Lymphoma, Malignant
Conditions
Keywords
Non Hodgkin Lymphoma
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.
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.
Interventions
DRUGbimiralisib
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.
Sponsors
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
PIQUR Therapeutics AG
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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: 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Change in tmax | During treatment on Day 1,2, 8,15 22, 50 | Continuous dosing and intermittent dosing |
| Change in Cmax | During treatment on Day 1,2, 8,15 22, 50 | Continuous dosing and intermittent dosing |
| Change in AUC 0-24 | During treatment on Day 1,2, 8,15 22, 50 | Continuous dosing and intermittent dosing |
| Change in AUClast | During treatment on Day 1,2, 8,15 22, 50 | Continuous dosing and intermittent dosing |
| Change in AUC0-∞, | During treatment on Day 1,2, 8,15 22, 50 | Continuous dosing and intermittent dosing |
| Change in t1/2 | During treatment on Day 1,2, 8,15 22, 50 | Continuous dosing and intermittent dosing |
| Change in RAC | During treatment on Day 1,2, 8,15 22, 50 | Continuous dosing and intermittent dosing |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in insulin/ C-Peptide/ glucose | During treatment on Day 1,2, 8,15 22, 50 | Continuous dosing and intermittent dosing |
Countries
Bosnia and Herzegovina, France, Israel, Serbia, United Kingdom, United States
Outcome results
None listed