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

Phase 1

Completed

Conditions: Advanced or Metastatic Breast Cancer

Interventions: Drug: MEN1611
Drug: Trastuzumab
Drug: Fulvestrant

Registration Number: NCT03767335

Lead Sponsor: Menarini Group

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 62

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
MEN1611	MEN1611	MEN1611 + Trastuzumab +/- Fulvestrant
MEN1611	Trastuzumab	MEN1611 + Trastuzumab +/- Fulvestrant
MEN1611	Fulvestrant	MEN1611 + Trastuzumab +/- Fulvestrant

Primary Outcome Measures

Name	Time	Method
MTD of MEN1611 in Combination With Trastuzumab ± Fulvestrant	Up to 28 Days	MTD was defined as the highest dose level at which no more than 1 participant experienced a DLT during the 28-day DLT assessment window.
Number of Participants With DLTs of MEN1611 in Combination With Trastuzumab ± Fulvestrant	Up to 28 days	DLT was defined as the occurrence of any of the protocol defined adverse drug reactions (ADRs) related to the combination regimens or to MEN1611 alone and unrelated to the participants' underlying disease or concomitant medication occurring during 28 days after the first MEN1611 administration.
RP2D of MEN1611 in Combination With Trastuzumab ± Fulvestrant	Up to 28 days	RP2D was defined as the highest dose level in milligrams (mg) at which no more than 1 participant experienced a DLT during the DLT assessment window (28days), or the maximum dose judged to be tolerable.

Secondary Outcome Measures

Name	Time	Method
Best Overall Response (BOR) of MEN1611 in Combination With Trastuzumab ± Fulvestrant	Up to 3 years	BOR was defined as percentage of participants who had a best overall response to therapy of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) and was defined according to Response Evaluation Criteria in Solid Tumors version 1.1 assessment locally performed using computed tomography scans or magnetic resonance imaging of the chest and abdomen (including pelvis and adrenal glands).
Objective Response Rate (ORR) of MEN1611 in Combination With Trastuzumab ± Fulvestrant	Up to 3 years	ORR was calculated as the sum of the Best Overall Response (BOR) of complete response (CR) and partial response (PR) rates. ORR was defined according to Response Evaluation Criteria in Solid Tumors version 1.1assessment performed using computed tomography scans or magnetic resonance imaging of the chest and abdomen (including pelvis and adrenal glands).
Disease Control Rate (DCR) of MEN1611 in Combination With Trastuzumab ± Fulvestrant	Up to 3 years	DCR was defined as percentage of participants whose disease shrank or remained stable over a certain time period and was calculated as the sum of the best overall response (BOR) rates of CR, PR and Stable Disease (SD) rates.
Duration of Response (DOR) of MEN1611 in Combination With Trastuzumab ± Fulvestrant	Up to 3 years	DOR was defined as time from first occurrence of a BOR of PR, CR or SD as locally assessed, until the disease has been shown to progress following treatment. Participants with a previous response who did not show a relapse or die without recording a relapse were censored at their last available relapse-free tumour assessment date. Participants with only one tumour assessment after baseline showing progressive disease (PD) were not included in the calculation.
Progression-free Survival (PFS) of MEN1611 in Combination With Trastuzumab ± Fulvestrant	Up to 3 years	PFS was defined as the number of days between the first study treatment administration to the date of first documented disease progression as per local assessment, relapse or death from any cause. Responding participants and participants who were lost to follow-up were censored at their last tumour assessment date.
Overall Survival (OS) of MEN1611 in Combination With Trastuzumab ± Fulvestrant	Up to 3 years	OS was defined as the number of days between the first study treatment administration and death from any cause. Participants still alive who had withdrawn from the study were censored using the latest among end of study and follow-up dates. Drop-out participants were considered censored and the last available date in which the participant was known to be alive were used for calculation.

Trial Locations

Locations (27): Holy Cross Hospital Inc.
🇺🇸
Fort Lauderdale, Florida, United States
Detroit Clinical Research Center
🇺🇸
Farmington Hills, Michigan, United States
Washington University
🇺🇸
Saint Louis, Missouri, United States
Cliniques Universitaires Saint-Luc
🇧🇪
Brussels, Belgium
Institut Jules Bordet
🇧🇪
Brussels, Belgium
UZ Leuven
🇧🇪
Leuven, Belgium
Centre Georges François Leclerc
🇫🇷
Dijon, France
Centre Oscar Lambret
🇫🇷
Lille Cedex, France
Institut Régional du Cancer de Montpellier
🇫🇷
Montferrier Sur Lez, France
ICO - Site René Gauducheau
🇫🇷
Saint-Herblain, France
Scroll for more (17 remaining)
Holy Cross Hospital Inc.
🇺🇸Fort Lauderdale, Florida, United States