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Trial record 1 of 1 for:    D8530C00001
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Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer (SERENA-1)

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ClinicalTrials.gov Identifier: NCT03616587
Recruitment Status : Recruiting
First Posted : August 6, 2018
Last Update Posted : December 1, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
A Phase 1 Dose Escalation and Expansion Study of AZD9833 Alone or in Combination in Women with ER Positive, HER2 Negative Advanced Breast Cancer

Condition or disease Intervention/treatment Phase
ER+ HER2- Advanced Breast Cancer Drug: AZD9833 Drug: AZD9833 with palbociclib Drug: AZD9833 with everolimus Phase 1

Detailed Description:
This is a multicentre dose escalation and expansion, first-in-human study designed to evaluate the safety and tolerability of AZD9833, alone (Parts A and B) or in combination with palbociclib (Parts C and D) or in combination with everolimus (Parts E and F), in women with endocrine-resistant ER+ HER2 breast cancer that is not amenable to treatment with curative intent.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 270 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

This is a multicentre dose escalation and expansion, first-in-human study designed to evaluate the safety and tolerability of AZD9833, alone (Parts A and B) or in combination with palbociclib (Parts C and D) or in combination with everolimus (Parts E and F), in women with endocrine-resistant ER+ HER2 breast cancer that is not amenable to treatment with curative intent.

Parts A, C, and E of the study allow for dose escalation of AZD9833 alone or in combination with palbociclib or everolimus.

Based on the findings in Parts A, C, and E, in Parts B, D, and F of the study (expansions), eligible subjects will be randomised to receive selected doses of AZD9833, alone or in combination with palbociclib, or in combination with everolimus.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Dose Escalation and Expansion Study of AZD9833 Alone or in Combination in Women With ER-positive, HER2-negative Advanced Breast Cancer (SERENA-1)
Actual Study Start Date : October 11, 2018
Estimated Primary Completion Date : January 28, 2022
Estimated Study Completion Date : March 31, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: AZD9833 monotherapy dose escalation Drug: AZD9833
Part A: AZD9833 monotherapy dose escalation.

Experimental: AZD9833 monotherapy dose expansion Drug: AZD9833
Part B: AZD9833 monotherapy expansion

Experimental: AZD9833 with palbociclib dose escalation Drug: AZD9833 with palbociclib
Part C: AZD9833 in combination with palbociclib dose escalation.

Experimental: AZD9833 with palbociclib dose expansion Drug: AZD9833 with palbociclib
Part D: AZD9833 in combination with palbociclib expansion

Experimental: AZD9833 with everolimus dose expansion Drug: AZD9833 with everolimus
Part F: AZD9833 in combination with everolimus dose expansion

Experimental: AZD9833 with everolimus dose escalation Drug: AZD9833 with everolimus
Part E: AZD9833 in combination with everolimus dose escalation




Primary Outcome Measures :
  1. The number of subjects with dose-limiting toxicity, as defined in the protocol. [ Time Frame: Minimum observation period 28 days on treatment. ]
    Dose-limiting toxicity as described in the protocol that is not related to disease progression, intercurrent illness or concomitant medications and that, despite optimal therapeutic intervention, meets protocol-defined criteria.

  2. The number of subjects with treatment-related adverse events as assessed by CTCAE v4.03. [ Time Frame: Minimum observation period 28 days on treatment, and will continue until the subject is off the study (approximately 1 year). ]
    Data will include clinical observations, ECG parameters, clinical chemistry and haematology and vital signs assessed as the number of subjects with treatment-related adverse events assessed by CTCAE v4.03.


Secondary Outcome Measures :
  1. Objective Response Rate [ Time Frame: Weeks 8, 16 and 24 and then every 12 weeks (weeks 36, 48 and 60) until the end of the study (approximately 1 year). ]
    Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)

  2. Duration of Response [ Time Frame: Weeks 8, 16 and 24 and then every 12 weeks (weeks 36, 48 and 60) until the end of the study (approximately 1 year). ]
    Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)

  3. Clinical benefit rate at 24 weeks [ Time Frame: Up to 24 weeks ]
    Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)

  4. Percentage Change in Tumour Size [ Time Frame: Weeks 8, 16 and 24 and then every 12 weeks (weeks 36, 48 and 60) until the end of the study (approximately 1 year). ]
    Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)

  5. Progression Free Survival [ Time Frame: Weeks 8, 16 and 24 and then every 12 weeks (weeks 36, 48 and 60) until the end of the study (approximately 1 year). ]
    Antitumour activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)

  6. Maximum Observed Plasma Concentration (Cmax) of AZD9833 alone or in combination with Palbociclib or Everolimus [ Time Frame: At predefined intervals throughout the AZD9833 treatment period (approximately 16 weeks ) ]
    Blood samples will be collected to assess plasma concentrations of AZD9833 alone or in combination with Palbociclib or Everolimus at a series of timepoints to derive Cmax

  7. Time to observed Cmax (Tmax) for AZD9833 alone or in combination with Palbociclib or Everolimus [ Time Frame: At predefined intervals throughout the AZD9833 treatment period (approximately 16 weeks ) ]
    Blood samples will be collected to assess plasma concentrations of AZD9833 alone or in combination with Palbociclib or Everolimus at a series of timepoints to derive Tmax

  8. Area under the plasma concentration-time curve (AUC) for AZD9833 alone or in combination with Palbociclib or Everolimus [ Time Frame: At predefined intervals throughout the AZD9833 treatment period (approximately 16 weeks ) ]
    Blood samples will be collected to assess plasma concentrations of AZD9833 alone or in combination with Palbociclib or Everolimus at a series of timepoints to derive AUC

  9. Renal clearance (CLR) for AZD9833 [ Time Frame: At predefined intervals throughout the AZD9833 treatment period (approximately 16 weeks ) ]
    Urine samples will be collected to assess urine concentrations of AZD9833 at a series of timepoints to derive renal clearance

  10. Assessment of biomarker changes [ Time Frame: At pre-defined time intervals throughout the AZD9833 treatment period and at discontinuation. (approximately1 year) ]
    Blood samples will be collected to assess biomarker changes of estrogen receptor (ER), progesterone receptor (PgR) and Ki67 protein at a series of timepoints to derive AZD9833 activity in tumour cells.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Pre-menopausal or Post-menopausal women
Accepts Healthy Volunteers:   No
Criteria

Inclusion

  1. Signed written informed consent.
  2. >= 18 years.
  3. Any menopausal status:

    1. Pre-menopausal women must have commenced treatment with an LHRH agonist at least 4 weeks prior to starting IMP (AZD9833 ± palbociclib or everolimus) and must be willing to continue to receive LHRH agonist therapy for the duration of the study.
    2. Post-menopausal defined according to standard criteria in the protocol.
  4. Histological or cytological confirmation of adenocarcinoma of the breast.
  5. Documented positive oestrogen receptor status of primary or metastatic tumour tissue, according to the local laboratory parameters. HER-2 negative.
  6. Metastatic disease or locoregionally recurrent disease which is refractory or intolerant to existing therapy(ies) known to provide clinical benefit.
  7. Metastatic or locoregionally recurrent disease and radiological or objective evidence of progression on or after the last systemic therapy prior to starting IMP.
  8. Prior chemotherapy, endocrine therapy and other therapy as follows:

    1. No more than 2 lines of chemotherapy for advanced disease.
    2. Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting.
    3. There is no limit on the number of lines of prior endocrine therapies.
    4. Prior treatment with CDK4/6 inhibitors is permitted.
  9. Women of childbearing potential must agree to use a highly effective contraceptive measure, must not be breast feeding, and must have a negative pregnancy test prior to the start of dosing.
  10. At least one lesion (measurable and/or non-measurable, as per RECIST 1.1 that can be accurately assessed at baseline and is suitable for repeated assessment by CT, MRI, or plain X-ray; or clinical examination. Blastic-only lesions in bone are not considered assessable.
  11. ECOG/ WHO performance status 0 to 1, with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.

Inclusion criteria for the paired tumour biopsy research:

12 Disease suitable for paired baseline and on-study tumour biopsies 13 Washout from prior fulvestrant: 6 months 14 Washout from prior tamoxifen: 4 months 15 Signed written informed consent for tumour biopsies Exclusion E.4 Principal exclusion criteria (list the most important, max 5000 characters) ●

  1. Intervention with any of the following a Any cytotoxic chemotherapy, investigational agents or other anti-cancer drugs for the treatment of advanced breast cancer from a previous treatment regimen or clinical study within 14 days of the first dose of IMP b Medications or herbal supplements known to be strong inhibitors/inducers of CYP3A4/5 sensitive CYP2B6 substrates and drugs which are substrates of CYP2C9 and/or CYP2C19, and which have a narrow therapeutic index ie, warfarin (and other coumarin-derived vitamin K antagonist anticoagulants) and phenytoin or inability to stop use within a suitable washout period prior to receiving the first dose of study treatments. Parts E & F will exclude the concomitant use of moderate CYP3A4 and/or P-gp inhibitors c Drugs that are known to prolong QT and have a known risk of Torsades de Pointes d Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of IMP, except patients receiving radiotherapy to more than 30% of the bone marrow/a wide field of radiation within 4 weeks of the first dose of IMP e Major surgical procedure/significant traumatic injury, as judged by the investigator, within 4 weeks of the first dose of IMP, or an anticipated need for major surgery and/or any surgery requiring general anaesthesia during the study
  2. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting IMP, with the exception of alopecia.
  3. Presence of life-threatening metastatic visceral disease, as judged by the investigator, uncontrolled CNS metastatic disease. Patients with spinal cord compression and/or brain metastases may be enrolled if definitively treated (eg, surgery or radiotherapy) and stable off steroids for at least 4 weeks prior to start of IMP
  4. Contraindication to, or known previous intolerance of, standard dose everolimus (10 mg) (Parts E & F only).
  5. Past medical history of ILD (Parts E & F only)
  6. Currently symptomatic radiotherapy-induced pneumonitis (Parts E & F only)
  7. Evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV)
  8. Any of the following cardiac criteria a Mean resting QTcF >470 msec obtained from a triplicate electrocardiogram b Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (eg, complete left bundle branch block, second- and third-degree heart block), or clinically significant sinus pause. Patients with controlled atrial fibrillation can be enrolled c Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as symptomatic heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome, or unexplained sudden death at <40 years of age. Hypertrophic cardiomyopathy and clinically significant stenotic valve disease d LVEF <50% and/or experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure NYHA Grade ≥2, cerebrovascular accident, or transient ischaemic attack.

e Uncontrolled hypertension. Hypertensive patients may be eligible but blood pressure must be adequately controlled at baseline. Patients may be re-screened regarding the blood pressure requirement 9 Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values a ANC <1.5 × 109/L b Platelet count <100 × 109/L c Haemoglobin <90 g/L d ALT >2.5 × the upper limit of normal (ULN) e AST >2.5 × ULN f TBL >1.5 × ULN or >3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) g GFR <50 mL/min 10 Involvement in the planning and conduct of the study 11 Refractory nausea and vomiting, uncontrolled chronic gastrointestinal (GI) diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9833 and relevant combination IMPs 12 History of hypersensitivity to active/inactive excipients of AZD9833 or drugs with a similar chemical structure/class to AZD9833. Parts C & D: Hypersensitivity to active/inactive excipients of palbociclib or drugs with similar chemical structure/class to palbociclib. Parts E & F: Hypersensitivity to everolimus or other rapamycin derivatives 13 The use of live vaccines (Part E & F) 14 Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements 15 Male subjects


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): NCT03616587


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: Cancer Study Locator 877 400 4656 AstraZeneca@emergingmed.com

Locations
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United States, Colorado
Research Site Recruiting
Aurora, Colorado, United States, 80045
United States, Florida
Research Site Recruiting
Sarasota, Florida, United States, 34232
United States, Tennessee
Research Site Recruiting
Nashville, Tennessee, United States, 37203
United States, Utah
Research Site Recruiting
Salt Lake City, Utah, United States, 84112
Spain
Research Site Recruiting
Barcelona, Spain, 08035
Research Site Recruiting
Barcelona, Spain, 8036
Research Site Withdrawn
Madrid, Spain, 28007
Research Site Recruiting
Madrid, Spain, 28041
Research Site Recruiting
Madrid, Spain, 28050
Research Site Recruiting
Sevilla, Spain, 41013
Research Site Recruiting
Valencia, Spain, 46010
United Kingdom
Research Site Recruiting
Cambridge, United Kingdom, CB2 0QQ
Research Site Suspended
Leeds, United Kingdom, LS9 7TF
Research Site Recruiting
London, United Kingdom, SW2 6JJ
Research Site Recruiting
Manchester, United Kingdom, M20 4BX
Research Site Recruiting
Sutton, United Kingdom, SM1 2DL
Research Site Recruiting
Sutton, United Kingdom, SM2 5PT
Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Richard Baird, MD PhD FRCP Breast Cancer Research Unit, University of Cambridge
Study Director: Justin Lindemann, MBChB MBA AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03616587    
Other Study ID Numbers: D8530C00001
2018-000667-92 ( EudraCT Number )
138396 ( Registry Identifier: IND )
First Posted: August 6, 2018    Key Record Dates
Last Update Posted: December 1, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Breast Cancer
Phase 1
Safety
Tolerability
Pharmacokinetics
ER Positive
HER2 Negative
Advanced Breast Cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Everolimus
Palbociclib
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action