Clinical trial NCT03127020: Phase 2 Study With PQR309 in Relapsed or Refractory Lymphoma Patients
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
Non-Hodgkin Lymphoma
Lead sponsor: PIQUR Therapeutics AG
Sponsor class: INDUSTRY
Collaborators: name: University Hospital, Basel, Switzerland
name: University Hospital Munich
name: University Hospital Freiburg
name: Charite University, Berlin, Germany
name: University of Stuttgart
First posted: 2017-04-25
Enrollment: 9
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 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 PQR309 in patients with relapsed or refractory lymphoma.

The maximum tolerated dose (MTD) of PQR309 in patients with advanced solid tumours was defined as 80 mg once daily given continuously (q.d. schedule) in a previous phase 1 study \[8\]. The safety run-in of this study will follow a modified 3 + 3 design to evaluate the safety of 60 and 80 mg PQR309 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 PQR309 for 28 days. Enrollment and treatment of all three patients may occur simultaneously as 80 mg PQR309 p.o. qd was established as the MTD maximum tolerated dose in solid tumours. Unless a DLT (dose-limiting toxicity) 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 PQR309, data emerge during the step 1 of the phase 2 expansion in this PQR309 002A study, indicating that daily dosing of PQR309 is not adequately tolerated or inefficacious.

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 PQR309, data emerge during the step 1 of the phase 2 expansion in this PQR309 002A study, indicating that daily dosing of PQR309 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 regardless of transformation status. 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
   5. Adequate renal function, defined as serum creatinine ≤ 1.5 times ULN
   6. Fasting glucose \< 7.0 mmol/L
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 consent1.5 cm in longest transverse diameter.

3. Age \>18 years 4. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1 5. Adequate organ system functions defined as:

1. Absolute neutrophil count (ANC) \>1.0x109/l
2. Platelets \> 75x109/l

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
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 and steroids (steroids as maintenance for adrenal insufficiency are allowed)).
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 (section 11.1.3.7).
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 4 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 (e.g. chronic active hepatitis) 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 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 days prior to first treatment (baseline), during study treatment every 8 weeks during first 6 months and every 6 months afterwards up to 48 months
Secondary outcomes:
measure: Incidence of serious adverse events (SAEs), incidence and severity of all adverse events (AEs)
timeFrame: During treatment on Day 1, 2, 8, 15, 22, 36 and 50; at the endof treatment and 30 days after last dose.
measure: Change in pulse rate
timeFrame: Before treatment on Day 1,2 and after treatment started on Day 1,2, 8, 15, 22, 36, 50 and subsequently every 4 weeks , at the end of treatment and 30 days after last treatment
measure: Change in blood pressure
timeFrame: Before treatment on Day 1,2 and after treatment started on Day 1,2, 8, 15, 22, 36, 50 and subsequently every 4 weeks , at the end of treatment and 30 days after last treatment
measure: Change in body temperature
timeFrame: Before treatment on Day 1,2 and after treatment started on Day 1, 8, 15, 22, 36, 50 and subsequently every 4 weeks , at the end of treatment and 30 days after last treatment
measure: Change in ECOG (Eastern Cooperative Oncology Group) Performance Status
timeFrame: Before treatment on Day 1,2 and after treatment started on Day 1,8, 15, 22, 36, 50 and subsequently every 4 weeks , at the end of treatment and 30 days after last treatment
measure: Change in bodyweight/kg
timeFrame: Before treatment on Day 1,2 and after treatment started on Day 1,2, 8, 15, 22, 36, 50 and subsequently every 4 weeks , at the end of treatment and 30 days after last treatment
measure: Change in haematology
timeFrame: Before treatment on Day 1,2 and after treatment started on Day 1, 8, 15, 22, 36, 50 and subsequently every 4 weeks , at the end of treatment and 30 days after last treatment
measure: Change in blood chemistry
timeFrame: Before treatment on Day 1and after treatment started on Day 1, 22, 50 and subsequently every 4 weeks and at the end of treatment
measure: Change in haemostasis
timeFrame: Before treatment on Day 1and after treatment started on Day 1, 22, 50 and subsequently every 4 weeks and at the end of treatment
measure: Change in ECG (electrocardiogram)
timeFrame: Before treatment on Day 1and after treatment started on Day 1, 22, 50 and subsequently every 4 weeks and at the end of treatment
measure: Change in urine analysis
timeFrame: Before treatment on Day 1and after treatment started on Day 1, 22, 50 and subsequently every 4 weeks and at the end of treatment
measure: Change in HbA1c
timeFrame: Before treatment on Day 1and after treatment started on Day 1, 22, 50 and subsequently every 4 weeks and at the end of treatment
measure: Change in Cmax
timeFrame: During treatment on Day1, 2,8, 15,22 and 50
measure: Change in tmax
timeFrame: During treatment on Day1, 2, 8, 15,22 and 50
measure: Change in AUC0-24 •
timeFrame: During treatment on Day1, 2, 8, 15,22 and 50
measure: Change in AUClast,
timeFrame: During treatment on Day1, 2, 8, 15,22 and 50
measure: Change in AUC0-∞,
timeFrame: During treatment on Day1, 2, 8, 15,22 and 50
measure: Change in t1/2 •
timeFrame: During treatment on Day1, 2, 8, 15,22 and 50
measure: Change in RAC •
timeFrame: During treatment on Day1, 2, 8, 15,22 and 50
Other outcomes:
measure: Change in insulin/ c-Peptide/ glucose
timeFrame: During treatment on Day 1, 2, 8,15,22 and 50
Locations:
city: Munich
country: Germany
facility: Medizinische Klinik und Poliklinik III
state: Bavaria
Study officials:
affiliation: Klinik Universität München
name: Martin Dreyling
role: STUDY_DIRECTOR
References: