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

NCT02216786 | Completed Phase 2 DMC

• 1 other identifier: 009175QM
• Study Type: interventional
• Target: 333
• Locations: 9 countries
• Sites: 79

Brief 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 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)

Conditions

Estrogen Receptor Positive Breast Cancer

Outcome Measures

Primary Outcomes (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.

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

Secondary Outcomes (4)

• Progression-free survival

  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, assessed up to 60 months

• Average change (%) in tumour size

  16 weeks after baseline

• Clinical Benefit (CB)

  Date of randomisation to 24 weeks.

Study Arms (4)

Fulvestrant and AZD2014 (continuous)

EXPERIMENTAL

Experimental arm

Drug: AZD2014; Drug: Fulvestrant

Everolimus and Fulvestrant

ACTIVE COMPARATOR

Comparator arm

Drug: Everolimus; Drug: Fulvestrant

Fulvestrant

ACTIVE COMPARATOR

Control 1

Drug: Fulvestrant

Fulvestrant +AZD2014 (intermittent)

EXPERIMENTAL

Experimental arm

Drug: AZD2014; Drug: Fulvestrant

Interventions

AZD2014 DRUG

Oral tablet

Fulvestrant +AZD2014 (intermittent); Fulvestrant and AZD2014 (continuous)

Everolimus DRUG

Oral tablet

Also known as: Afinitor

Everolimus and Fulvestrant

Fulvestrant DRUG

Im injection

Also known as: Faslodex

Everolimus and Fulvestrant; Fulvestrant; Fulvestrant +AZD2014 (intermittent); Fulvestrant and AZD2014 (continuous)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Queen Mary University of London: lead
• AstraZeneca: collaborator

Study Sites (79)

ICO Paul Papin

Angers, France

Location

Institut Sainte Catherine

Avignon, France

Location

Antoine Lacassagne Centre De Lutte Contre Le Cancer De Nice

Nice, France

Location

Hospital Center Private Saint-Grégoire

Saint-Grégoire, France

Location

Centre Paul Strauss

Strasbourg, France

Location

Clinic Health House

Tbilisi, Georgia

Location

Institute of Clinical Oncology

Tbilisi, Georgia

Location

S. Khechinashvili University Clinic

Tbilisi, Georgia

Location

Tbilisi Cancer Center

Tbilisi, Georgia

Location

Frauenärztliche Gemeinschaftspraxis - Onkologie

Braunschweig, Germany

Location

Kliniken Essen-Mitte Senologie

Essen, Germany

Location

Klinik für Gynäkologie & Geburtshilfe/Brustzentrum

Frankfurt, Germany

Location

Praxis für interdisziplinäre Onkologie & Hämatologie

Freiburg im Breisgau, Germany

Location

MediProjekt GbR Hannover

Hannover, Germany

Location

SLK-Kliniken Heilbronn GmbH

Heilbronn, Germany

Location

Dokusan GmbH

Herne, Germany

Location

St. Vincentius Kliniken

Karlsruhe, Germany

Location

Schwerpunktpraxis Hämatologie / Onkologie MVZ Lahr

Lahr, Germany

Location

Klinikum Neumarkt

Neumarkt, Germany

Location

Onkologische Praxis

Oldenburg, Germany

Location

Praxis für Innere Medizin

Singen, Germany

Location

MVZ Klinik Dr. Hancken GmbH

Stade, Germany

Location

Mutterhaus der Borromäerinnen

Trier, Germany

Location

Schwarzwald Baar Klinikum, Villingen-Schwenningen

Villingen-Schwenningen, Germany

Location

Uzsoki Street Hospital

Budapest, Hungary

Location

Bacs-Kiskun County Hospital

Kalocsa, Hungary

Location

University of Pecs, Institute of Oncology

Pécs, Hungary

Location

Zala County Szent Rafael Hospital

Zalaegerszeg, Hungary

Location

Hospital da Luz

Lisbon, Portugal

Location

Ipo Porto

Porto, Portugal

Location

Center of Oncology Euroclinic

Bucharest, Romania

Location

Oncology Center Sf Nectarie

Caracal, Romania

Location

Cluj County Clinical Emergency Hospital, Clinical Department of Medical Oncology

Cluj-Napoca, Romania

Location

Oncology Institute "Prof. Dr. Ion Chiricuta"

Cluj-Napoca, Romania

Location

Oncology Center Oncolab Craiova

Craiova, Romania

Location

National Cancer Center South Korea

Goyang, South Korea

Location

Korea University Medical Center Guro Hospital

Seoul, South Korea

Location

Yonsei University Health System

Seoul, South Korea

Location

Hospital Universitari Vall D'Hebron

Barcelona, Spain

Location

Instituto Oncologico Dr. Rosell

Barcelona, Spain

Location

Consorcio Hospitalario Provincial de Castellon

Castelló, Spain

Location

Cafeteria Hospital San Pedro de Alcantara

Cáceres, Spain

Location

Hospital Ico Josep Trueta

Girona, Spain

Location

University Hospital Arnau de Vilanova

Lleida, Spain

Location

Hospital Clinico Universitario San Carlos

Madrid, Spain

Location

Hospital Son Llàtzer

Palma, Spain

Location

Hospital Son Espases

Palma de Mallorca, Spain

Location

Hospital Universitario de Canarias

San Cristóbal de La Laguna, Spain

Location

Hospital Universitari Sant Joan de Reus

Tarragona, Spain

Location

Wansbeck General Hospital

Ashington, United Kingdom

Location

Princess of Wales Hospital

Bridgend, United Kingdom

Location

Royal Sussex County Hospital

Brighton, United Kingdom

Location

Kent and Canterbury Hospital

Canterbury, United Kingdom

Location

Cumberland Infirmary

Carlisle, United Kingdom

Location

Broomfield Hospital

Chelmsford, United Kingdom

Location

University Hospital of North Durham

Durham, United Kingdom

Location

Calderdale Royal Hospital

Halifax, United Kingdom

Location

Huddersfield Royal Infirmary

Huddersfield, United Kingdom

Location

Kidderminster Hospital

Kidderminster, United Kingdom

Location

Royal Glamorgan Hospital

Llantrisant, United Kingdom

Location

Queen Mary University of London

London, EC1M6BQ, United Kingdom

Location

Charring Cross Hospital

London, United Kingdom

Location

King's College Hospital

London, United Kingdom

Location

Mount Vernon Hospital

London, United Kingdom

Location

Queen Elizabeth Hospital, Woolwich

London, United Kingdom

Location

Saint Bartholomew's Hospital

London, United Kingdom

Location

The Royal Free Hospital

London, United Kingdom

Location

The Kent Oncology Centre

Maidstone, United Kingdom

Location

North Tyneside General Hospital

North Shields, United Kingdom

Location

Nottingham City Hospital

Nottingham, United Kingdom

Location

Derriford Hospital

Plymouth, United Kingdom

Location

Weston Park Hospital

Sheffield, United Kingdom

Location

Solihull Hospital

Solihull, United Kingdom

Location

Southend University Hospital

Southend-on-Sea, United Kingdom

Location

Royal Stoke University Hospital

Stoke-on-Trent, United Kingdom

Location

King's Mill Hospital

Sutton in Ashfield, United Kingdom

Location

Great Western Hospital

Swindon, United Kingdom

Location

Wrexham Maelor

Wrexham, United Kingdom

Location

Yeovil District Hospital

Yeovil, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 31465093 RESULT

MeSH Terms

Interventions

vistusertib; Everolimus; Fulvestrant

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Peter Schmid, Prof

  Queen Mary's University of London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 12, 2014
• First Posted: August 15, 2014
• Study Start: January 16, 2014
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2021
• Last Updated: December 2, 2024

Record last verified: 2024-11

Locations

GE (4); RO (5); ES (11); FR (5); GB (30); DE (15); HU (4); PT (2); KR (3)