PQR309 and Eribulin in Metastatic HER2 Negative and Triple-negative Breast Cancer (PIQHASSO)

• ClinicalTrials.gov Identifier: NCT02723877
• Recruitment Status: Completed
• First Posted: March 31, 2016
• Last Update Posted: March 22, 2019
• Sponsor: PIQUR Therapeutics AG
• Collaborators: Hospital Universitario Ramon y Cajal; Hospital Universitari Vall d'Hebron Research Institute; Institut Català d'Oncologia; Churchill Hospital; Barts Cancer Institute; Fundación Instituto Valenciano de Oncología
• Information provided by (Responsible Party): PIQUR Therapeutics AG

Study Description

Brief Summary:

This study is an open-label,non randomized, multi-center, phase 1/2b (dose escalation followed by expansion part) study evaluating clinical safety, efficacy and pharmacokinetics of PQR309 in combination with standard dose of eribulin in patients with locally advanced or metastatic HER2-negative (escalation part) and Triple Negative Breast Cancer (expansion part).

Condition or disease	Intervention/treatment	Phase
Metastatic Breast Cancer	Drug: PQR309; Drug: Eribulin	Phase 1; Phase 2

Detailed Description:

• The primary objective of the escalation part is to assess the maximum tolerated dose (MTD) of PQR309 combined with the standard eribulin dose in patients with HER2 negative breast cancer following a "modified" 3 by 3 design.
• For the expansion part the objective is to evaluate efficacy of PQR309 in combination with eribulin in patients with Triple Negative Breast Cancer
• Once the MTD of continuous daily PQR309 dosing has been established, intermittent schedules of PQR309 ("2 days on/ 5 days off" or "Monday / Thursday") will be evaluated.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: March 28, 2016
• Actual Primary Completion Date: October 3, 2018
• Actual Study Completion Date: October 3, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Eribulin and PQR309; PQR309 in combination with standard approved dose of eribulin mesylate 1.4 mg/m2 intravenous (iv) on days 1 and 8 in a period of 21 days per cycle will be investigated. . PQR309 will be administered maximum 15 minutes after eribulin iv dosing.	Drug: PQR309; Dual phosphatidylinositol 3-kinase phosphoinositide 3-kinase/ mammalian target of rapamycin Inhibitor (= PI3K/mTOR Inhibitor); Drug: Eribulin; non.taxane microtubule dynamics inhibitor; Other Names: eribulin mesylate; Halaven®

Outcome Measures

Primary Outcome Measures :

1. Number of patients with treatment related Adverse Events and Serious Adverse Events as assessed by NCI CTCAEV4.03 [ Time Frame: Up to 6 months ]
   Continous dosing and intermittent schedules of PQR309
2. RECIST the Response criteria for solid tumors will be used to identify clinical benefit rate (CBR) including complete Response (CR), partial Response (PR) and stable disease (SD) [ Time Frame: Up to 15 months ]
   Continous dosing and intermittent schedules of PQR309

Secondary Outcome Measures :

1. Number of patients with Adverse Events and Serious Adverse Events and number of anormal laboratory values that constitute an Adverse Events on their own [ Time Frame: Up to 12 months ]
   Continous dosing and intermittent schedules of PQR309
2. Number and percent of patients having each ECOG (Eastern Oncology Cooperative Group) performance status level will be presented for baseline and each post-baseline measurement. [ Time Frame: up to 12 months ]
   Continous dosing and intermittent schedules of PQR309
3. Assessment of PQR309 and Eribulin blood concentration [ Time Frame: up to 12 months ]
   Continous dosing and intermittent schedules of PQR309
4. Physical examination, Body weight in kg [ Time Frame: up to 12 months ]
   Continous dosing and intermittent schedules
5. Physical examination, ECG [ Time Frame: up to 12 months ]
   Continous dosing and intermittent schedules of PQR309
6. Vital signs like heart rate [ Time Frame: up to 12 months ]
   Continous dosing and intermittent schedules of PQR309
7. Vital signs like blood pressure [ Time Frame: up to 12 months ]
   Continous dosing and intermittent schedules of PQR309
8. Vital signs like body temperature [ Time Frame: up to 12 months ]
   Continous dosing and intermittent schedules of PQR309
9. Objective Response Rate (ORR), is defined as the best overall response (confirmed CR or PR) recorded for each patient since baseline. [ Time Frame: up to 12 months ]
   Continous dosing and intermittent schedules of PQR309
10. Time to Response (TTR) is defined, for patients with tumor response, as the time from the date of study entry to the first documentation of response (complete or partial) [ Time Frame: up to 12 months ]
    Continous dosing and intermittent schedules of PQR309
11. Duration of response (DOR) is defined, for the patients with tumor response, as the time from the date of the first confirmed response to disease progression. [ Time Frame: up to 12 months ]
    Continous dosing and intermittent schedules of PQR309
12. Progression- free survival (PFS) is defined as the time from study entry to progression or death due to any cause [ Time Frame: up to 12 months ]
    Continous dosing and intermittent schedules of PQR309
13. Time to treatment failure (TTF) is defined as the time from study entry to any treatment failure including disease progression or discontinuation of treatment [ Time Frame: up to 12 months ]
    Continous dosing and intermittent schedules of PQR309
14. 1-year survival, defined as the time from study entry to death as a result of any cause at 1-year cut-off date [ Time Frame: up to 12 months ]
    Continous dosing and intermittent schedules of PQR309
15. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: tmax [ Time Frame: On Cycle 1 Day 8: pre-dose, end of eribulin infusion, 2h and 6h post end of eribulin infusion and on Day 15: pre-dose and one sample between 1 and 3 hours post PQR309 dose ]
    Intermittent schedule B: "Monday/ Thursday"
16. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: cmax [ Time Frame: On Cycle 1 Day 8: pre-dose, end of eribulin infusion, 2h and 6h post end of eribulin infusion and on Day 15: pre-dose and one sample between 1 and 3 hours post PQR309 dose ]
    Intermittent schedule B: "Monday/ Thursday"
17. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: AUC0-24 [ Time Frame: On Cycle 1 Day 8: pre-dose, end of eribulin infusion, 2h and 6h post end of eribulin infusion and on Day 15: pre-dose and one sample between 1 and 3 hours post PQR309 dose ]
    Intermittent schedule B: "Monday/ Thursday"
18. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: AUC0-∞ [ Time Frame: On Cycle 1 Day 8: pre-dose, end of eribulin infusion, 2h and 6h post end of eribulin infusion and on Day 15: pre-dose and one sample between 1 and 3 hours post PQR309 dose ]
    Intermittent schedule B: "Monday/ Thursday"
19. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: RAC(Racemate) [ Time Frame: On Cycle 1 Day 8: pre-dose, end of eribulin infusion, 2h and 6h post end of eribulin infusion and on Day 15: pre-dose and one sample between 1 and 3 hours post PQR309 dose ]
    Intermittent schedule B: "Monday/ Thursday"
20. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: cmax [ Time Frame: PK is being assessed during Cycle 1 on Day 8: pre-dose, end of eribulin infusion, 2h and 6h post end of eribulin infusion. On Cycle 1 Day 15: pre-dose and one sample between 1 and 3 hours post PQR309 dose. ]
    Intermittent schedule A: 2 days on/5 days off
21. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: tmax [ Time Frame: PK is being assessed during Cycle 1 on Day 8: pre-dose, end of eribulin infusion, 2h and 6h post end of eribulin infusion. On Cycle 1 Day 15: pre-dose and one sample between 1 and 3 hours post PQR309 dose. ]
    Intermittent schedule A: 2 days on/5 days off
22. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: AUC0-24 [ Time Frame: PK is being assessed during Cycle 1 on Day 8: pre-dose, end of eribulin infusion, 2h and 6h post end of eribulin infusion. On Cycle 1 Day 15: pre-dose and one sample between 1 and 3 hours post PQR309 dose. ]
    Intermittent schedule A: 2 days on/5 days off
23. PK parameters of PQR309 and eribulin will include: AUC0-∞ [ Time Frame: PK is being assessed during Cycle 1 on Day 8: pre-dose, end of eribulin infusion, 2h and 6h post end of eribulin infusion. On Cycle 1 Day 15: pre-dose and one sample between 1 and 3 hours post PQR309 dose. ]
    Intermittent schedule A: 2 days on/5 days off
24. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: RAC [ Time Frame: PK is being assessed during Cycle 1 on Day 8: pre-dose, end of eribulin infusion, 2h and 6h post end of eribulin infusion. On Cycle 1 Day 15: pre-dose and one sample between 1 and 3 hours post PQR309 dose. ]
    Intermittent schedule A: 2 days on/5 days off
25. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: cmax [ Time Frame: It will be measured pre-dose and at the end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end and at end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end of eribulin during Cycle 1 on day 1 and 8 and beyond cycle 1 on day 1 ]
    Continous Dosing
26. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: AUC0-24 [ Time Frame: It will be measured pre-dose and at the end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end and at end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end of eribulin during Cycle 1 on day 1 and 8 and beyond cycle 1 on day 1 ]
    Continous Dosing
27. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: AUC0-∞ [ Time Frame: It will be measured pre-dose and at the end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end and at end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end of eribulin during Cycle 1 day on 1 and 8 and beyond cycle 1 on day 1 ]
    Continous Dosing
28. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: t1/2 [ Time Frame: It will be measured pre-dose and at the end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end and at end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end of eribulin during Cycle 1 on day 1 and 8 and beyond cycle 1 on day 1 ]
    Continous Dosing
29. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: tmax [ Time Frame: It will be measured pre-dose and at the end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end and at end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end of eribulin during Cycle 1 on day 1 and 8 and beyond cycle 1 on day 1 ]
    Continous Dosing
30. Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: RAC (Racemate) [ Time Frame: It will be measured pre-dose and at the end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end and at end of eribulin infusion and 0.5h, 1h, 2h, 4h, and 8h post end of eribulin during Cycle 1 on day 1 and 8 and beyond cycle 1 on day 1 ]
    Continous Dosing
31. Changes in glucose levels [ Time Frame: 12 months ]
    Continous dosing and intermittent schedules of PQR309
32. Changes in Insulin levels [ Time Frame: 12 months ]
    Continous dosing and intermittent schedules of PQR309
33. Changes of Routine laboratory -Haematology [ Time Frame: 12 months ]
    Continous dosing and intermittent schedules of PQR309
34. Changes of Routine laboratory -blood chemistry [ Time Frame: 12 months ]
    Continous dosing and intermittent schedules of PQR309
35. Changes of Routine laboratory -urinanalysis [ Time Frame: 12 months ]
    Continous dosing and intermittent schedules of PQR309

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologically/cytologically confirmed diagnosis of breast cancer. Radiological evidence of inoperable locally advanced or metastatic breast cancer.
• HER2 negative breast cancer (based on the most recent analyzed biopsy) defined as a negative in situ hybridization test or an immunohistochemistry status of 0, 1+ or 2+.
• Received at least 2 and no more than 5 prio chemotherapeutic regimens in locally advanced and/or metastatic setting.
• Prior therapy has to include an anthracycline and a taxane in any combination or order.
• For Expansion part:

Triple-negative breast cancer defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0,1+ or 2+ER abnd PR status <10% by local laboratory testing.

Exclusion Criteria:

• Previous systemic treatment with PI3K,mTOR or AKT inhibitors (allowed in the escalation part).
• Previous treatment with eribulin (allowed in the escalation part). Known hypersensitivity to any of the excipients of PQR309 or eribulin.Concurrent treatment with other approved or investigational antineoplastic agent.
• Symptomatic Central Nervous System 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).
• Clinically manifested diabetes mellitus(treated and/or clinical signs with fasting glucose >125mg/dl or HbA1c>7%), or documented steroid induced diabetes mellitus.

Contacts and Locations

Locations

Spain

Hospital Universitarsi Vall d'Hebron

Barcelona, Catalan, Spain, 08035

Insitut Català d´Oncologia

Barcelona, Spain

Fundación Instituto Valenciano de Oncología

Valencia, Spain

United Kingdom

Barts Cancer Institute

London, United Kingdom

Churchill hospital

Oxford, United Kingdom

Sponsors and Collaborators

PIQUR Therapeutics AG

Hospital Universitario Ramon y Cajal

Hospital Universitari Vall d'Hebron Research Institute

Institut Català d'Oncologia

Churchill Hospital

Barts Cancer Institute

Fundación Instituto Valenciano de Oncología

Investigators

• Study Director: Javier Cortes, PD Dr. med; Hospital Universitario Ramon y Cajal

More Information

• Responsible Party: PIQUR Therapeutics AG
• ClinicalTrials.gov Identifier: NCT02723877
• Other Study ID Numbers: PQR309-007
• First Posted: March 31, 2016
• Last Update Posted: March 22, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by PIQUR Therapeutics AG:

TNBC

Additional relevant MeSH terms:

Breast Neoplasms; Triple Negative Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases