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Estrogen Receptor Positive Breast CancerPhase 2MANTANCT02216786

A Randomized Study of AZD2014 in Combination With Fulvestrant in Metastatic or Advanced Breast Cancer

A Phase 2 study testing AZD2014, Everolimus and Fulvestrant in people with Estrogen Receptor Positive Breast Cancer, run by Queen Mary University of London at 79 sites in 9 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This is an open-label, multicentre, 4-arm randomised phase II trial of fulvestrant + AZD2014 versus fulvestrant + everolimus versus fulvestrant alone in patients with ER-positive, HER2-negative advanced or metastatic breast cancer, whose disease relapsed during treatment with (or within 12 months after discontinuation… Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Estrogen Receptor Positive Breast Cancer
What is being tested?
AZD2014, Everolimus and Fulvestrant
Could I receive a placebo?
No, everyone receives an active treatment
How many people
333 participants
Where
79 sitesin 9 countries
Study dates
16 Jan 2014to 31 Dec 2021
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Written informed consent prior to admission to this study
  • Women, age ≥18 years
  • Histologically confirmed breast cancer
  • Metastatic or locally recurrent disease; locally recurrent disease must not be amenable to resection with curative intent (patients who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible).
  • Patients must have:
  • at least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements, or
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  • lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable disease as defined above; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible
  • Radiological or clinical evidence of recurrence or progression
  • ER-positive disease
  • HER2-negative disease with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH.
  • Formalin fixed, paraffin embedded tumour sample from the primary and/or recurrent cancer must be available for central testing
  • Postmenopausal women.
  • Disease refractory to aromatase inhibitors (AI)
  • Haematologic and biochemical indices within acceptable limits
  • ECOG performance status 0-2
  • Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had a hysterectomy, bilateral oophorectomy, bilateral tubular ligation or is post-menopausal (total cessation of menses for ≥ 1 year

Who cannot join

  • Presence of life-threatening metastatic visceral disease, defined as extensive hepatic involvement or any degree of brain or leptomeningeal involvement (past or present), or symptomatic pulmonary lymphangitic spread. Patients with discrete pulmonary parenchymal metastases are eligible, provided their respiratory function is not compromised as a result of disease.
  • More than one line of prior chemotherapy for metastatic breast cancer
  • Prior chemotherapy, biological therapy, androgens, thalidomide, immunotherapy, other anticancer agents or any investigational agents within 14 days of starting study treatment (not including palliative radiotherapy at focal sites), radiotherapy with a wide field of radiation (greater than or equal to 30% marrow or whole pelvis or spine) within 4 weeks of starting study treatment, or strontium-90 (or other radiopharmaceuticals) within the past 3 months or major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access); with the exception of alopecia, all unresolved toxicities from prior treatment should be no greater than CTCAE grade 1 at the time of starting study treatment
  • Prior treatment with fulvestrant or everolimus
  • Prior treatment with PI3K inhibitors, Akt inhibitors or other mTOR inhibitors.
  • Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids (≥10 mg prednisolone or an equivalent dose of other anti-inflammatory corticosteroids) use for ≥28 days at the time of study entry except in cases outlined below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients on stable low dose of corticosteroids for at least two weeks before randomisation are allowed
Show all 23Show fewer
  • Current refractory nausea and vomiting, chronic gastrointestinal disease or inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of the study medication
  • Clinically significant pulmonary dysfunction
  • Significant cardiovascular disease
  • QTc prolongation defined as a QTc interval >470 msecs or other significant ECG abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate <50 beats/min)
  • Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age)
  • Clinically significant abnormalities of glucose metabolism
  • Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 within 2 weeks before the first dose of study treatment
  • Exposure to potent or moderate inhibitors or inducers of CYP2C8 within 1 week before the first dose of study treatment.
  • Application of haemopoietic growth factors (e.g. G-CSF, GM-CSF) within 2 weeks before receiving study drug
  • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
  • History of hypersensitivity to active or inactive excipients of AZD2014 or everolimus or drugs with a similar chemical structure or class to AZD2014 or everolimus
  • History of hypersensitivity to active or inactive excipients of fulvestrant and/or castor oil.
  • Patients presenting with anaemia symptoms (haemoglobin ≤ 90 g/L).
  • Currently receiving (and are unwilling to discontinue) oestrogen replacement therapy (last dose ≤ 7 days prior to randomisation)
  • Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
  • Detained persons or prisoners
  • Pregnant or nursing women (including no breast feeding from two weeks before the first dose of study medication, till 8 weeks after the last dose of study medication).

Trial locations and contacts

79 sites in 9 countries.

79 sites in 9 countries

United Kingdom30 sites

  • Wansbeck General Hospital

    Ashington

  • Princess of Wales Hospital

    Bridgend

  • Royal Sussex County Hospital

    Brighton

  • Kent and Canterbury Hospital

    Canterbury

  • Cumberland Infirmary

    Carlisle

  • Broomfield Hospital

    Chelmsford

  • University Hospital of North Durham

    Durham

  • Calderdale Royal Hospital

    Halifax

  • Huddersfield Royal Infirmary

    Huddersfield

  • Kidderminster Hospital

    Kidderminster

  • Royal Glamorgan Hospital

    Llantrisant

  • Queen Mary University of London

    London, EC1M6BQ

  • Charring Cross Hospital

    London

  • King's College Hospital

    London

  • Mount Vernon Hospital

    London

  • Queen Elizabeth Hospital, Woolwich

    London

  • Saint Bartholomew's Hospital

    London

  • The Royal Free Hospital

    London

  • The Kent Oncology Centre

    Maidstone

  • North Tyneside General Hospital

    North Shields

  • Nottingham City Hospital

    Nottingham

  • Derriford Hospital

    Plymouth

  • Weston Park Hospital

    Sheffield

  • Solihull Hospital

    Solihull

  • Southend University Hospital

    Southend-on-Sea

  • Royal Stoke University Hospital

    Stoke-on-Trent

  • King's Mill Hospital

    Sutton in Ashfield

  • Great Western Hospital

    Swindon

  • Wrexham Maelor

    Wrexham

  • Yeovil District Hospital

    Yeovil

Other trials in United Kingdom

Germany15 sites

  • Frauenärztliche Gemeinschaftspraxis - Onkologie

    Braunschweig

  • Kliniken Essen-Mitte Senologie

    Essen

  • Klinik für Gynäkologie & Geburtshilfe/Brustzentrum

    Frankfurt

  • Praxis für interdisziplinäre Onkologie & Hämatologie

    Freiburg im Breisgau

  • MediProjekt GbR Hannover

    Hannover

  • SLK-Kliniken Heilbronn GmbH

    Heilbronn

  • Dokusan GmbH

    Herne

  • St. Vincentius Kliniken

    Karlsruhe

  • Schwerpunktpraxis Hämatologie / Onkologie MVZ Lahr

    Lahr

  • Klinikum Neumarkt

    Neumarkt

  • Onkologische Praxis

    Oldenburg

  • Praxis für Innere Medizin

    Singen

  • MVZ Klinik Dr. Hancken GmbH

    Stade

  • Mutterhaus der Borromäerinnen

    Trier

  • Schwarzwald Baar Klinikum, Villingen-Schwenningen

    Villingen-Schwenningen

Other trials in Germany

Spain11 sites

  • Hospital Universitari Vall D'Hebron

    Barcelona

  • Instituto Oncologico Dr. Rosell

    Barcelona

  • Cafeteria Hospital San Pedro de Alcantara

    Cáceres

  • Consorcio Hospitalario Provincial de Castellon

    Castelló

  • Hospital Ico Josep Trueta

    Girona

  • University Hospital Arnau de Vilanova

    Lleida

  • Hospital Clinico Universitario San Carlos

    Madrid

  • Hospital Son Llàtzer

    Palma

  • Hospital Son Espases

    Palma de Mallorca

  • Hospital Universitario de Canarias

    San Cristóbal de La Laguna

  • Hospital Universitari Sant Joan de Reus

    Tarragona

Other trials in Spain

France5 sites

  • ICO Paul Papin

    Angers

  • Institut Sainte Catherine

    Avignon

  • Antoine Lacassagne Centre De Lutte Contre Le Cancer De Nice

    Nice

  • Hospital Center Private Saint-Grégoire

    Saint-Grégoire

  • Centre Paul Strauss

    Strasbourg

Other trials in France

Romania5 sites

  • Center of Oncology Euroclinic

    Bucharest

  • Oncology Center Sf Nectarie

    Caracal

  • Cluj County Clinical Emergency Hospital, Clinical Department of Medical Oncology

    Cluj-Napoca

  • Oncology Institute "Prof. Dr. Ion Chiricuta"

    Cluj-Napoca

  • Oncology Center Oncolab Craiova

    Craiova

Other trials in Romania

Georgia4 sites

  • Clinic Health House

    Tbilisi

  • Institute of Clinical Oncology

    Tbilisi

  • S. Khechinashvili University Clinic

    Tbilisi

  • Tbilisi Cancer Center

    Tbilisi

Other trials in Georgia

Hungary4 sites

  • Uzsoki Street Hospital

    Budapest

  • Bacs-Kiskun County Hospital

    Kalocsa

  • University of Pecs, Institute of Oncology

    Pécs

  • Zala County Szent Rafael Hospital

    Zalaegerszeg

Other trials in Hungary

South Korea3 sites

  • National Cancer Center South Korea

    Goyang

  • Korea University Medical Center Guro Hospital

    Seoul

  • Yonsei University Health System

    Seoul

Other trials in South Korea

Portugal2 sites

  • Hospital da Luz

    Lisbon

  • Ipo Porto

    Porto

Other trials in Portugal

About this study

Official title: 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

This is an open-label, multicentre, 4-arm randomised phase II trial of fulvestrant + AZD2014 versus fulvestrant + everolimus versus fulvestrant alone in patients with ER-positive, HER2-negative advanced or metastatic breast cancer, whose disease relapsed during treatment with (or within 12 months after discontinuation of) an AI in the adjuvant setting or progressed during treatment with an AI in the metastatic setting. Patients will be randomised (2:3:3:2) to one of the four treatment arms:

  • Fulvestrant
  • Fulvestrant + AZD2014 (continuous daily schedule)
  • Fulvestrant + AZD2014 (intermittent schedule - 2 days on, 5 days off)
  • Fulvestrant + everolimus
Read more

Randomization will be stratified by the following criteria:

  • Measurable disease (vs. non-measurable).
  • Sensitivity to prior endocrine therapy (sensitive versus resistant)
Read the detailed description

This is an open-label, multicentre, 4-arm randomised phase II trial of fulvestrant + AZD2014 versus fulvestrant + everolimus versus fulvestrant alone in patients with ER-positive, HER2-negative advanced or metastatic breast cancer, whose disease relapsed during treatment with (or within 12 months after discontinuation of) an AI in the adjuvant setting or progressed during treatment with an AI in the metastatic setting. Patients will be randomised (2:3:3:2) to one of the four treatment arms:

  • Fulvestrant
  • Fulvestrant + AZD2014 (continuous daily schedule)
  • Fulvestrant + AZD2014 (intermittent schedule - 2 days on, 5 days off)
  • Fulvestrant + everolimus

Randomization will be stratified by the following criteria:

  • Measurable disease (vs. non-measurable).
  • Sensitivity to prior endocrine therapy (sensitive versus resistant) Sensitivity to prior endocrine therapy is defined as (i) at least 24 months of endocrine therapy before recurrence in the adjuvant setting or (ii) a complete or partial response to prior metastatic endocrine treatment, or (iii) stabilization for at least 24 weeks of endocrine therapy for advanced disease.

Treatment will be continued until disease progression unless there is evidence of unacceptable toxicity or if the patient requests to be withdrawn from the study. If one of the treatments (fulvestrant or mTOR inhibitor) is discontinued prior to disease progression, patients should be continued on single agent treatment until progression, evidence of unacceptable toxicity or if the patient requests to be withdrawn from the study.

At the time of documented disease progression (using RECIST 1.1), patients randomised to receive fulvestrant + everolimus who still meet eligibility criteria may be permitted to receive open-label crossover treatment with fulvestrant + AZD2014. Crossover therapy must begin no later than 28 days after the clinic visit at which progression was determined. Patients will receive crossover therapy until progression, intolerable toxicity, elective withdrawal from the study, or until the completion or termination of the study, whichever occurs first.

Tumour evaluations will be performed before the initiation of treatment, every 8 weeks during the first 40 weeks and every 12 weeks thereafter until disease progression.

The study will also assess the relationship between the anticipated anti-tumour activity of the treatment regimen and biological characteristics of patients' tumour at baseline

Being tested
AZD2014, Everolimus, Fulvestrant

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AZD2014Drug

    Oral tablet

  • EverolimusDrug

    Also called Afinitor

    Oral tablet

  • FulvestrantDrug

    Also called Faslodex

    Im injection

Study groups in NCT02216786
Study groupRoleWhat they receive
Fulvestrant and AZD2014 (continuous)ExperimentalExperimental arm
Receives: Drug: AZD2014; Drug: Fulvestrant
Everolimus and FulvestrantActive comparatorComparator arm
Receives: Drug: Everolimus; Drug: Fulvestrant
FulvestrantActive comparatorControl 1
Receives: Drug: Fulvestrant
Fulvestrant +AZD2014 (intermittent)ExperimentalExperimental arm
Receives: Drug: AZD2014; Drug: Fulvestrant

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free survival

    Defined as the time from the date of randomisation to the date of first documented tumour progression based on investigator assessment (using RECIST 1.1) or death from any cause, whichever occurs first.

    Measured: Date of randomisation to date of first documented progression, assessed up to 100 weeks

Secondary outcomes (4)

  1. Progression-free survival

    Progression-free survival, defined as the time from the date of randomisation to the date of first documented tumour progression as assessed by an independent review facility [IRF] (using RECIST 1.1) or death from any cause, whichever occurs first.

    Measured: time from the date of randomisation to the date of first documented tumour progression, assessed up to 100 weeks

  2. Objective response

    Time from date of randomisation to documented objective response, defined as a complete or partial response, based on investigator and IRF assessment (using RECIST 1.1)

    Measured: Time from date of randomisation to documented objective response, assessed up to 60 months

  3. Average change (%) in tumour size

    Average change (%) in tumour size at 16 weeks compared to baseline, based on investigator and IRF assessment using RECIST 1.1; tumour size is defined as the sum of the longest diameters of the target (i.e. measurable tumour) lesions

    Measured: 16 weeks after baseline

  4. Clinical Benefit (CB)

    Clinical Benefit (CB), defined as number of patients with complete or partial response or stable disease maintained ≥24 weeks, based on investigator and IRF assessment using RECIST 1.1.

    Measured: Date of randomisation to 24 weeks.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Aug 2014 (estimated)
  2. Study start16 Jan 2014
  3. Primary completion31 Dec 2021
  4. Study completion31 Dec 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
333 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02216786
Sponsor's protocol ID
009175QM
Acronym
MANTA
Status last verified
Nov 2024
First submitted
12 Mar 2014
Last updated
2 Dec 2024
Results posted
No
Data monitoring committee
Yes

Publications

  • Schmid P, Zaiss M, Harper-Wynne C, Ferreira M, Dubey S, Chan S, Makris A, Nemsadze G, Brunt AM, Kuemmel S, Ruiz I, Perello A, Kendall A, Brown J, Kristeleit H, Conibear J, Saura C, Grenier J, Mahr K, Schenker M, Sohn J, Lee KS, Shepherd CJ, Oelmann E, Sarker SJ, Prendergast A, Marosics P, Moosa A, Lawrence C, Coetzee C, Mousa K, Cortes J. Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor-Positive Metastatic Breast Cancer: The MANTA Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019 Nov 1;5(11):1556-1564. doi: 10.1001/jamaoncol.2019.2526.

    PubMed 31465093

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing AZD2014, Everolimus and Fulvestrant in people with Estrogen Receptor Positive Breast Cancer, run by Queen Mary University of London at 79 sites in 9 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 79 sites in United Kingdom, Germany, Spain, France, Romania and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free survival (time frame: Date of randomisation to date of first documented progression, assessed up to 100 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02216786, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2024.

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