or other indicated according to institutional standard practice), clinical examination and bone marrow biopsy

    Secondary Outcome Measures

    1. Incidence of serious adverse events (SAE) and severity of all adverse events (AEs) [Before treatment on Day -1,-2 and during treatment on Day 1,2,8,15,22,36,50, at the end of treatment up to 1 year and 30 days after last dose]

      Continuous dosing and intermittent dosing

    2. Change of pulse rate [Before treatment on Day -1,-2 and during treatment on Day 1,2,8,15,22,36,50, at the end of treatment up to 1 year and 30 days after last dose]

      Continuous dosing and intermittent dosing

    3. Change in blood pressure [Before treatment on Day -1,-2 and during treatment on Day 1,2,8,15,22,36,50, subsequently every 4 weeks up to 1 year, at the end of treatment up to 1 year and 30 days after last dose]

      Continuous dosing and intermittent dosing

    4. Change in body temperature [Before treatment on Day -1,-2 and during treatment on Day 1,2,8,15,22,36,50, subsequently every 4 weeks up to 1 year, at the end of treatment up to 1 year and 30 days after last dose]

      Continuous dosing and intermittent dosing

    5. Change in ECOG (Eastern Cooperative Oncology Group) Performance status [Before treatment on Day -1,-2 and during treatment on Day 1,2,8,15,22,36,50, subsequently every 4 weeks up to 1 year, at the end of treatment up to 1 year and 30 days after last dose]

      Continuous dosing and intermittent dosing

    6. Change in body weight [Before treatment on Day -1,-2 and during treatment on Day 1,2,8,15,22,36,50, subsequently every 4 weeks up to 1 year, at the end of treatment up to 1 year and 30 days after last dose]

      Continuous dosing and intermittent dosing

    7. Change in haematology [Before treatment on Day -1,-2 and during treatment on Day 1,2,8,15,22,36,50, subsequently every 4 weeks up to 1 year, at the end of treatment up to 1 year and 30 days after last dose]

      Continuous dosing and intermittent dosing

    8. Change in blood chemistry [Before treatment on Day -1 and during treatment on Day 1,22,50, subsequently every 4 weeks up to 1 year, at the end of treatment up to 1 year]

      Continuous dosing and intermittent dosing

    9. Change in ECG (electrocardiogram) [Before treatment on Day -1 and during treatment on Day 1,22,50, subsequently every 4 weeks up to 1 year, at the end of treatment up to 1 year]

      Continuous dosing and intermittent dosing

    10. Change of urine analysis [Before treatment on Day -1 and during treatment on Day 1,22,50, subsequently every 4 weeks up to 1 year, at the end of treatment up to 1 year]

      Continuous dosing and intermittent dosing

    11. Change in HbA1c [Before treatment on Day -1 and during treatment on Day 1,22,50, subsequently every 4 weeks up to 1 year, at the end of treatment up to 1 year]

      Continuous dosing and intermittent dosing

    12. Change in tmax [During treatment on Day 1,2, 8,15 22, 50]

      Continuous dosing and intermittent dosing

    13. Change in Cmax [During treatment on Day 1,2, 8,15 22, 50]

      Continuous dosing and intermittent dosing

    14. Change in AUC 0-24 [During treatment on Day 1,2, 8,15 22, 50]

      Continuous dosing and intermittent dosing

    15. Change in AUClast [During treatment on Day 1,2, 8,15 22, 50]

      Continuous dosing and intermittent dosing

    16. Change in AUC0-∞, [During treatment on Day 1,2, 8,15 22, 50]

      Continuous dosing and intermittent dosing

    17. Change in t1/2 [During treatment on Day 1,2, 8,15 22, 50]

      Continuous dosing and intermittent dosing

    18. Change in RAC [During treatment on Day 1,2, 8,15 22, 50]

      Continuous dosing and intermittent dosing

    Other Outcome Measures

    1. Change in insulin/ C-Peptide/ glucose [During treatment on Day 1,2, 8,15 22, 50]

      Continuous dosing and intermittent dosing

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Histologically confirmed diagnosis* of relapsed or refractory lymphoma, received at least two prior lines of therapy including immuno-chemotherapy. Patients with relapsed Chronic Lymphoid Leukemia (CLL) are eligible if they have received one or more prior lines of any approved standard therapy. * archival biopsies may be used if obtained up to a year prior to enrollment; re-biopsy is strongly recommended if last biopsy was obtained more than a year ago.

    2. Only for patients in the Phase 2 part: At least one measurable nodal or extra-nodal lesion defined as follows: Clearly measurable (i.e. well-defined boundaries) in at least two perpendicular dimensions on imaging scan with > 1.5 cm in longest transverse diameter.

    3. Age ≥ 18 years

    4. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1 (See Appendix 2).

    5. Adequate organ system functions defined as:

    6. Absolute neutrophil count (ANC) ≥1.0x109/l

    7. Platelets ≥ 75x109/l

    8. Haemoglobin ≥ 85g/L

    9. Adequate hepatic function, defined as Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) and Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN (or ALT/AST ≤ 5 times ULN in patients with liver involvement)

    10. Adequate renal function, defined as serum creatinine ≤ 1.5 times ULN

    11. Fasting glucose < 7.0 mmol/L; Glycated haemoglobin (HbA1c) < 6.4%

    12. Ability and willingness to swallow and retain oral medication.

    13. Willingness and ability to comply with the trial procedures

    14. Female and male patients with reproductive potential must agree to use effective contraception from screening until 90 days after discontinuation of PQR309

    15. Signed informed consent

    Exclusion Criteria:
    Any of the following conditions precludes enrollment of a patient:
    1. Immunosuppression due to:

    • Allogeneic hematopoietic stem cell transplant (HSCT)

    • Any immune-suppressive therapy within 4 weeks prior to trial treatment start

    • Known HIV infection

    1. Autologous stem cell transplant within 3 months prior to trial treatment start.

    2. Concomitant anticancer therapy (e.g. chemotherapy, radiotherapy, hormonal therapy, immunotherapy, biological response modifier, signal transduction inhibitors).

    3. 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.

    4. Use of any investigational drug within 21 days prior to trial treatment start.

    5. Patients who experienced National Cancer Institute (NCI) Common Terminology Criteria For Adverse Events (CTCAE) ≥ Grade 3 on PI3K/mTOR inhibitors

    6. Any major surgery, chemotherapy or immunotherapy within 21 days prior to trial treatment start.

    7. Symptomatic or progressing Central nervous system (CNS) involvement. Exception: Patients with meningeal involvement can be included upon discussion between the sponsor and the investigator.

    8. Persisting toxicities NCI CTCAE ≥2 related to prior anticancer therapy

    9. Presence of gastrointestinal disease or any other condition that could interfere significantly with the absorption of the study drug.

    10. Severe/unstable angina, myocardial infarction or coronary artery bypass within the last 3 years prior to trial treatment start, symptomatic congestive heart failure New York Heart Association (NYHA) Class 3 or 4, hypertension BP>150/100mmHg

    11. A serious active infection at the time of treatment, or another serious underlying medical condition that could impair the ability of the patient to receive treatment.

    12. Lack of appropriate contraceptive measures (male and female)

    13. Pregnant or lactating women

    14. Known HIV infection

    15. Significant medical conditions which could jeopardize compliance with the protocol.

    16. Uncontrolled diabetes mellitus; patients with controlled diabetes may be enrolled (see fasting glucose and HbA1c levels in inclusion criteria).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Weill Cornell Medicine New York New York United States 10065
    2 University Clinical Center Republic of Srpska Banja Luka Bosnia and Herzegovina 78000
    3 University Clinical Center Sarajevo Sarajevo Bosnia and Herzegovina 71000
    4 Insitute Curie Saint-Cloud Paris France 92210
    5 Univeristy Hospital Haifa Haifa Israel
    6 Institute for Oncology and radiology of Serbia Belgrade Serbia 110000
    7 Clinical Center Kragujevac Kragujevac Serbia 34000
    8 Clinical Center Nis Nis Serbia 118000
    9 Guy's Hospital London United Kingdom SE1 9RT
    10 Royal Marsden NHS Foundation Trust London United Kingdom
    11 University College Hospital London London United Kingdom
    12 Churchill Hospital Oxford United Kingdom OX3 7DQ

    Sponsors and Collaborators

    • PIQUR Therapeutics AG
    • University College London Hospitals
    • Churchill Hospital
    • Royal Marsden NHS Foundation Trust
    • University of Haifa
    • Weill Medical College of Cornell University
    • Institut Curie
    • University Clinical Center, Sarajevo
    • Clinical Center Kragujevac
    • Clinical Center Nis, Nis
    • Institute for Oncology and Radiology Serbia, Belgrade
    • University Clinical Centre of Republic of Srpska

    Investigators

    • Principal Investigator: Rakesh Popat, Univeristy College London
    • Principal Investigator: David Cunningham, Royal Marsden NHS Foundation Trust
    • Principal Investigator: Paul Fields, Guy's Hospital
    • Principal Investigator: Graham Collins, Churchill Hospital
    • Principal Investigator: Netanel Horowitz, University of Haifa
    • Principal Investigator: Giulino Roth, Weill Cornell Medicine New York
    • Principal Investigator: Carole Soussain, Curie Institute
    • Principal Investigator: Sinisa Radulovic, Institute for Oncology and Radiology Serbia
    • Principal Investigator: Ivan Tijanic, Clinical Center Nis
    • Principal Investigator: Nebojsa Andjelkovic, Clinical Center Kragujevac
    • Principal Investigator: Sabrina Kurtovic, University Clinical Center, Sarajevo
    • Principal Investigator: Danijela Mandic, University Clinical Centre of Republic of Srpska

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    PIQUR Therapeutics AG
    ClinicalTrials.gov Identifier:
    NCT02249429
    Other Study ID Numbers:
    • PQR309-002
    First Posted:
    Sep 25, 2014
    Last Update Posted:
    Sep 6, 2019
    Last Verified:
    Aug 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by PIQUR Therapeutics AG
    Non Hodgkin Lymphoma
    Additional relevant MeSH terms:
    Lymphoma

    Study Results

    No Results Posted as of Sep 6, 2019