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

Estrogen Receptor Positive Breast Cancer Clinical Trial

— MANTA  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02216786
• Other study ID #: 009175QM
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 2014
• Est. completion date: July 31, 2020

Study information

• Verified date: February 2020
• Source: Queen Mary University of London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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)

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 333
• Est. completion date: July 31, 2020
• Est. primary completion date: July 31, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Breast Neoplasms
• Estrogen Receptor Positive Breast Cancer

Intervention

Drug:
• AZD2014
Oral tablet
• Everolimus
Oral tablet
• Fulvestrant
Im injection

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Queen Mary University of London	AstraZeneca

Countries where clinical trial is conducted

France,  Georgia,  Germany,  Hungary,  Korea, Republic of,  Portugal,  Romania,  Spain,  United Kingdom, 

References & 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, Perelló A, Kendall A, Brown J, Kristeleit H, Conibear J, Saura C, Grenier J, Máhr K, Schenker M, Sohn J, Lee KS, Shepherd CJ, Oelmann E, Sar — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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.