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

• Sponsor: Queen Mary University of London (Other)
• Overall Status: Unknown status
• CT.gov ID: NCT02216786
• Collaborator: AstraZeneca (Industry)
• Enrollment: 333
• Locations: 79
• Arms: 4
• Anticipated Duration (Months): 78.9
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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)

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor Positive Breast Cancer	Drug: AZD2014; Drug: Everolimus; Drug: Fulvestrant	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 333 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jan 1, 2014
• Anticipated Primary Completion Date: Jul 31, 2020
• Anticipated Study Completion Date: Jul 31, 2020

Arms and Interventions

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: Everolimus; Oral tablet; Other Names: Afinitor ; Drug: Fulvestrant; Im injection; Other Names: Faslodex
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

Outcome Measures

Primary Outcome Measures

1. Progression-free survival [Date of randomisation to date of first documented progression, assessed up to 100 weeks]

   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.

Secondary Outcome Measures

1. Progression-free survival [time from the date of randomisation to the date of first documented tumour progression, assessed up to 100 weeks]

   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.

2. Objective response [Time from date of randomisation to documented objective response, assessed up to 60 months]

   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)

3. Average change (%) in tumour size [16 weeks after baseline]

   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

4. Clinical Benefit (CB) [Date of randomisation to 24 weeks.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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:

6. 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

7. 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

8. Radiological or clinical evidence of recurrence or progression

9. ER-positive disease

10. HER2-negative disease with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH.

11. Formalin fixed, paraffin embedded tumour sample from the primary and/or recurrent cancer must be available for central testing

12. Postmenopausal women.

13. Disease refractory to aromatase inhibitors (AI)

14. Haematologic and biochemical indices within acceptable limits

15. ECOG performance status 0-2

16. 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ICO Paul Papin	Angers		France
2	Institut Sainte Catherine	Avignon		France
3	Antoine Lacassagne Centre De Lutte Contre Le Cancer De Nice	Nice		France
4	Hospital Center Private Saint-Grégoire	Saint-Grégoire		France
5	Centre Paul Strauss	Strasbourg		France
6	Clinic Health House	Tbilisi		Georgia
7	Institute of Clinical Oncology	Tbilisi		Georgia
8	S. Khechinashvili University Clinic	Tbilisi		Georgia
9	Tbilisi Cancer Center	Tbilisi		Georgia
10	Frauenärztliche Gemeinschaftspraxis - Onkologie	Braunschweig		Germany
11	Kliniken Essen-Mitte Senologie	Essen		Germany
12	Klinik für Gynäkologie & Geburtshilfe/Brustzentrum	Frankfurt		Germany
13	Praxis für interdisziplinäre Onkologie & Hämatologie	Freiburg		Germany
14	MediProjekt GbR Hannover	Hannöver		Germany
15	SLK-Kliniken Heilbronn GmbH	Heilbronn		Germany
16	Dokusan GmbH	Herne		Germany
17	St. Vincentius Kliniken	Karlsruhe		Germany
18	Schwerpunktpraxis Hämatologie / Onkologie MVZ Lahr	Lahr		Germany
19	Klinikum Neumarkt	Neumarkt		Germany
20	Onkologische Praxis	Oldenburg		Germany
21	Praxis für Innere Medizin	Singen		Germany
22	MVZ Klinik Dr. Hancken GmbH	Stade		Germany
23	Mutterhaus der Borromäerinnen	Trier		Germany
24	Schwarzwald Baar Klinikum, Villingen-Schwenningen	Villingen-Schwenningen		Germany
25	Uzsoki Street Hospital	Budapest		Hungary
26	Bacs-Kiskun County Hospital	Kalocsa		Hungary
27	University of Pecs, Institute of Oncology	Pécs		Hungary
28	Zala County Szent Rafael Hospital	Zalaegerszeg		Hungary
29	National Cancer Center South Korea	Goyang		Korea, Republic of
30	Korea University Medical Center Guro Hospital	Seoul		Korea, Republic of
31	Yonsei University Health System	Seoul		Korea, Republic of
32	Hospital da Luz	Lisboa		Portugal
33	Ipo Porto	Porto		Portugal
34	Center of Oncology Euroclinic	Bucharest		Romania
35	Oncology Center Sf Nectarie	Caracal		Romania
36	Cluj County Clinical Emergency Hospital, Clinical Department of Medical Oncology	Cluj-Napoca		Romania
37	Oncology Institute "Prof. Dr. Ion Chiricuta"	Cluj-Napoca		Romania
38	Oncology Center Oncolab Craiova	Craiova		Romania
39	Hospital Universitari Vall D'Hebron	Barcelona		Spain
40	Instituto Oncologico Dr. Rosell	Barcelona		Spain
41	Consorcio Hospitalario Provincial de Castellon	Castelló		Spain
42	Cafeteria Hospital San Pedro de Alcantara	Cáceres		Spain
43	Hospital Ico Josep Trueta	Girona		Spain
44	University Hospital Arnau de Vilanova	Lleida		Spain
45	Hospital Clinico Universitario San Carlos	Madrid		Spain
46	Hospital Son Espases	Palma De Mallorca		Spain
47	Hospital Son Llàtzer	Palma		Spain
48	Hospital Universitario de Canarias	San Cristobal de la Laguna		Spain
49	Hospital Universitari Sant Joan de Reus	Tarragona		Spain
50	Wansbeck General Hospital	Ashington		United Kingdom
51	Princess of Wales Hospital	Bridgend		United Kingdom
52	Royal Sussex County Hospital	Brighton		United Kingdom
53	Kent and Canterbury Hospital	Canterbury		United Kingdom
54	Cumberland Infirmary	Carlisle		United Kingdom
55	Broomfield Hospital	Chelmsford		United Kingdom
56	University Hospital of North Durham	Durham		United Kingdom
57	Calderdale Royal Hospital	Halifax		United Kingdom
58	Huddersfield Royal Infirmary	Huddersfield		United Kingdom
59	Kidderminster Hospital	Kidderminster		United Kingdom
60	Royal Glamorgan Hospital	Llantrisant		United Kingdom
61	Queen Mary University of London	London		United Kingdom	EC1M6BQ
62	Charring Cross Hospital	London		United Kingdom
63	King's College Hospital	London		United Kingdom
64	Mount Vernon Hospital	London		United Kingdom
65	Queen Elizabeth Hospital, Woolwich	London		United Kingdom
66	Saint Bartholomew's Hospital	London		United Kingdom
67	The Royal Free Hospital	London		United Kingdom
68	The Kent Oncology Centre	Maidstone		United Kingdom
69	North Tyneside General Hospital	North Shields		United Kingdom
70	Nottingham City Hospital	Nottingham		United Kingdom
71	Derriford Hospital	Plymouth		United Kingdom
72	Weston Park Hospital	Sheffield		United Kingdom
73	Solihull Hospital	Solihull		United Kingdom
74	Southend University Hospital	Southend-on-Sea		United Kingdom
75	Royal Stoke University Hospital	Stoke-on-Trent		United Kingdom
76	King's Mill Hospital	Sutton in Ashfield		United Kingdom
77	Great Western Hospital	Swindon		United Kingdom
78	Wrexham Maelor	Wrexham		United Kingdom
79	Yeovil District Hospital	Yeovil		United Kingdom

Sponsors and Collaborators

• Queen Mary University of London
• AstraZeneca

Investigators

• Principal Investigator: Peter Schmid, Prof, Queen Mary's University of London

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Queen Mary University of London
• ClinicalTrials.gov Identifier: NCT02216786
• Other Study ID Numbers: 009175QM
• First Posted: Aug 15, 2014
• Last Update Posted: Feb 25, 2020
• Last Verified: Feb 1, 2020

• Additional relevant MeSH terms: Breast Neoplasms; Everolimus; Fulvestrant

Study Results

No Results Posted as of Feb 25, 2020