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

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ClinicalTrials.gov Identifier: NCT02216786
Recruitment Status : Unknown
Verified August 2017 by Queen Mary University of London.
Recruitment status was:  Active, not recruiting
First Posted : August 15, 2014
Last Update Posted : August 28, 2017
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Queen Mary University of London

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


Layout table for study information
Study Type : Interventional  (Clinical Trial)
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 : January 2014
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Fulvestrant and AZD2014 (continuous)
Experimental arm
Drug: AZD2014
Oral tablet

Drug: Fulvestrant
Im injection
Other Name: Faslodex

Active Comparator: Everolimus and Fulvestrant
Comparator arm
Drug: Everolimus
Oral tablet
Other Name: Afinitor

Drug: Fulvestrant
Im injection
Other Name: Faslodex

Active Comparator: Fulvestrant
Control 1
Drug: Fulvestrant
Im injection
Other Name: Faslodex

Experimental: Fulvestrant +AZD2014 (intermittent)
Experimental arm
Drug: AZD2014
Oral tablet

Drug: Fulvestrant
Im injection
Other Name: Faslodex




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: 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 Frame: 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 Frame: 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 [ Time Frame: 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) [ Time Frame: 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02216786


  Show 79 Study Locations
Sponsors and Collaborators
Queen Mary University of London
AstraZeneca
Investigators
Layout table for investigator information
Principal Investigator: Peter Schmid, Prof Queen Mary's University of London

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT02216786     History of Changes
Other Study ID Numbers: 009175QM
First Posted: August 15, 2014    Key Record Dates
Last Update Posted: August 28, 2017
Last Verified: August 2017
Additional relevant MeSH terms:
Layout table for MeSH terms
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Sirolimus
Everolimus
Fulvestrant
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists