Study investigating safety and efficacy of PQR309 and eribulin combination in patients with locally advanced or metastatic HER2 negative and triple-negative breast cancer

• Register: EUCTR
• Last refreshed on: 15 October 2018
• Main ID: EUCTR2015-004225-14-ES
• Date of registration: 12/11/2015
• Prospective Registration: Yes
• Primary sponsor: PIQUR Therapeutics AG
• Public title: Study investigating safety and efficacy of PQR309 and eribulin combination in patients with locally advanced or metastatic HER2 negative and triple-negative breast cancer
• Scientific title: An open label, non-randomized, multicenter phase 1/2b study investigating safety and efficacy of PQR309 and eribulin combination in patients with locally advanced or metastatic HER2 negative and triple-negative breast cancer - PQR309-007
• Date of first enrolment: 19/01/2016
• Target sample size: 31
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-004225-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other:
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Spain

Contacts

• Name: MedSIR ARO
• Affiliation: Medica Scientia Innovation Research (MedSIR ARO)

• Name: MedSIR ARO
• Affiliation: Medica Scientia Innovation Research (MedSIR ARO)

Key inclusion & exclusion criteria

Inclusion criteria:
1. Female ? 18 years old at the time of informed consent.
2. Histologically/cytologically confirmed diagnosis of breast cancer.
3. Radiological evidence of inoperable locally advanced or metastatic breast cancer.
4. HER2 negative breast cancer (based on the most recent analyzed biopsy) defined as a negative in situ hybridization test (ISH) or an immunohistochemistry (IHC) status of 0, 1+ or 2+ (if IHC 2+, a negative in situ hybridization test is required) by local laboratory testing.
5. Negative estrogen receptor and progesterone receptor status known as per local laboratory testing.
6. Received at least 2 and no more than 5 prior chemotherapeutic regimens in locally advanced and/or metastatic setting. Prior therapy has to include an anthracycline and a taxane in any combination or order (unless contraindicated for a certain patient). Prior anti-hormonal therapy is allowed.
7. Stable Eastern Cooperative Oncology Group (ECOG) performance status ? 2.
8. More than 4 weeks from any investigational agent.
9. Adequate bone marrow and organ function as defined by the following laboratory values:
- Absolute neutrophil count (ANC) ? 1.5x10^9/l, platelets ? 100x10^9/l, hemoglobin ? 100g/L.
- Potassium, calcium (corrected for serum albumin) and magnesium within normal limits (WNL) for the institution.
- Total bilirubin ? 1.5 times the upper limit of normal (ULN).
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ? 2.5 times ULN or ? 5.0 x ULN if liver metastases are present.
- Serum creatinine ? 1.5 times ULN.
- Fasting plasma glucose ? 125 mg/dL (? 7 mmol/L) or HbA1c ? 7%.
10. Able and willing to swallow and retain oral medication.
11. Written informed consent obtained according to local guidelines.
Expansion part:
12. Triple-negative breast cancer (based on most recently analyzed biopsy) defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+ (if IHC 2+, a negative in situ hybridization is required), ER and PR status < 10% by local laboratory testing.
13. Measurable disease according to RECIST v.1.1 or non-measurable lytic or mixed (lytic + blastic) bone lesions with an identifiable soft tissue component that meets the measurability criteria per RECIST v.1.1
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 31
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 31

Exclusion criteria:
1. Previous systemic treatment with PI3K, mTOR or AKT inhibitors (allowed in the escalation part).
2. Previous treatment with eribulin (allowed in the escalation part).
3. Known hypersensitivity to any of the excipients of PQR309 or eribulin.
4. Concurrent treatment with other approved or investigational antineoplastic agent.
5. Symptomatic CNS metastases. The patient must have completed any prior local treatment for CNS metastases ? 28 days prior to first dose of the study drug (including radiotherapy and/or surgery).
6. Clinically manifested diabetes mellitus (treated and/or clinical signs with fasting glucose > 125 mg/dl or HbA1c >7%), or documented steroid induced diabetes mellitus.
7. Peripheral neuropathy ? CTC AE grade 2.
8. Anxiety ? CTC AE grade 3.
9. Concurrent malignancy other than HER2 negative BC or malignancy within 3 years of study enrollment (with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer).
10. Received radiotherapy ? 3 weeks or limited field radiation for palliation ? 2 weeks prior to starting study drug, and not recovered or improved to grade 1 from related side effects of such therapy (exceptions include alopecia) and/or from whom ? 30% of the bone marrow was irradiated.
11. Not recovered or improved to grade 1 from related side effects (except alopecia) of any prior antineoplastic therapy.
12. Major surgery within 14 days prior to first dose of the study drug or not recovered from major side effects.
13. Received systemically high doses of corticosteroids ? 2 weeks prior to starting study drug, or not fully recovered from side effects of such treatment.
Stable doses of corticosteroids, no more than 1 mg of dexamethasone a day or equivalent, e.g. 6 mg prednisone or 25 mg hydrocortisone for at least 5 days prior to first dose of the study drug is allowed.
14. Currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
15. Treatment with medicinal products that increase the pH (reduce acidity) of the upper Gastro-Intestinal (GI) tract, including, but not limited to: protonpump 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.
16. Using herbal preparations or medications within ? 7 days prior to first dose of the study drug.
17. Any severe or uncontrolled cardiac disease or history of cardiac dysfunction (Section 9.3 of protocol).
18. Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).
19. Cardiac conduction abnormalities (Section 9.3 of protocol).
20. QTcF > 480 msec on the screening ECG (using the QTcF formula).
21. Currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to randomization.
22. Impairment of hepatic function (Child-Pugh score > 5).
23. Severe impairment of kidney function (CrCL: 15-29 mL/min - according to Cockcroft-Gault formula).
24. Gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PQR309.
25. Any other concurrent severe and/or uncontrolled medical condition that would, in

Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Locally advanced or metastatic HER2 negative and triple-negative breast cancer
MedDRA version: 18.1 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 100000004864
MedDRA version: 18.1 Level: LLT Classification code 10072740 Term: Locally advanced breast cancer System Organ Class: 100000004864

Intervention(s)

Product Name: PQR309
Product Code: PQR309
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not available yet
CAS Number: 1225037-39-7
Current Sponsor code: PQR309
Other descriptive name: 5-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)-2-pyridinamine
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Product Name: PQR309
Product Code: PQR309
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Not available yet
CAS Number: 1225037-39-7
Current Sponsor code: PQR309
Other descriptive name: 5-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)-2-pyridinamine
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-

Trade Name: HALAVEN
Product Name: Halaven
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ERIBULIN MESYLATE
CAS Number: 441045-17-6
Other descriptive name: ERIBULIN MESYLATE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 0.44-

Primary Outcome(s)

Main Objective: For the escalation part: To identify maximum tolerated dose (MTD) of
PQR309 administered in combination with eribulin in patients with HER2 negative BC.
For the expansion part: To evaluate efficacy of PQR309 in combination with eribulin in patients with TNBC

Primary end point(s): In the escalation part: MTD based on the incidence of dose limiting toxicities (DLTs)
In the expansion part: Clinical Benefit Rate (CBR) including complete
response (CR), partial response (PR) and stable disease (SD) according to the response evaluation criteria in solid tumors (RECIST), version 1.1

Secondary Objective: To assess safety and tolerability of the combination
To assess the pharmacokinetics (PK) of PQR309 in combination with eribulin and to investigate the potential effect of PQR309 on the pharmacokinetics of eribulin

Timepoint(s) of evaluation of this end point: In the escalation part: Weekly
In the expansion part: every 6 weeks for the first 24 weeks, then every 9 weeks

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: - AEs/SAEs, vital signs, ECOG status, physical examinations: weekly
- ECG: on Day 1 of each cycle
- Hematology, blood chemistry: weekly
- Urinalysis: on Day 1 of each cycle
- Additional Clinical Efficacy: every 6 weeks for the first 24 weeks, then every 9 weeks
- Pharmacokinetics (PK): Day 1, 8, 15 of cycle 1 and Day 1 of subsequent cycles

Secondary end point(s): Safety and tolerability:
- Incidence and severity of AEs including SAEs
- Changes in vital signs (heart rate, blood pressure, body temperature), ECOG status, physical examinations, body weight, and ECG
- Changes of routine laboratory assessments (hematology, blood chemistry, urinalysis)
Additional Clinical Efficacy:
- Overall response rate (ORR), time to response (TTR), duration of response (DOR), time to treatment failure (TTF), progression-free survival (PFS) and 1-year survival rates.
Pharmacokinetics (PK):
- PQR309 and eribulin plasma concentration, PK parameters: Cmax, tmax,AUC0-24, AUC0??, t1/2 and RAC

Secondary ID(s)

PQR309-007

Source(s) of Monetary Support

PIQUR Therapeutics AG