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

Open-Label, Non Randomized Phase 2 Study With Safety Run-In Evaluating Efficacy and Safety of PQR309 in Patients With Relapsed or Refractory Lymphoma

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma, Malignant
• Intervention / Treatment: Drug: bimiralisib

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 Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina, 78000
    • University Clinical center Republic of Srpska
  • Sarajevo, Bosnia and Herzegovina, 71000
    • University Clinical Center Sarajevo
• France
  • Paris
    • Saint-Cloud, Paris, France, 92210
      • Insitute Curie
• Israel
  • Haifa, Israel
    • Univeristy Hospital Haifa
• Serbia
  • Belgrade, Serbia, 110000
    • Institute for Oncology and Radiology of Serbia
  • Kragujevac, Serbia, 34000
    • Clinical Center Kragujevac
  • Nis, Serbia, 118000
    • Clinical Center Nis
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Guy's Hospital
  • London, United Kingdom
    • University College Hospital London
  • London, United Kingdom
    • Royal Marsden NHS Foundation Trust
  • Oxford, United Kingdom, OX3 7DQ
    • Churchill Hospital
• United States
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: PI3K Inhibitor (phosphatidylinositol 3-kinase); PQR309

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Radiological lymphoma Evaluation (CT or other indicated according to institutional standard practice), clinical examination and bone marrow biopsy	28 day prior to first treatment (baseline), during treatment every 8 weeks during 6 months and every 6 months afterwards up to 1 year)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of serious adverse events (SAE) and severity of all adverse events (AEs)	Continuous dosing and intermittent dosing	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
Change of pulse rate	Continuous dosing and intermittent dosing	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
Change in blood pressure	Continuous dosing and intermittent dosing	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
Change in body temperature	Continuous dosing and intermittent dosing	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
Change in ECOG (Eastern Cooperative Oncology Group) Performance status	Continuous dosing and intermittent dosing	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
Change in body weight	Continuous dosing and intermittent dosing	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
Change in haematology	Continuous dosing and intermittent dosing	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
Change in blood chemistry	Continuous dosing and intermittent dosing	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
Change in ECG (electrocardiogram)	Continuous dosing and intermittent dosing	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
Change of urine analysis	Continuous dosing and intermittent dosing	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
Change in HbA1c	Continuous dosing and intermittent dosing	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
Change in tmax	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Change in Cmax	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Change in AUC 0-24	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Change in AUClast	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Change in AUC0-∞,	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Change in t1/2	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Change in RAC	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in insulin/ C-Peptide/ glucose	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50

Collaborators and Investigators

• Sponsor: PIQUR Therapeutics AG
• Collaborators: Royal Marsden NHS Foundation Trust; University College London Hospitals; Weill Medical College of Cornell University; University of Haifa; Institut Curie; University Clinical Centre of Republic of Srpska; Churchill Hospital; University Clinical Center, Sarajevo; Clinical Center Kragujevac; Clinical Center Nis, Nis; Institute for Oncology and Radiology Serbia, Belgrade
• Investigators: Principal Investigator: David Cunningham, Royal Marsden NHS Foundation Trust; Principal Investigator: Graham Collins, Churchill Hospital; Principal Investigator: Rakesh Popat, Univeristy College London; Principal Investigator: Paul Fields, Guy's 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 record dates

Study Major Dates

• Study Start (Actual): May 1, 2015
• Primary Completion (Actual): September 11, 2018
• Study Completion (Actual): September 11, 2018

Study Registration Dates

• First Submitted: September 8, 2014
• First Submitted That Met QC Criteria: September 23, 2014
• First Posted (Estimate): September 25, 2014

Study Record Updates

• Last Update Posted (Actual): September 6, 2019
• Last Update Submitted That Met QC Criteria: August 27, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Non Hodgkin Lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma
• Other Study ID Numbers: PQR309-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No