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

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ClinicalTrials.gov Identifier: NCT02249429
Recruitment Status : Completed
First Posted : September 25, 2014
Last Update Posted : October 19, 2018
Sponsor:
Collaborators:
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 Center Republic of Srpska, Banja Luka
Information provided by (Responsible Party):
PIQUR Therapeutics AG

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 PQR309 administered orally, as once daily capsules continuously and now on intermittent schedule in patients with relapsed or refractory lymphomas.

Condition or disease Intervention/treatment Phase
Lymphoma, Malignant Drug: PQR309 Phase 1 Phase 2

Detailed Description:

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

The maximum tolerated dose (MTD) of PQR309 in patients with advanced solid tumours was defined as 80 mg once daily given continuously (q.d. schedule) in a previous phase 1 study [8]. The safety run-in of this study will follow a modified 3 + 3 design to evaluate the safety of 60 and 80 mg PQR309 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 PQR309 for 28 days. Enrollment and treatment of all three patients may occur simultaneously as 80 mg PQR309 p.o. qd was established as the MTD in solid tumours. 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 PQR309, data emerge during the step 1 of the phase 2 expansion in this PQR309 002A study, indicating that daily dosing of PQR309 is not adequately tolerated or inefficacious.

Intermittent dosing schedules may be evaluated if, based on the overall evaluation of all the clinical and PK data from this and other studies with PQR309, data emerge during the step 1 of the phase 2 expansion in this PQR309 002A study, indicating that daily dosing of PQR309 is not adequately tolerated or inefficacious.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 53 participants
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 2015
Actual Primary Completion Date : September 11, 2018
Actual Study Completion Date : September 11, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: PQR309 Drug: PQR309
60 mg or 80 mg PQR309 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 Name: PI3K Inhibitor (phosphatidylinositol 3-kinase)




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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: During treatment on Day 1,2, 8,15 22, 50 ]
    Continuous dosing and intermittent dosing

  13. Change in Cmax [ Time Frame: During treatment on Day 1,2, 8,15 22, 50 ]
    Continuous dosing and intermittent dosing

  14. Change in AUC 0-24 [ Time Frame: During treatment on Day 1,2, 8,15 22, 50 ]
    Continuous dosing and intermittent dosing

  15. Change in AUClast [ Time Frame: During treatment on Day 1,2, 8,15 22, 50 ]
    Continuous dosing and intermittent dosing

  16. Change in AUC0-∞, [ Time Frame: During treatment on Day 1,2, 8,15 22, 50 ]
    Continuous dosing and intermittent dosing

  17. Change in t1/2 [ Time Frame: During treatment on Day 1,2, 8,15 22, 50 ]
    Continuous dosing and intermittent dosing

  18. Change in RAC [ Time Frame: 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 [ Time Frame: During treatment on Day 1,2, 8,15 22, 50 ]
    Continuous dosing and intermittent dosing



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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:

    1. Absolute neutrophil count (ANC) ≥1.0x109/l
    2. Platelets ≥ 75x109/l
    3. Haemoglobin ≥ 85g/L
    4. 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)
    5. Adequate renal function, defined as serum creatinine ≤ 1.5 times ULN
    6. Fasting glucose < 7.0 mmol/L; Glycated haemoglobin (HbA1c) < 6.4%
  6. Ability and willingness to swallow and retain oral medication.
  7. Willingness and ability to comply with the trial procedures
  8. Female and male patients with reproductive potential must agree to use effective contraception from screening until 90 days after discontinuation of PQR309
  9. 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
  2. Autologous stem cell transplant within 3 months prior to trial treatment start.
  3. Concomitant anticancer therapy (e.g. chemotherapy, radiotherapy, hormonal therapy, immunotherapy, biological response modifier, signal transduction inhibitors).
  4. 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.
  5. Use of any investigational drug within 21 days prior to trial treatment start.
  6. Patients who experienced National Cancer Institute (NCI) Common Terminology Criteria For Adverse Events (CTCAE) ≥ Grade 3 on PI3K/mTOR inhibitors
  7. Any major surgery, chemotherapy or immunotherapy within 21 days prior to trial treatment start.
  8. Symptomatic or progressing Central nervous system (CNS) involvement. Exception: Patients with meningeal involvement can be included upon discussion between the sponsor and the investigator.
  9. Persisting toxicities NCI CTCAE ≥2 related to prior anticancer therapy
  10. Presence of gastrointestinal disease or any other condition that could interfere significantly with the absorption of the study drug.
  11. 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
  12. 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.
  13. Lack of appropriate contraceptive measures (male and female)
  14. Pregnant or lactating women
  15. Known HIV infection
  16. Significant medical conditions which could jeopardize compliance with the protocol.
  17. Uncontrolled diabetes mellitus; patients with controlled diabetes may be enrolled (see fasting glucose and HbA1c levels in inclusion criteria).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02249429


Locations
United States, New York
Weill Cornell Medicine
New York, New York, United States, 10065
Bosnia and Herzegovina
University Clinical Center Republic of Srpska
Banja Luka, Bosnia and Herzegovina, 78000
University Clinical Center Sarajevo
Sarajevo, Bosnia and Herzegovina, 71000
France
Insitute Curie
Saint-Cloud, Paris, France, 92210
Israel
Univeristy Hospital Haifa
Haifa, Israel
Serbia
Institute for Oncology and radiology of Serbia
Belgrade, Serbia, 110000
Clinical Center Kragujevac
Kragujevac, Serbia, 34000
Clinical Center Nis
Nis, Serbia, 118000
United Kingdom
Guy's Hospital
London, United Kingdom, SE1 9RT
Royal Marsden NHS Foundation Trust
London, United Kingdom
University College Hospital London
London, United Kingdom
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 Center Republic of Srpska, Banja Luka
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 Center Republic of Srpska

Responsible Party: PIQUR Therapeutics AG
ClinicalTrials.gov Identifier: NCT02249429     History of Changes
Other Study ID Numbers: PQR309-002
First Posted: September 25, 2014    Key Record Dates
Last Update Posted: October 19, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases