Clinical trial NCT02216786: A Randomized Study of AZD2014 in Combination With Fulvestrant in Metastatic or Advanced Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Estrogen Receptor Positive Breast Cancer
Lead sponsor: Queen Mary University of London
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2014-08-15
Enrollment: 333
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)

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

Eligibility criteria: 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).

Primary outcomes:
measure: Progression-free survival
timeFrame: Date of randomisation to date of first documented progression, assessed up to 100 weeks
Secondary outcomes:
measure: Progression-free survival
timeFrame: time from the date of randomisation to the date of first documented tumour progression, assessed up to 100 weeks
measure: Objective response
timeFrame: Time from date of randomisation to documented objective response, assessed up to 60 months
measure: Average change (%) in tumour size
timeFrame: 16 weeks after baseline
measure: Clinical Benefit (CB)
timeFrame: Date of randomisation to 24 weeks.
Other outcomes:
Locations:
city: Angers
country: France
facility: ICO Paul Papin
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Nice
country: France
facility: Antoine Lacassagne Centre De Lutte Contre Le Cancer De Nice
city: Saint-Grégoire
country: France
facility: Hospital Center Private Saint-Grégoire
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Tbilisi
country: Georgia
facility: Clinic Health House
city: Tbilisi
country: Georgia
facility: Institute of Clinical Oncology
city: Tbilisi
country: Georgia
facility: S. Khechinashvili University Clinic
city: Tbilisi
country: Georgia
facility: Tbilisi Cancer Center
city: Braunschweig
country: Germany
facility: Frauenärztliche Gemeinschaftspraxis - Onkologie
city: Essen
country: Germany
facility: Kliniken Essen-Mitte Senologie
city: Frankfurt
country: Germany
facility: Klinik für Gynäkologie & Geburtshilfe/Brustzentrum
city: Freiburg
country: Germany
facility: Praxis für interdisziplinäre Onkologie & Hämatologie
city: Hannöver
country: Germany
facility: MediProjekt GbR Hannover
city: Heilbronn
country: Germany
facility: SLK-Kliniken Heilbronn GmbH
city: Herne
country: Germany
facility: Dokusan GmbH
city: Karlsruhe
country: Germany
facility: St. Vincentius Kliniken
city: Lahr
country: Germany
facility: Schwerpunktpraxis Hämatologie / Onkologie MVZ Lahr
city: Neumarkt
country: Germany
facility: Klinikum Neumarkt
city: Oldenburg
country: Germany
facility: Onkologische Praxis
city: Singen
country: Germany
facility: Praxis für Innere Medizin
city: Stade
country: Germany
facility: MVZ Klinik Dr. Hancken GmbH
city: Trier
country: Germany
facility: Mutterhaus der Borromäerinnen
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald Baar Klinikum, Villingen-Schwenningen
city: Budapest
country: Hungary
facility: Uzsoki Street Hospital
city: Kalocsa
country: Hungary
facility: Bacs-Kiskun County Hospital
city: Pécs
country: Hungary
facility: University of Pecs, Institute of Oncology
city: Zalaegerszeg
country: Hungary
facility: Zala County Szent Rafael Hospital
city: Goyang
country: Korea, Republic of
facility: National Cancer Center South Korea
city: Seoul
country: Korea, Republic of
facility: Korea University Medical Center Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System
city: Lisboa
country: Portugal
facility: Hospital da Luz
city: Porto
country: Portugal
facility: Ipo Porto
city: Bucharest
country: Romania
facility: Center of Oncology Euroclinic
city: Caracal
country: Romania
facility: Oncology Center Sf Nectarie
city: Cluj-Napoca
country: Romania
facility: Cluj County Clinical Emergency Hospital, Clinical Department of Medical Oncology
city: Cluj-Napoca
country: Romania
facility: Oncology Institute "Prof. Dr. Ion Chiricuta"
city: Craiova
country: Romania
facility: Oncology Center Oncolab Craiova
city: Barcelona
country: Spain
facility: Hospital Universitari Vall D'Hebron
city: Barcelona
country: Spain
facility: Instituto Oncologico Dr. Rosell
city: Castelló
country: Spain
facility: Consorcio Hospitalario Provincial de Castellon
city: Cáceres
country: Spain
facility: Cafeteria Hospital San Pedro de Alcantara
city: Girona
country: Spain
facility: Hospital Ico Josep Trueta
city: Lleida
country: Spain
facility: University Hospital Arnau de Vilanova
city: Madrid
country: Spain
facility: Hospital Clinico Universitario San Carlos
city: Palma De Mallorca
country: Spain
facility: Hospital Son Espases
city: Palma
country: Spain
facility: Hospital Son Llàtzer
city: San Cristobal de la Laguna
country: Spain
facility: Hospital Universitario de Canarias
city: Tarragona
country: Spain
facility: Hospital Universitari Sant Joan de Reus
city: Ashington
country: United Kingdom
facility: Wansbeck General Hospital
city: Bridgend
country: United Kingdom
facility: Princess of Wales Hospital
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Carlisle
country: United Kingdom
facility: Cumberland Infirmary
city: Chelmsford
country: United Kingdom
facility: Broomfield Hospital
city: Durham
country: United Kingdom
facility: University Hospital of North Durham
city: Halifax
country: United Kingdom
facility: Calderdale Royal Hospital
city: Huddersfield
country: United Kingdom
facility: Huddersfield Royal Infirmary
city: Kidderminster
country: United Kingdom
facility: Kidderminster Hospital
city: Llantrisant
country: United Kingdom
facility: Royal Glamorgan Hospital
city: London
country: United Kingdom
facility: Queen Mary University of London
city: London
country: United Kingdom
facility: Charring Cross Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: Mount Vernon Hospital
city: London
country: United Kingdom
facility: Queen Elizabeth Hospital, Woolwich
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
city: London
country: United Kingdom
facility: The Royal Free Hospital
city: Maidstone
country: United Kingdom
facility: The Kent Oncology Centre
city: North Shields
country: United Kingdom
facility: North Tyneside General Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Solihull
country: United Kingdom
facility: Solihull Hospital
city: Southend-on-Sea
country: United Kingdom
facility: Southend University Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
city: Sutton in Ashfield
country: United Kingdom
facility: King's Mill Hospital
city: Swindon
country: United Kingdom
facility: Great Western Hospital
city: Wrexham
country: United Kingdom
facility: Wrexham Maelor
city: Yeovil
country: United Kingdom
facility: Yeovil District Hospital
Study officials:
affiliation: Queen Mary's University of London
name: Peter Schmid, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.