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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: PQR309
* Drug: Eribulin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eribulin and PQR309<br>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<br>* Dual phosphatidylinositol 3-kinase phosphoinositide 3-kinase/ mammalian target of rapamycin Inhibitor (= PI3K/mTOR Inhibitor)<br>Drug: Eribulin<br>* non.taxane microtubule dynamics inhibitor<br>* Other names: Halaven®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with treatment related Adverse Events and Serious Adverse Events as assessed by NCI CTCAEV4.03 | Continous dosing and intermittent schedules of PQR309 | Up to 6 months | 
| 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) | Continous dosing and intermittent schedules of PQR309 | Up to 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with Adverse Events and Serious Adverse Events and number of anormal laboratory values that constitute an Adverse Events on their own | Continous dosing and intermittent schedules of PQR309 | Up to 12 months | 
| 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. | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| Assessment of PQR309 and Eribulin blood concentration | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| Physical examination, Body weight in kg | Continous dosing and intermittent schedules | up to 12 months | 
| Physical examination, ECG | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| Vital signs like heart rate | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| Vital signs like blood pressure | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| Vital signs like body temperature | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| Objective Response Rate (ORR), is defined as the best overall response (confirmed CR or PR) recorded for each patient since baseline. | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| 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) | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| 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. | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| Progression- free survival (PFS) is defined as the time from study entry to progression or death due to any cause | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| Time to treatment failure (TTF) is defined as the time from study entry to any treatment failure including disease progression or discontinuation of treatment | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| 1-year survival, defined as the time from study entry to death as a result of any cause at 1-year cut-off date | Continous dosing and intermittent schedules of PQR309 | up to 12 months | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: tmax | Intermittent schedule B: Monday/ Thursday | 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 | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: cmax | Intermittent schedule B: Monday/ Thursday | 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 | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: AUC0-24 | Intermittent schedule B: Monday/ Thursday | 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 | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: AUC0-∞ | Intermittent schedule B: Monday/ Thursday | 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 | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: RAC(Racemate) | Intermittent schedule B: Monday/ Thursday | 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 | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: cmax | Intermittent schedule A: 2 days on/5 days off | 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. | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: tmax | Intermittent schedule A: 2 days on/5 days off | 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. | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: AUC0-24 | Intermittent schedule A: 2 days on/5 days off | 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. | 
| PK parameters of PQR309 and eribulin will include: AUC0-∞ | Intermittent schedule A: 2 days on/5 days off | 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. | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: RAC | Intermittent schedule A: 2 days on/5 days off | 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. | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: cmax | Continous Dosing | 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 | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: AUC0-24 | Continous Dosing | 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 | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: AUC0-∞ | Continous Dosing | 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 | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: t1/2 | Continous Dosing | 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 | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: tmax | Continous Dosing | 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 | 
| Pharmacokinetic (PK) parameters of PQR309 and eribulin will include: RAC (Racemate) | Continous Dosing | 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 | 
| Changes in glucose levels | Continous dosing and intermittent schedules of PQR309 | 12 months | 
| Changes in Insulin levels | Continous dosing and intermittent schedules of PQR309 | 12 months | 
| Changes of Routine laboratory -Haematology | Continous dosing and intermittent schedules of PQR309 | 12 months | 
| Changes of Routine laboratory -blood chemistry | Continous dosing and intermittent schedules of PQR309 | 12 months | 
| Changes of Routine laboratory -urinanalysis | Continous dosing and intermittent schedules of PQR309 | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TNBC