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Clinical Trial Results:
A Randomized Phase II Study of Fulvestrant in Combination with the dual mTOR Inhibitor AZD2014 or Everolimus or Fulvestrant alone in Estrogen Receptor Positive Advanced or Metastatic Breast Cancer.

Summary
EudraCT number	2013-002403-34
Trial protocol	DE PT ES HU FR
Global end of trial date	31 Dec 2021

Results information
Results version number	v1(current)
This version publication date	25 Mar 2023
First version publication date	25 Mar 2023
Other versions
Summary report(s)	JAMA Oncology Publication Adverse Event Summary

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
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Trial information

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Sponsor protocol code

009175QM

ISRCTN number

US NCT number

NCT02216786

WHO universal trial number (UTN)

Sponsor organisation name

Queen Mary University of London

Sponsor organisation address

Mile End Road, London, United Kingdom, E1 2EF

Public contact

Centre for Experimental Cancer Medicine, Queen Mary University of London, +44 02078828490, bci-MANTA@qmul.ac.uk

Scientific contact

Centre for Experimental Cancer Medicine, Queen Mary University of London, +44 02078828490, bci-MANTA@qmul.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Mar 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Oct 2017

Global end of trial reached?

Yes

Global end of trial date

31 Dec 2021

Was the trial ended prematurely?

Main objective of the trial

The main aims of this study are to: - Determine whether dual inhibition of mTORC 1 and mTORC2 with AZD2014 will increase the antitumour activity of endocrine treatment with fulvestrant in ER positive advanced or metastatic breast cancer. - Determine whether inhibition of both mTORC 1 and mTORC2 using AZD2014 will have superior antitumour activity compared to inhibition of mTORC1 alone with everolimus, when combined with fulvestrant. - Explore whether additional efficacy is likely to be present in a subgroup with PI3K pathway activation for whom it is hypothesised that there will be greater sensitivity to mTOR inhibitors - Characterize the patient population who might benefit from fulvestrant plus AZD2014 to identify potential predictors of sensitivity The primary objectives of this study are to: - Estimate the clinical benefit (CB) of fulvestrant+AZD2014 relative to fulvestrant+everolimus or fulvestrant alone, as measured by investigator assessed progression free survival (PFS

Protection of trial subjects

Eligibility criteria for this study were selected to enhance the safety of patients in this trial. A number of exclusion criteria were specifically based on the known safety profiles of the study drug treatments, including the known safety profile of everolimus, as well as nonclinical and clinical data for AZD2014. All enrolled patients were evaluated clinically and with standard laboratory tests before and at regular intervals during their participation in this study. Safety evaluations consisted of medical interviews, recording of adverse events, physical examinations, and laboratory measurements. Patients were evaluated for adverse events (all grades), serious adverse events, and any adverse events requiring drug interruption or discontinuation throughout the course of the study. Two committees were convened to evaluate the safety of this trial, the trial steering committee (TSC) and the independent data monitoring committee (IDMC).

Background therapy

Evidence for comparator

Current clinical mTOR inhibitors such as everolimus inhibit the mTORC1 complex only through an indirect mechanism that does not involve the mTOR kinase, and there is increasing evidence that this mechanism sets off a negative feedback loop leading to the activation of mTORC2, AKT phosphorylation, and ultimately treatment resistance. Preclinical studies have demonstrated that rapamycin analogues are unable to completely abrogate mTORC1 signaling and the residual activity of the downstream effector 4E-BP1 can continue to initiate protein translation. Mammalian target of rapamycin kinase inhibitors have been developed to enhance the antitumor activity through more complete TORC1 inhibition and abrogating AKT-mediated TORC2 activation. Vistusertib (AZD2014) is a dual inhibitor of both mTORC1 and mTORC2 complexes; compared with everolimus, vistusertib has demonstratedmore complete growth inhibition and cell death in vitro and in vivo based on a greater inhibitory function againstmTORC1 and additional inhibition o fmTORC2, especially in ER-positive breast cancer models. Most preclinical and clinical applications of PI3K inhibitors or mTOR inhibitors use continuous daily dosing schedules. However, high-dose pulsatile administration has been proposed as a way to induce more complete suppression of mTOR signaling to maximize therapeutic benefit while reducing toxic effects by allowing for recovery of nontarget tissues during dosing breaks. Using intermittent dosing (2 days on and 5 days off), vistusertib induced rapid tumor regression in preclinical models. The MANTA trial evaluated whether the addition of vistusertib (AZD2014) increases PFS and other measures of antitumor activity of fulvestrant in postmenopausal women with ER-positive advanced or metastatic breast cancer who have failed prior therapy with AIs. The study also evaluated whether dual inhibition of mTORC1 and mTORC2 with vistusertib leads to improved efficacy compared with daily treatment.

Actual start date of recruitment

01 Oct 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country