MEN1611 With Trastuzumab (+/- Fulvestrant) in Metastatic Breast Cancer

Study Overview
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Brief Summary
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The main purpose of this open-label, dose-escalation, phase Ib study is to identify the appropriate dose of MEN1611 to be used in combination with Trastuzumab with/without Fulvestrant for the treatment of advanced or metastatic HER2-positive breast cancer

Detailed Description
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This Phase Ib study will investigate the safety and anti-tumor activity of daily oral doses MEN1611 in combination with Trastuzumab with/without Fulvestrant in female and male patients affected by advanced or metastatic HER2-positive breast cancer. Fulvestrant will be added to the post-menopausal patients with hormone-sensitive disease. MEN1611 is an investigational drug which blocks a protein called PI3K (phosphoinositide 3-kinase) involved in cancer cells growth. The Maximum Tolerated Dose (MTD) of MEN1611 given as single agent was assessed in a phase I trial in patients with advanced solid tumors. This Phase IB will start with a dose escalation part (Step 1) to identify the MTD of MEN1611 given in combination with Trastuzumab with/without Fulvestrant. The study will continue with a cohort expansion (Step 2) to investigate the anti-tumor activity of the selected MEN1611 dose level considered to be tolerable by a Safety Review Committee.

Official Title
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Open-label, Multicentre, Phase Ib Dose-escalation Study of MEN1611, a PI3K Inhibitor Combined With Trastuzumab With or Without Fulvestrant, in Subjects With PIK3CA Mutated HER2 Positive Locally Recurrent Unresectable (Advanced) or Metastatic (a/m) Breast Cancer Progressed to Anti-HER2 Based Therapy

Conditions
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Advanced or Metastatic Breast Cancer

Intervention / Treatment
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* Drug: MEN1611
* Drug: Trastuzumab
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Histologically confirmed invasive adenocarcinoma of the breast Known HER2+ breast cancer Advanced or metastatic breast cancer harbouring PIK3CA mutation on tissue sample > 2 lines of anti-HER2 based regimens with at least 1 regimen with trastuzumab Radiological documented evidence of progressive disease Life expectancy ≥ 12 weeks Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Main Exclusion Criteria: Previous treatment with PI3K inhibitors Brain metastases untreated, unless treated > 4 weeks and only if clinically stable and not receiving corticosteroids History of clinically significant bowel disease ≥ grade 2 diarrhoea History of significant, uncontrolled, or active cardiovascular disease Any serious and/or unstable pre-existing psychiatric or neurologic illness or other conditions that could interfere with patient's safety Not controlled diabetes mellitus (glycated haemoglobin [HbA1c] >7%) and fasting plasma glucose >126 mg/dL Concurrent chronic treatment with steroids, as immunosuppressant, or another immunosuppressive agent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Sequential Assignment
Interventional Model Description: Step 1 Dose escalation / Step 2 Cohort expansion in two selected breast cancer sub-populations
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEN1611<br>MEN1611 + Trastuzumab +/- Fulvestrant | Drug: MEN1611<br>* MEN1611 oral dose administered twice daily for a continuous 28-day cycle<br>Drug: Trastuzumab<br>* Trastuzumab solution for infusion administered weekly via IV<br>Drug: Fulvestrant<br>* Fulvestrant solution for injection administered monthly via IM (only for HR-positive postmenopausal women)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 dose (RP2D) |  | 28 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment emergent adverse events (TEAEs) |  | 2 years | 
| Progression Free Survival |  | 2 years | 
| Overall Survival |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Breast Cancer, Metastatic Breast Cancer, PI3K inhibitor, HER2-positive