Inclusion criteria, exclusion criteria and study summary
These criteria are to be checked to confirm eligibility of an ESR1m positive patient prior to randomisation for entry into the Study Treatment Phase of the study. Informed Consent 2.1 Evidence of a personally signed and dated informed consent document (ICF2) indicating that the patient (or legal representative) has been informed of all pertinent aspects of the study before any study-specific activity is performed. ICF2 must be signed and dated prior to initiation of the interventional study screening activities and randomisation outlined in Table 4. For those patients that wish to participate, provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports Genomic Initiative. This consent should be signed at Treatment Phase screening. If for any reason these samples are not collected at Treatment Phase screening, they may be taken at any time until the post treatment/disease relapse follow-up visit. For those patients that wish to participate, provision of signed and dated written Optional Pre-treatment and/or At Progression Tumour Sample Collection informed consent prior to collection of sample for optional translational research. This consent should be signed at the second screening for the Treatment Phase. Consent for tumour samples at disease progression could occur during the Treatment Phase. Weight 2.2 Minimum body weight of 35 kg. Type of Patient and Disease Characteristics 2.3 Patients who have ESR1m positive disease irrespective of concurrent mutation(s) detected by ctDNA during screening or surveillance. Qualifying ESR1m status (see Section 8.7.1.1) will be assessed by a prespecified Sponsor-selected assay at a central laboratory (see Section 8.7.1.1). 2.4 Confirmation that the patients are currently on treatment and have received ≥ 6 months (ie, 24 weeks) of AI (letrozole or anastrozole) + CDK4/6 inhibitor (palbociclib or abemaciclib) ± LHRH agonist treatment as their initial endocrine based treatment for their advanced disease in accordance with local palbociclib and abemaciclib label or treatment guidelines (a) Confirmation the patient has had no change in therapy since the start of STEP 1. Please note: (b) Dose modifications of the ongoing therapy are acceptable. 2.5 Documented absence of disease progression (by investigator assessment) prior to randomisation. (a) Clinical progression defined as unequivocal evidence of disease progression on clinical grounds in the absence of radiological progression, including development of new sites of disease or significant increase in tumour burden. (b) Radiological progression defined as unequivocal progression compared to previous imaging obtained during or prior to initiation of CDK4/6 inhibitor + AI. 2.6 Patients must be willing to provide archival radiological images (CT, MRI or bone scan, if not available, then available PET-CT scan is acceptable) used for tumour assessment at the initiation and/or during CDK4/6 inhibitor + AI for their metastatic disease treatment that support the non-PD assessment. 2.7 Eastern Cooperative Oncology Group performance status of 0 to 1. 2.8 Patients must have at least one evaluable lesion (defined as one lesion non previously irradiated, measurable and/or non-measurable, that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment). Patients with bone disease only must have at least one non previously irradiated lytic or mixed (lytic + sclerotic) bone lesion that can be assessed by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible. Bone scan at baseline is required. 2.9 Adequate organ and marrow function as follows: (a) Haemoglobin ≥ 9 g/dL (90 g/L). (b) Absolute neutrophil count ≥ 1000/mm3 (1.0 × 109/L) or documented institutional normal range for restarting palbociclib. (c) Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia). (d) Alanine aminotransferase and aspartate aminotransferase ≤ 2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤ 5 × ULN; for patients on abemaciclib treatment, ALT and AST ≤ 5 × ULN. (e) Alkaline phosphatase ≤ 2.5 × ULN (≤ 5.0 × ULN if bone or liver metastases present) (f) Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 30 mL/min as determined by Cockcroft-Gault (using actual body weight). (i) Males: CrCL = Weight (kg) × (140 - Age) (mL/min) 72 × serum creatinine (mg/dL) (i) Females: CrCL = Weight (kg) × (140 - Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL) Reproduction 2.10 For those female or male patients who are not abstinent (in line with their preferred and usual lifestyle choice), and intend to be heterosexually active with a partner: Female patients must be using 2 highly effective non-hormonal contraceptive measures from the time of screening until 4 weeks after discontinuation of study treatment, and must have a negative serum pregnancy test (with a test sensitivity of at least 25 mIU/mL) before first dose of any study treatment if they are of childbearing potential; or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: (a) Post-menopausal, defined as women with (i) Cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause (ii) Cessation of regular menses for at least 6 consecutive months with no alternative pathological or physiological cause AND with serum oestradiol and follicle stimulating hormone level within the laboratory's reference range for post-menopausal females (iii) Previous bilateral surgical oophorectomy Non sterilised male partners of a patient who is a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period (see Appendix G for complete list of highly effective birth control methods). Male patients who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception (see Appendix G) from the time of screening throughout the total duration of the study and the drug washout period (6 months after the last dose of study treatment) to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period. Concurrent Treatment 2.11 Pre-menopausal females and males who are currently receiving concurrent LHRH agonist (goserelin or leuprorelin) treatment while on CDK4/6 inhibitor + AI must be willing to continue to be treated with monthly LHRH agonists during the entire STEP2 treatment phase of the study. If the patients are currently receiving inhibition of LHRH treatment with alternative drugs or schedule other than monthly goserelin or leuprorelin, they must be willing to switch at the earliest practical time within STEP 2. 2.12 Male patients not currently receiving concurrent LHRH agonist treatment whilst on CDK4/6 inhibitor + AI must be willing to be treated with monthly LHRH agonists (goserelin or leuprorelin) unless the patients have clear orchiectomy medical history. Tumour Sample Requirements 2.13 Willingness and ability to provide an archived tissue tumour sample (Blocks or 12 unstained slides) to assess the correlation between genes, proteins, and RNAs relevant to the ER pathways and sensitivity/resistance to the investigational agents’ status/expression prior to enrolment as described in Section 8.7. Tissue from the most recent biopsy in the metastatic setting is preferred. If not available (for example bone only disease patients), then archival samples from the primary breast cancer will be required for patient participation. 2.14 Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Patients are excluded from the study if any of the following criteria apply: Type of Patient and Disease Characteristics 2.1 No evidence of disease, or bone only disease with sclerotic/osteoblastic bone lesions only at the screening for STEP 2. Medical Conditions 2.2 Have advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal]), pulmonary lymphangitis. 2.3 Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral oedema, and/or progressive growth. Patients with a history of brain or other CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before the screening phase of the study. 2.4 Any evidence of severe or uncontrolled systemic diseases which, in the investigator’s opinion, makes it undesirable for the patient to participate in the study or that would jeopardise compliance with the protocol. 2.5 Chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of CDK4/6 inhibitor and/or study (AI or AZD9833) treatment. 2.6 History of another primary malignancy except for the following: (a) Malignancy treated with curative intent with no known active disease ≥ 3 years before the first dose of study treatment, and of very low potential risk for recurrence. (b) Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of disease (c) Other exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has undergone potentially curative therapy. 2.7 Persistent non-haematological toxicities (CTCAE Grade > 2) caused by CDK4/6 inhibitor and/or AI treatment. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study treatment may be included (eg, hearing loss) after consultation with the AstraZeneca study physician. 2.8 Patients with CDK4/6 inhibitor treatment-induced symptomatic interstitial lung disease (Grade ≥ 2). 2.9 Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), HBV (known positive HBsAg result), and HCV. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Screening for chronic conditions is not required. 2.10 Known to have tested positive for HIV. Patients with HIV may be enrolled if they fulfil the criteria recommended by FDA and ASCO guidelines (FDA Guidance, Uldrick et al 2017): (a) CD4+ T-cell (CD4+) counts ≥ 350 cells/uL, AND (b) No history of AIDS-defining opportunistic infections within the past 12 months (prophylactic antimicrobials allowed if no drug-drug interactions or overlapping toxicities), AND (c) On established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrolment. Effective ART is defined as a drug, dosage, and schedule associated with reduction and control of the viral load. 2.11 Unexplained syncope, symptomatic hypotension or asymptomatic hypotension with systolic blood pressure < 90 mmHg. 2.12 Second- and third-degree heart block, or clinically significant sinus pause or sinoatrial block. Patients with pacemakers or medically controlled atrial fibrillation are not excluded. 2.13 Left ventricular ejection fraction < 50% with heart failure NYHA Grade ≥ 2. 2.14 Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, any other structural heart disease interventions (eg, cardiac valve repair or replacement surgery or transcatheter valve intervention), severe aortic regurgitation (Grade 3 and 4), myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischaemic attack. 2.15 Untreated electrolyte abnormalities with potential QT-prolonging effect including serum/plasma potassium*, magnesium* and calcium* below the LLN. *Correction of electrolyte abnormalities to within normal ranges can be performed during screening. 2.16 Mean resting QTcF interval > 480 ms, obtained from triplicate ECGs performed at screening. 2.17 Resting heart rate < 60 beats per minute. 2.18 Uncontrolled hypertension. Blood pressure systolic > 160 and diastolic > 90 mmHg. Hypertensive patients may be eligible, but blood pressure must be adequately controlled at baseline. Patients may be rescreened regarding blood pressure requirement. Prior/Concomitant Therapy 2.19 Any concurrent anticancer treatment not specified in the protocol. Concurrent use of non-topical hormonal therapy for non cancer-related conditions (eg, hormone replacement therapy) is not allowed. 2.20 Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study treatment. 2.21 Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 28 days of the first dose of study treatment or an anticipated need for major surgery and/or any surgery requiring general anaesthesia during the study. 2.22 Patients treated: (a) Within the last 2 weeks before randomisation: 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 which have a narrow therapeutic index ie, warfarin (and other coumarin-derived vitamin K antagonist anticoagulants) and phenytoin. (b) Within the timeframe indicated in Table I29 with drugs that are known to prolong the QT interval and have a known risk of TdP, as indicated in Appendix I 1. 2.23 Previous treatment with AZD9833, investigational SERDs/endocrine agents or fulvestrant. Prior/Concurrent Clinical Study Experience 2.24 Previous randomisation in the present study. 2.25 Participation in another clinical study with a study treatment or investigational medicinal device administered in the last 4 weeks prior to randomisation or concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study. 2.26 Patients with known hypersensitivity to anastrozole, or any of its excipients, or history of hypersensitivity to active or inactive excipients of AZD9833/placebo or drugs with a similar chemical structure or class to AZD9833 or known hypersensitivity to palbociclib and its excipients. In pre/perimenopausal female and male patients, known hypersensitivity to LHRH agonists or any of its excipients, that would preclude the patient from receiving any LHRH agonist. Note for patients who are receiving LHRH agonists. - Female patients with undiagnosed vaginal bleeding will be excluded. - Patients who are anticoagulated (INR > 2) and at higher risk of vascular injury and subsequent bleeding will be excluded. Other Exclusions 2.30 Currently pregnant (confirmed with positive serum pregnancy test) or breastfeeding. 2.31 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site or relative of those site staff members). 2.32 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.
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