A Randomized Study of AZD2014 in Combination With Fulvestrant in Metastatic... | Not Recruiting
A Randomized Study of AZD2014 in Co... | Not Recruiting
A Randomized Study of AZD2014 in Combination With Fulvestrant in Metastatic or Advanced Breast Cancer
MANTA

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Medical Conditions
  • Estrogen Receptor Positive Breast Cancer
Primary Contact Details
Unfortunately contact details are not available for this trial.
Recruitment Status
Not Recruiting
Trial source and source ID number
NCT02216786
This information is designed to help you decide whether this trial is of interest. In some cases it is provided as a link to more detailed patient information or it may still be awaited from the organisation running the trial. Please look again shortly if the information you need is not here or, if named, contact the researcher named above.
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)
Research Details
  • 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
Phase
Phase 2
Study Design
Sorry, this information is not available
Study Type
Interventional
Intervention
Drug : AZD2014, Drug : Everolimus, Drug : Fulvestrant

Study Arm Groups : Fulvestrant and AZD2014 (continuous), Fulvestrant +AZD2014 (intermittent), Everolimus and Fulvestrant, Fulvestrant and AZD2014 (continuous), Everolimus and Fulvestrant, Fulvestrant, Fulvestrant +AZD2014 (intermittent)

Intervention Type
See Interventions above
Primary Outcome Measures
    Progression-free survival; Date of randomisation to date of first documented progression, assessed up to 100 weeks
Secondary Outcome Measures
    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.
Publication(s)
Sorry, this information is not available
Result Reports
Check availability of results on the Clinicaltrials.gov website
This information is designed to help you decide whether this trial is of interest. In some cases it is provided as a link to more detailed patient information or it may still be awaited from the organisation running the trial. Please look again shortly if the information you need is not here or, if named, contact the researcher named above.
Gender
Female
Age Range
18 Years - N/A
Who Can Participate
Patients
Number of Participants
Sorry, this information is not available
Participant Inclusion 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, defined as tumour cells being positive for ER with ≥ 1% of tumour cells positive for ER on IHC or IHC score (Allred) of ≥ 3

    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. Women will be considered postmenopausal if they meet one of the following criteria:

    1. Age ≥ 50 years and 1 year or more of amenorrhea

    2. Age < 50 years and 1 year or more of amenorrhea, with an estradiol assay < 20pg/mL

    3. Age < 50 with prior hysterectomy but intact ovaries with an estradiol assay < 20pg/mL

    4. Status after bilateral oophorectomy (≥ 28 days prior to first study treatment) Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LHRH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression.

    Each patient must meet all of the following inclusion criteria to be enrolled in the study:

    11. Disease refractory to aromatase inhibitors (AI), defined as

    1. Disease recurrence while on, or within 12 months of end of adjuvant treatment with letrozole, anastrozole, or exemestane.

    2. Progression while on, or within one month of end of letrozole, anastrozole or exemestane treatment for locally advanced or metastatic Breast Cancer.

    Note: Any number of lines of hormonal therapy before or after AI therapy is allowed.

    Note: Letrozole, anastrozole or exemestane do not have to be the last treatment prior to randomisation.

    12. Haematologic and biochemical indices within the ranges shown below. These measurements must be performed within one week prior to randomisation

    1. ANC ≥ 1500 cells/μl, haemoglobin ≥ 9g/dl, and platelet count ≥ 100000/μl.

    2. Serum Creatinine < 1.5 times ULN concurrent with creatinine clearance ≥ 50ml/min (measured or calculated by Cockcroft and Gault equation), confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN.

    3. Bilirubin level < 1.5 x ULN if no demonstrable liver metastases or < 3 times ULN in the presence of liver metastases.

    4. AST or ALT < 2.5 x ULN.

    5. International normalized ratio (INR) < 1.5 and activated partial thromboplastin time (aPTT) < 1.5 x ULN; for patients requiring therapeutic anticoagulation therapy, a stable INR ≤ 2.5 x ULN is required to mitigate potential bleeding.

    6. No clinically relevant and treatment resistant abnormalities in potassium, sodium, calcium (corrected for plasma albumin) or magnesium.

    7. Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 ×ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy and when the above mentioned values have been achieved.

    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 Note: A chemotherapy line in advanced disease is an anticancer regimen(s) that contains at least 1 cytotoxic chemotherapy agent and given for 21 days or longer. If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease progression and lasted less than 21 days, then this regimen does not count as a "prior line of chemotherapy"

    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; patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months are excluded:

    1. History of myocardial infarction, acute coronary syndromes (including unstable angina), or history of coronary angioplasty/stenting/bypass grafting.

    2. History of symptomatic congestive heart failure (CHF) New York Heart Association (NYHA) Classes II-IV or LVEF <50% by either ECHO or MUGA

    3. Severe cardiac arrhythmia requiring medication or severe conduction abnormalities

    4. Poorly controlled hypertension (resting diastolic blood pressure >100 mmHg)

    5. Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy

    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 as defined by any of the following

    1. Diagnosis of diabetes mellitus type I (irrespective of management).or uncontrolled diabetes mellitus type II

    2. Glycosylated haemoglobin (HbA1C) ≥8.0% at screening (64 mmol/mol) (conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C (%) - 2.15] x 10.929)

    13. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort and 5 weeks for phenobarbitone) (for details please refer to Appendix 6).

    1. Inhibitors (competitive): ketoconazole, itraconazole, indinavir, saquinovir, nelfinavir, atazanavir, amprenavir, fosamprenavir, troleandomycin, telithromycin, fluconazole, nefazodone, cimetidine, aprepitant, miconazole, fluvoxamine, P-glycoprotein, grapefruit juice, or seville oranges (1 week minimum wash-out period), amiodarone (27 week minimum wash-out period)

    2. Inhibitors (time dependent): erythromycin, clarithromycin, verapamil, ritonavir, diltiazem (2 week minimum wash-out period)

    3. Inducers: phenytoin, rifampicin, St. John's Wort, carbamazepine, dexamethasone, primidone, griseofulvin, carbamazepine, barbiturates, troglitazone, pioglitazone, oxcarbazepine, nevirapine, efavirenz, rifabutin (3 week minimum wash-out period) and phenobarbitone (5 week minimum wash-out period)

    14. Exposure to potent or moderate inhibitors or inducers of CYP2C8 within 1 week before the first dose of study treatment (for details please refer to Appendix 6).

    a. Inhibitors: Gemfibrozil, trimethoprim, glitazones, montelukast, quercetin (1 week minimum wash-out period)

    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).
Participant Exclusion Criteria
This is in the inclusion criteria above
This information is designed to help you decide whether this trial is of interest. In some cases it is provided as a link to more detailed patient information or it may still be awaited from the organisation running the trial. Please look again shortly if the information you need is not here or, if named, contact the researcher named above.
Trial Location(s)
Local Institution
Plymouth
Devon
Local Institution
London
Greater London
Sheffield
Broomfield Hospital
Chelmsford
Greenwood Medical Center
Nottingham
Huddersfield
Uni Hospital North Staffordshire
Stoke-on-Trent
Great Western Hospital
Swindon
Brighton
205.389.3612 Boehringer Ingelheim Investigational Site
Wrexham
Research Site
Solihull
West Midlands
Barts Health NHS Trust
London
EC1M6BQ
Kent and Canterbury Hospital
Canterbury
Kent
1218.74.44040 Boehringer Ingelheim Investigational Site
Durham
Bridgend
North Shields
Calderdale Royal Infirmary
Halifax
Cumberland Infirmary
Carlisle
Ashington
Yeovil District Hospital
Yeovil
Kings Mill Hospital
Sutton-in-Ashfield
Research Site
Southend-on-Sea
Kidderminster Hospital
Kidderminster
The Kent Oncology Centre
Kent, Medway
Royal Glamorgan Hospital
Ynysmaerdy, Talbot Green
Trial Contact(s)
Primary Trial Contact
Sorry, this information is not available
Other Trial Contacts
Sorry, this information is not available
Countries Recruiting
France, Georgia, Germany, Hungary, Korea, Republic of, Portugal, Romania, Spain, United Kingdom
This information is designed to help you decide whether this trial is of interest. In some cases it is provided as a link to more detailed patient information or it may still be awaited from the organisation running the trial. Please look again shortly if the information you need is not here or, if named, contact the researcher named above.
Scientific 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
EudraCT Number
Not available for this trial
Funder(s)
  • AstraZeneca
Other Study ID Numbers
009175QM
Sponsor(s)
Queen Mary University of London
Key Dates

Recruitment Start Date

Jan 2014

Recruitment End Date

Jun 2019

Trial Start Date
Date Not Available
Trial End Date
Date Not Available
Date added to source

12 Mar 2014

Date updated in source

25 Aug 2017