Clinical trial NCT02249429: Open-Label, Non Randomized Phase 2 Study With Safety Run-In
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lymphoma, Malignant
Keywords: Non Hodgkin Lymphoma
Lead sponsor: PIQUR Therapeutics AG
Sponsor class: INDUSTRY
Collaborators: name: University College London Hospitals
name: Churchill Hospital
name: Royal Marsden NHS Foundation Trust
name: University of Haifa
name: Weill Medical College of Cornell University
name: Institut Curie
name: University Clinical Center, Sarajevo
name: Clinical Center Kragujevac
name: Clinical Center Nis, Nis
name: Institute for Oncology and Radiology Serbia, Belgrade
name: University Clinical Centre of Republic of Srpska
First posted: 2014-09-25
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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).

Primary outcomes:
measure: 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)
timeFrame: 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 outcomes:
measure: Incidence of serious adverse events (SAE) and severity of all adverse events (AEs)
timeFrame: 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
measure: Change of pulse rate
timeFrame: 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
measure: Change in blood pressure
timeFrame: 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
measure: Change in body temperature
timeFrame: 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
measure: Change in ECOG (Eastern Cooperative Oncology Group) Performance status
timeFrame: 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
measure: Change in body weight
timeFrame: 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
measure: Change in haematology
timeFrame: 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
measure: Change in blood chemistry
timeFrame: 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
measure: Change in ECG (electrocardiogram)
timeFrame: 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
measure: Change of urine analysis
timeFrame: 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
measure: Change in HbA1c
timeFrame: 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
measure: Change in tmax
timeFrame: During treatment on Day 1,2, 8,15 22, 50
measure: Change in Cmax
timeFrame: During treatment on Day 1,2, 8,15 22, 50
measure: Change in AUC 0-24
timeFrame: During treatment on Day 1,2, 8,15 22, 50
measure: Change in AUClast
timeFrame: During treatment on Day 1,2, 8,15 22, 50
measure: Change in AUC0-∞,
timeFrame: During treatment on Day 1,2, 8,15 22, 50
measure: Change in t1/2
timeFrame: During treatment on Day 1,2, 8,15 22, 50
measure: Change in RAC
timeFrame: During treatment on Day 1,2, 8,15 22, 50
Other outcomes:
measure: Change in insulin/ C-Peptide/ glucose
timeFrame: During treatment on Day 1,2, 8,15 22, 50
Locations:
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Banja Luka
country: Bosnia and Herzegovina
facility: University Clinical Center Republic of Srpska
city: Sarajevo
country: Bosnia and Herzegovina
facility: University Clinical Center Sarajevo
city: Saint-Cloud
country: France
facility: Insitute Curie
state: Paris
city: Haifa
country: Israel
facility: Univeristy Hospital Haifa
city: Belgrade
country: Serbia
facility: Institute for Oncology and radiology of Serbia
city: Kragujevac
country: Serbia
facility: Clinical Center Kragujevac
city: Nis
country: Serbia
facility: Clinical Center Nis
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust
city: London
country: United Kingdom
facility: University College Hospital London
city: Oxford
country: United Kingdom
facility: Churchill Hospital
Study officials:
affiliation: Univeristy College London
name: Rakesh Popat
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Marsden NHS Foundation Trust
name: David Cunningham
role: PRINCIPAL_INVESTIGATOR
affiliation: Guy's Hospital
name: Paul Fields
role: PRINCIPAL_INVESTIGATOR
affiliation: Churchill Hospital
name: Graham Collins
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Haifa
name: Netanel Horowitz
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Cornell Medicine New York
name: Giulino Roth
role: PRINCIPAL_INVESTIGATOR
affiliation: Curie Institute
name: Carole Soussain
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute for Oncology and Radiology Serbia
name: Sinisa Radulovic
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Center Nis
name: Ivan Tijanic
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Center Kragujevac
name: Nebojsa Andjelkovic
role: PRINCIPAL_INVESTIGATOR
affiliation: University Clinical Center, Sarajevo
name: Sabrina Kurtovic
role: PRINCIPAL_INVESTIGATOR
affiliation: University Clinical Centre of Republic of Srpska
name: Danijela Mandic
role: PRINCIPAL_INVESTIGATOR
References: