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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Lymphoma, Malignant

Intervention / Treatment
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* Drug: bimiralisib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1 (See Appendix 2). Adequate organ system functions defined as: Absolute neutrophil count (ANC) ≥1.0x109/l Platelets ≥ 75x109/l Haemoglobin ≥ 85g/L 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) Adequate renal function, defined as serum creatinine ≤ 1.5 times ULN Fasting glucose < 7.0 mmol/L; Glycated haemoglobin (HbA1c) < 6.4% Ability and willingness to swallow and retain oral medication. Willingness and ability to comply with the trial procedures Female and male patients with reproductive potential must agree to use effective contraception from screening until 90 days after discontinuation of PQR309 Signed informed consent Exclusion Criteria: Any of the following conditions precludes enrollment of a patient: Immunosuppression due to: Allogeneic hematopoietic stem cell transplant (HSCT) Any immune-suppressive therapy within 4 weeks prior to trial treatment start Known HIV infection Autologous stem cell transplant within 3 months prior to trial treatment start. Concomitant anticancer therapy (e.g. chemotherapy, radiotherapy, hormonal therapy, immunotherapy, biological response modifier, signal transduction inhibitors). 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. Use of any investigational drug within 21 days prior to trial treatment start. Patients who experienced National Cancer Institute (NCI) Common Terminology Criteria For Adverse Events (CTCAE) ≥ Grade 3 on PI3K/mTOR inhibitors Any major surgery, chemotherapy or immunotherapy within 21 days prior to trial treatment start. Symptomatic or progressing Central nervous system (CNS) involvement. Exception: Patients with meningeal involvement can be included upon discussion between the sponsor and the investigator. Persisting toxicities NCI CTCAE ≥2 related to prior anticancer therapy Presence of gastrointestinal disease or any other condition that could interfere significantly with the absorption of the study drug. 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 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. Lack of appropriate contraceptive measures (male and female) Pregnant or lactating women Known HIV infection Significant medical conditions which could jeopardize compliance with the protocol. Uncontrolled diabetes mellitus; patients with controlled diabetes may be enrolled (see fasting glucose and HbA1c levels in inclusion criteria).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bimiralisib (PQR309)<br> | Drug: bimiralisib<br>* 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.<br>* Other names: PI3K Inhibitor (phosphatidylinositol 3-kinase);|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Hodgkin Lymphoma