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

Lymphoma, Malignant Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02249429
• Other study ID #: PQR309-002
• Status: Completed
• Phase: Phase 2
• Start date: May 2015
• Est. completion date: September 11, 2018

Study information

• Verified date: August 2019
• Source: PIQUR Therapeutics AG
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 53
• Est. completion date: September 11, 2018
• Est. primary completion date: September 11, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Malignant

Intervention

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.

Locations

Country	Name	City	State
Bosnia and Herzegovina	University Clinical Center Republic of Srpska	Banja Luka
Bosnia and Herzegovina	University Clinical Center Sarajevo	Sarajevo
France	Insitute Curie	Saint-Cloud	Paris
Israel	Univeristy Hospital Haifa	Haifa
Serbia	Institute for Oncology and radiology of Serbia	Belgrade
Serbia	Clinical Center Kragujevac	Kragujevac
Serbia	Clinical Center Nis	Nis
United Kingdom	Guy's Hospital	London
United Kingdom	Royal Marsden NHS Foundation Trust	London
United Kingdom	University College Hospital London	London
United Kingdom	Churchill Hospital	Oxford
United States	Weill Cornell Medicine	New York	New York

Sponsors (12)

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

Countries where clinical trial is conducted

United States,  Bosnia and Herzegovina,  France,  Israel,  Serbia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in insulin/ C-Peptide/ glucose	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in tmax	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Secondary	Change in Cmax	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Secondary	Change in AUC 0-24	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Secondary	Change in AUClast	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Secondary	Change in AUC0-8,	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Secondary	Change in t1/2	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50
Secondary	Change in RAC	Continuous dosing and intermittent dosing	During treatment on Day 1,2, 8,15 22, 50