Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer (SERENA-1)

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

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Contacts

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

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

• Principal Investigator: Richard Baird, MD PhD FRCP; Breast Cancer Research Unit, University of Cambridge
• Study Director: Justin Lindemann, MBChB MBA; AstraZeneca

More Information

• 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
• 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

• 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:

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