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

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

Randomization will be stratified by the following criteria:

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

Study Overview

• Status: Completed
• Conditions: Estrogen Receptor Positive Breast Cancer
• Intervention / Treatment: Drug: AZD2014; Drug: Fulvestrant; Drug: Everolimus

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

• Study Type: Interventional
• Enrollment (Actual): 333
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France
    • ICO Paul Papin
  • Avignon, France
    • Institut Sainte Catherine
  • Nice, France
    • Antoine Lacassagne Centre De Lutte Contre Le Cancer De Nice
  • Saint-Grégoire, France
    • Hospital Center Private Saint-Grégoire
  • Strasbourg, France
    • Centre Paul Strauss
• Georgia
  • Tbilisi, Georgia
    • S. Khechinashvili University Clinic
  • Tbilisi, Georgia
    • Institute of Clinical Oncology
  • Tbilisi, Georgia
    • Clinic Health House
  • Tbilisi, Georgia
    • Tbilisi Cancer Center
• Germany
  • Braunschweig, Germany
    • Frauenärztliche Gemeinschaftspraxis - Onkologie
  • Essen, Germany
    • Kliniken Essen-Mitte Senologie
  • Frankfurt, Germany
    • Klinik für Gynäkologie & Geburtshilfe/Brustzentrum
  • Freiburg, Germany
    • Praxis für interdisziplinäre Onkologie & Hämatologie
  • Hannöver, Germany
    • MediProjekt GbR Hannover
  • Heilbronn, Germany
    • SLK-Kliniken Heilbronn GmbH
  • Herne, Germany
    • Dokusan GmbH
  • Karlsruhe, Germany
    • St. Vincentius Kliniken
  • Lahr, Germany
    • Schwerpunktpraxis Hämatologie / Onkologie MVZ Lahr
  • Neumarkt, Germany
    • Klinikum Neumarkt
  • Oldenburg, Germany
    • Onkologische Praxis
  • Singen, Germany
    • Praxis für Innere Medizin
  • Stade, Germany
    • MVZ Klinik Dr. Hancken GmbH
  • Trier, Germany
    • Mutterhaus der Borromäerinnen
  • Villingen-Schwenningen, Germany
    • Schwarzwald Baar Klinikum, Villingen-Schwenningen
• Hungary
  • Budapest, Hungary
    • Uzsoki Street Hospital
  • Kalocsa, Hungary
    • Bacs-Kiskun County Hospital
  • Pécs, Hungary
    • University of Pecs, Institute of Oncology
  • Zalaegerszeg, Hungary
    • Zala County Szent Rafael Hospital
• Korea, Republic of
  • Goyang, Korea, Republic of
    • National Cancer Center South Korea
  • Seoul, Korea, Republic of
    • Yonsei University Health System
  • Seoul, Korea, Republic of
    • Korea University Medical Center Guro Hospital
• Portugal
  • Lisboa, Portugal
    • Hospital da Luz
  • Porto, Portugal
    • IPO Porto
• Romania
  • Bucharest, Romania
    • Center of Oncology Euroclinic
  • Caracal, Romania
    • Oncology Center Sf Nectarie
  • Cluj-Napoca, Romania
    • Cluj County Clinical Emergency Hospital, Clinical Department of Medical Oncology
  • Cluj-Napoca, Romania
    • Oncology Institute "Prof. Dr. Ion Chiricuță"
  • Craiova, Romania
    • Oncology Center Oncolab Craiova
• Spain
  • Barcelona, Spain
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain
    • Instituto Oncológico Dr. Rosell
  • Castelló, Spain
    • Consorcio Hospitalario Provincial de Castellon
  • Cáceres, Spain
    • Cafeteria Hospital San Pedro de Alcantara
  • Girona, Spain
    • Hospital Ico Josep Trueta
  • Lleida, Spain
    • University Hospital Arnau de Vilanova
  • Madrid, Spain
    • Hospital Clinico Universitario San Carlos
  • Palma, Spain
    • Hospital Son Llatzer
  • Palma De Mallorca, Spain
    • Hospital Son Espases
  • San Cristobal de la Laguna, Spain
    • Hospital Universitario de Canarias
  • Tarragona, Spain
    • Hospital Universitari Sant Joan de Reus
• United Kingdom
  • Ashington, United Kingdom
    • Wansbeck General Hospital
  • Bridgend, United Kingdom
    • Princess of Wales Hospital
  • Brighton, United Kingdom
    • Royal Sussex County Hospital
  • Canterbury, United Kingdom
    • Kent and Canterbury Hospital
  • Carlisle, United Kingdom
    • Cumberland Infirmary
  • Chelmsford, United Kingdom
    • Broomfield Hospital
  • Durham, United Kingdom
    • University Hospital of North Durham
  • Halifax, United Kingdom
    • Calderdale Royal Hospital
  • Huddersfield, United Kingdom
    • Huddersfield Royal Infirmary
  • Kidderminster, United Kingdom
    • Kidderminster Hospital
  • Llantrisant, United Kingdom
    • Royal Glamorgan Hospital
  • London, United Kingdom
    • King's College Hospital
  • London, United Kingdom
    • The Royal Free Hospital
  • London, United Kingdom
    • Mount Vernon Hospital
  • London, United Kingdom, EC1M6BQ
    • Queen Mary University of London
  • London, United Kingdom
    • Charring Cross Hospital
  • London, United Kingdom
    • Queen Elizabeth Hospital, Woolwich
  • London, United Kingdom
    • Saint Bartholomew's Hospital
  • Maidstone, United Kingdom
    • The Kent Oncology Centre
  • North Shields, United Kingdom
    • North Tyneside General Hospital
  • Nottingham, United Kingdom
    • Nottingham City Hospital
  • Plymouth, United Kingdom
    • Derriford Hospital
  • Sheffield, United Kingdom
    • Weston Park Hospital
  • Solihull, United Kingdom
    • Solihull Hospital
  • Southend-on-Sea, United Kingdom
    • Southend University Hospital
  • Stoke-on-Trent, United Kingdom
    • Royal Stoke University Hospital
  • Sutton in Ashfield, United Kingdom
    • King's Mill Hospital
  • Swindon, United Kingdom
    • Great Western Hospital
  • Wrexham, United Kingdom
    • Wrexham Maelor
  • Yeovil, United Kingdom
    • Yeovil District Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Written informed consent prior to admission to this study
2. Women, age ≥18 years
3. Histologically confirmed breast cancer
4. 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).

5. Patients must have:

   1. 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
   2. 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
6. Radiological or clinical evidence of recurrence or progression
7. ER-positive disease
8. HER2-negative disease with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH.
9. Formalin fixed, paraffin embedded tumour sample from the primary and/or recurrent cancer must be available for central testing
10. Postmenopausal women.
11. Disease refractory to aromatase inhibitors (AI)
12. Haematologic and biochemical indices within acceptable limits
13. ECOG performance status 0-2
14. 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

Exclusion criteria:

1. 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.
2. More than one line of prior chemotherapy for metastatic breast cancer
3. 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
4. Prior treatment with fulvestrant or everolimus
5. Prior treatment with PI3K inhibitors, Akt inhibitors or other mTOR inhibitors.
6. 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
7. 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
8. Clinically significant pulmonary dysfunction
9. Significant cardiovascular disease
10. 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)
11. 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)
12. Clinically significant abnormalities of glucose metabolism
13. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 within 2 weeks before the first dose of study treatment
14. Exposure to potent or moderate inhibitors or inducers of CYP2C8 within 1 week before the first dose of study treatment.
15. Application of haemopoietic growth factors (e.g. G-CSF, GM-CSF) within 2 weeks before receiving study drug
16. 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.
17. 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
18. History of hypersensitivity to active or inactive excipients of fulvestrant and/or castor oil.
19. Patients presenting with anaemia symptoms (haemoglobin ≤ 90 g/L).
20. Currently receiving (and are unwilling to discontinue) oestrogen replacement therapy (last dose ≤ 7 days prior to randomisation)
21. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
22. Detained persons or prisoners
23. 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fulvestrant and AZD2014 (continuous); Experimental arm	Drug: AZD2014; Oral tablet; Drug: Fulvestrant; Im injection; Other Names: Faslodex
Active Comparator: Everolimus and Fulvestrant; Comparator arm	Drug: Fulvestrant; Im injection; Other Names: Faslodex; Drug: Everolimus; Oral tablet; Other Names: Afinitor
Active Comparator: Fulvestrant; Control 1	Drug: Fulvestrant; Im injection; Other Names: Faslodex
Experimental: Fulvestrant +AZD2014 (intermittent); Experimental arm	Drug: AZD2014; Oral tablet; Drug: Fulvestrant; Im injection; Other Names: Faslodex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Date of randomisation to date of first documented progression, assessed up to 100 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	time from the date of randomisation to the date of first documented tumour progression, assessed up to 100 weeks
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)	Time from date of randomisation to documented objective response, assessed up to 60 months
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	16 weeks after baseline
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.	Date of randomisation to 24 weeks.

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Peter Schmid, Prof, Queen Mary's University of London

Publications and helpful links

General 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. Erratum In: JAMA Oncol. 2021 Feb 1;7(2):312. doi: 10.1001/jamaoncol.2020.7104.

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2014
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: March 12, 2014
• First Submitted That Met QC Criteria: August 14, 2014
• First Posted (Estimated): August 15, 2014

Study Record Updates

• Last Update Posted (Estimated): December 2, 2024
• Last Update Submitted That Met QC Criteria: November 28, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; MTOR Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Protein Kinase Inhibitors; Hormone Antagonists; Estrogen Receptor Antagonists; Estrogen Antagonists; Fulvestrant; Everolimus
• Other Study ID Numbers: 009175QM