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

Conditions

Advanced or Metastatic Breast Cancer

Keywords

Advanced Breast Cancer, Metastatic Breast Cancer, PI3K inhibitor, HER2-positive

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.

Alessio Fiascarelli, Giuseppe Merlino, Stefania Capano, Simone Talucci, Diego Bisignano et al. (17 authors)

Breast Cancer Research and Treatment2023-03-137 citations

10.1007/s10549-023-06895-2

Abstract 1376: Dosing frequency/PD/efficacy relationship of MEN1611 in HER2 amplified, PIK3CA mutated, and refractory to Trastuzumab xenograft model of breast cancer

Alessio Fiascarelli, Giuseppe Merlino, Stefania Capano, Alessandro Bressan, Mario Bigioni et al. (8 authors)

Cancer Research2021-07-01

10.1158/1538-7445.am2021-1376

B-PRECISE-01 Study: A phase Ib trial of MEN1611, a PI3K Inhibitor, combined with trastuzumab ± fulvestrant for the treatment of HER2-positive advanced or metastatic breast cancer.

Martine Piccart, Philippe Aftimos, François P. Duhoux, Hans Wildiers, Nicolás Isambert et al. (20 authors)

Journal of Clinical Oncology2019-05-205 citations

10.1200/jco.2019.37.15_suppl.tps1101

Interventions

DRUGMEN1611

MEN1611 oral dose administered twice daily for a continuous 28-day cycle

DRUGTrastuzumab

Trastuzumab solution for infusion administered weekly via IV

DRUGFulvestrant

Fulvestrant solution for injection administered monthly via IM (only for HR-positive postmenopausal women)

Study design

Allocation

NA

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

Step 1 Dose escalation / Step 2 Cohort expansion in two selected breast cancer sub-populations

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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).
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.
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.
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.

Countries

Belgium, France, Italy, Spain, United Kingdom, United States

Participant flow

Recruitment details

A total of 73 participants were screened for study eligibility, of which 11 were considered as screen failures.

Pre-assignment details

The study included a Dose Escalation part and a Dose Expansion part. The Dose Escalation part of the study included Cohorts 1 and 2. It was prespecified that 3 participants who enrolled in Dose Expansion Cohort were to be included in the Dose-Limiting Toxicity (DLT) population. As prespecified, data were collected for the DLT population for the Maximum Tolerated Dose (MTD), DLT, Recommended Phase 2 Dose (RP2D) Outcome Measures,

Participants by arm

Arm	Count
Dose Escalation Cohort 1 Participants received low dose of MEN1611 twice daily administered in combination with trastuzumab once every 3 weeks ± fulvestrant once every 4 weeks.	3
Dose Escalation Cohort 2 Participants received medium dose of MEN1611 twice daily administered in combination with trastuzumab once every 3 weeks ± fulvestrant once every 4 weeks.	3
Dose Expansion Cohort Participants received high dose of MEN1611 (RP2D) twice daily administered in combination with trastuzumab once every 3 weeks ± fulvestrant once every 4 weeks.	56
Total	62

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Death	0	0	2
Overall Study	Disease progression needing additional medication	0	0	17
Overall Study	Other Medical Reasons	0	0	3
Overall Study	Participant excluded from efficacy population	0	0	1
Overall Study	Physician Decision	1	1	0
Overall Study	Progressive Disease	2	2	2
Overall Study	Sponsor decision	0	0	2
Overall Study	Withdrawal by Subject	0	0	6

Baseline characteristics

Characteristic	Dose Escalation Cohort 1	Dose Escalation Cohort 2	Dose Expansion Cohort	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	2 Participants	1 Participants	13 Participants	16 Participants
Age, Categorical Between 18 and 65 years	1 Participants	2 Participants	43 Participants	46 Participants
Age, Continuous	65 years STANDARD_DEVIATION 7.937	59.33 years STANDARD_DEVIATION 14.468	53.36 years STANDARD_DEVIATION 11.112	56.02 years STANDARD_DEVIATION 55.5
Race/Ethnicity, Customized Hispanic or Latino	0 Participants	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	3 Participants	3 Participants	50 Participants	56 Participants
Race/Ethnicity, Customized Unknown	0 Participants	0 Participants	5 Participants	5 Participants
Sex: Female, Male Female	3 Participants	3 Participants	56 Participants	62 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	3 / 3	3 / 3	28 / 56
other Total, other adverse events	2 / 3	3 / 3	56 / 56
serious Total, serious adverse events	2 / 3	3 / 3	21 / 56

Outcome results

Primary

MTD of MEN1611 in Combination With Trastuzumab ± Fulvestrant

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.

Time frame: Up to 28 Days

Population: DLT population included all participants from Dose Escalation Cohorts 1, 2 and 3 participants from the Dose Expansion Cohort.~DLT population consisted of all participants who received at least 80% of MEN1611 and 100% of trastuzumab and/or fulvestrant during 28 days after the first MEN1611 drug administration with a Safety Follow-up of 28 days after the first administration of the study treatment.

Arm	Measure	Value (NUMBER)
Dose Escalation Cohorts 1 and 2, and Dose Expansion Cohort	MTD of MEN1611 in Combination With Trastuzumab ± Fulvestrant	48 milligrams (mg)

Primary

Number of Participants With DLTs of MEN1611 in Combination With Trastuzumab ± Fulvestrant

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.

Time frame: Up to 28 days

Population: DLT population included all participants from Dose Escalation Cohorts 1, 2 and 3 participants from the Dose Expansion Cohort.~DLT population consisted of all participants who received at least 80% of MEN1611 and 100% of trastuzumab and/or fulvestrant during 28 days after the first MEN1611 drug administration with a Safety Follow-up of 28 days after the first administration of the study treatment.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Dose Escalation Cohorts 1 and 2, and Dose Expansion Cohort	Number of Participants With DLTs of MEN1611 in Combination With Trastuzumab ± Fulvestrant	0 Participants
Dose Escalation Cohort 2	Number of Participants With DLTs of MEN1611 in Combination With Trastuzumab ± Fulvestrant	0 Participants
Dose Escalation Cohort 3	Number of Participants With DLTs of MEN1611 in Combination With Trastuzumab ± Fulvestrant	0 Participants

Primary

RP2D of MEN1611 in Combination With Trastuzumab ± Fulvestrant

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.

Time frame: Up to 28 days

Population: DLT population included all participants from Dose Escalation Cohorts 1, 2 and 3 participants from the Dose Expansion Cohort.~DLT population consisted of all participants who received at least 80% of MEN1611 and 100% of trastuzumab and/or fulvestrant during 28 days after the first MEN1611 drug administration with a Safety Follow-up of 28 days after the first administration of the study treatment.

Arm	Measure	Value (NUMBER)
Dose Escalation Cohorts 1 and 2, and Dose Expansion Cohort	RP2D of MEN1611 in Combination With Trastuzumab ± Fulvestrant	48 mg

Secondary

Best Overall Response (BOR) of MEN1611 in Combination With Trastuzumab ± Fulvestrant

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).

Time frame: Up to 3 years