IRB Study Number 23-933
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To demonstrate superiority of extended therapy with camizestrant as compared to standard ET by assessment of invasive breast cancer-free survival (IBCFS).
Secondary Objectives
To demonstrate superiority of extended therapy with camizestrant as compared to standard ET by assessment of invasive disease-free survival (IDFS).
To demonstrate superiority of extended therapy with camizestrant as compared to standard ET by assessment of distant relapse-free survival (DRFS).
To demonstrate superiority of extended therapy with camizestrant as compared to standard ET by assessment of overall survival (OS).
Inclusion Criteria
Informed Consent
1 Capable of giving signed informed consent as described in Appendix A 3 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Age
2 Patient must be ≥18 years at the time of screening (or per national guidelines).
Patient and Disease Characteristics
3 Documented histologically confirmed ER+/HER2- early-stage resected invasive breast cancer with absence of any evidence of advanced disease. Estrogen receptor and HER2 measurement should be performed under institutional guidelines. Estrogen receptor testing should utilise an assay consistent with ASCO CAP 2020 guidelines (Allison et al, 2020). Estrogen receptor-positive tumour is defined as estrogen receptor expression in >10% of tumour cells. Please refer to Appendix J if only Allred or H-score is available.HER2-negative tumour is determined as IHC score 0/1+ or negative by in situhybridisation (FISH/CISH/SISH/DISH) defined as a HER2/CEP17 ratio <2 or for singleprobe assessment a HER2 copy number <4, consistent with ASCO CAP 2018 guidelines(ASCO CAP, 2018).
(a)Patients with multicentric and/or multifocal early invasive breast cancer whosehistopathologically examined tumours all meet pathologic criteria for ER+ (ie, >10%positive stained cells), irrespective of PgR status, and HER2- are eligible.
(b)Patients with bilateral invasive breast cancer (diagnosed simultaneously or within6 months of each other) are eligible if all lesions tested on both sides are ER+ (ie,>10% positive stained cells), irrespective of PgR status, and HER2- AND adequatesurgery has been performed in both breasts and any systemic treatment to eitherbreast meets the inclusion criteria for the study.
4 Pre-, peri-, and post-menopausal women, and men, with at least one of the following criteria below. For this study, locoregional lymph nodes include ipsilateral regional lymph nodes (axillary, infraclavicular, supraclavicular, and internal mammary), but exclude intramammary lymph nodes. Patients will be staged following the American Joint Committee on Cancer (AJCC) staging edition v8. Of note, pathological tumour size and pathological nodal involvement after surgery should be used (regardless of whether chemotherapy was given in the adjuvant or neoadjuvant setting) except for T4 tumours, or for supraclavicular, infraclavicular, or internal mammary adenopathy (see Section 8.1 for detailed guidance).
(a)T4 tumours (tumour of any size with direct extension to the chest wall and/or the skinulceration or macroscopic nodules), regardless of nodal status. Note: Patients withinflammatory breast cancer are not eligible. Patients who received neoadjuvanttherapy will be eligible if staged as T4 either clinically or pathologically.
(b)T3 tumours (pathological primary invasive tumour size >5 cm, regardless of nodalstatus).
(c)Pathological tumour of any size with involvement in ≥2 ipsilateral lymph nodes.
(d)T1c-T2 (pathological primary invasive tumour size >1 cm and ≤5 cm) withinvolvement of 1 lymph node if at least one of the following features is present:
(i)Pathological grade 3
(ii)Pre-existing high risk of recurrence per genomic signature assessment (OncotypeDX ≥26 or MammaPrint High or Prosigna ROR High or EndoPredict High) frommedical record if in compliance with local regulations and conducted inaccordance with intended use (see Section 4.1)
(iii) Centrally assessed Ki-67 >20% via an AstraZeneca-provided laboratory testusing archival formalin-fixed paraffin-embedded (FFPE) tumour sample wherecountry-specific in vitro diagnostic approvals are available, as required.
(e)T1c-T2 (pathological primary invasive tumour size >1 cm and ≤5 cm) withoutinvolvement of any ipsilateral lymph nodes if at least one of the following features ispresent:
(i)Pathological grade 3
(ii)Pre-existing high risk of recurrence per genomic signature assessment (OncotypeDX ≥26 or MammaPrint High or Prosigna ROR High or EndoPredict) frommedical record if in compliance with local regulations and conducted inaccordance with intended use (see Section 4.1)
(iii) Centrally assessed Ki-67 >20% via an AstraZeneca-provided laboratory testusing archival FFPE tumour sample where country-specific in vitro diagnosticapprovals are available, as required.
(iv) Prior cytotoxic chemotherapy for the current diagnosis of breast cancer.Note: Inclusion of patients with T1c-T2, N0 tumours will be capped at 30%.
5 The patient must have undergone adequate (definitive) locoregional therapy (surgery with or without radiotherapy) for the primary breast tumour(s), with or without (neo)adjuvant systemic therapy (chemotherapy and/or ET). Prior adjuvant treatment with olaparib in patients with germline BRCA1/2 mutations is allowed.
6 At the time of randomisation, the patient must have completed at least 2 years but no more than 5 years (+3 months) of adjuvant ET (regardless of missed doses) and is currently still receiving ET (ie, within the past 3 months). Patients who have received a (neo)adjuvant CDK4/6 inhibitor plus ET are eligible but must have completed the planned CDK4/6 inhibitor part of treatment.
7 Patient must have at least 5 years of remaining adjuvant ET planned, consistent with local treatment guideline/recommendation based on individualised benefit-risk assessment after review of risk of recurrence and potential toxicity. If, per investigator’s assessment, the planned duration of 5 years of therapy does not seem realistic in a given patient (due to advanced age, poor performance status, co-morbidities, or other factors), the patient should not be enrolled in the study.
8 The patient has a performance status ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale (Oken et al, 1982).
9 The patient has adequate bone marrow reserve and organ function as follows:
-Haemoglobin ≥9.0 g/dL.
-Absolute neutrophil count ≥1.5 × 109/L. Note: Patients with a history of DuffyNull Associated Neutrophil Count (formerly benign ethnic neutropenia) areeligible if absolute neutrophil count ≥1.0 × 109/L.
-Platelet count ≥75 × 109/L.
-Total bilirubin (TBL) ≤1.5 × the upper limit of normal (ULN) or ≤3 × ULN inthe presence of documented Gilbert’s syndrome (unconjugatedhyperbilirubinemia).
-Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤2.5 × ULN.
-Estimated glomerular filtration rate or estimated creatinine clearance asdetermined by Cockcroft-Gault ≥30 mL/min per FDA guidance (FDA, 2020).
Tumour Sample Requirements
10 All patients must provide an archival FFPE tumour tissue sample. If the patient has not received any neoadjuvant treatment, a tumour sample collected during definitive surgery is preferable (although tumour sample collected during initial diagnostic workup will be accepted). If the patient has received neoadjuvant treatment, then a tumour sample collected during initial diagnostic workup is required. For further details on tumour sample requirements, please refer to Section 8.8.1.1.
Reproduction
11 Female patients must have a negative highly sensitive serum pregnancy test during the screening period if they are of childbearing potential and agree to use highly effective contraceptive methods (please refer to Appendix F 3) to prevent pregnancy during the study and for 28 days following the last dose of camizestrant or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
(i)Natural cessation of regular menses for at least 12 consecutive months with noalternative pathological or physiological cause, including prior chemotherapy
(ii)Previous complete hysterectomy, bilateral surgical oophorectomy or bilateralsalpingectomy
12 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) from the time of screening throughout the total duration of the study until 28 days after last dose of camizestrant (see Appendix F 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 F) from the time of screening throughout the total duration of the study and the drug washout period (6 months after the last dose of camizestrant) to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period.
Other Inclusion Criteria
13 The patient is able to swallow oral medications.
Exclusion Criteria
Medical Conditions
1 Patients with inoperable locally advanced breast cancer, or distant metastatic (including contralateral axillary lymph nodes) disease.
2 Patients with pathological complete response (ypT0/ypTis ypN0) following treatment with neoadjuvant therapy.
3 Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in situ of the cervix or considered a very low risk of recurrence per investigator judgement [eg, papillary thyroid cancer treated with surgery]), unless in complete remission with no therapy for a minimum of 5 years from the date of randomisation are excluded.
4 Patients with a history of previous invasive breast cancer. Ipsilateral ductal carcinoma in situ (DCIS) treated by locoregional therapy alone ≥5 years prior to diagnosis of the invasive breast cancer or contralateral DCIS treated with locoregional therapy at any time are allowed. Patients with DCIS (either ipsilateral or contralateral) who were treated with ET must have completed ET ≥5 years prior to the diagnosis of invasive breast cancer.
Patients with a history of atypical hyperplasia are eligible, but if they received ET this should have been completed ≥5 years prior to the diagnosis of invasive breast cancer.
5 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.
6 Chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would, in the opinion of the investigator, preclude adequate absorption, distribution, metabolism, or excretion of study treatment.
7 Cardiac symptoms, procedures, or test results as follows:
(a)Unexplained syncope (within the last 6 months prior to randomisation), or ongoingsymptomatic hypotension, or ongoing asymptomatic hypotension with systolic BP<90 mmHg.
(b)Second- and third-degree heart block, or clinically significant sinus pause orsinoatrial block. Patients with pacemakers or medically controlled atrial fibrillationare not excluded.
(c)Known left ventricular ejection fraction <50% with heart failure NYHA Grade ≥2.
(d)Untreated electrolyte abnormalities with potential QT-prolonging effect includingserum/plasma potassium, magnesium, and calcium below the lower limit of normal.Note: Correction of electrolyte abnormalities to within normal ranges can beperformed during screening.
(e)Mean resting QTcF interval >480 ms, obtained from ECG performed at screening,congenital long QT syndrome, immediate family history of long QT syndrome, orunexplained sudden death under 40 years of age in first-degree relatives.
(f)Resting heart rate consistently <50 bpm for patients that are either taking heart ratereducing concomitant medications or that have a history of stroke, coronary heartdisease, or disrhythmia. Repeat measurements are permitted during the screeningperiod.
(g)Uncontrolled hypertension. Blood pressure systolic >160 and diastolic >90 mmHgdespite optimal medical management. Hypertensive patients may be eligible, but BPmust be adequately controlled at baseline.
(h)Experience of any of the following procedures or conditions in the preceding6 months: coronary artery bypass graft, angioplasty, vascular stent, any otherstructural heart disease interventions (eg, cardiac valve repair or replacement surgeryor transcatheter valve treatment), severe aortic regurgitation (Grades 3 and 4),myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transientischaemic attack.
Prior/Concomitant Therapy
8 More than 5 years (+3 months) has elapsed from the first dose of adjuvant ET, regardless of missed doses.
9 The patient is receiving concurrent exogenous reproductive hormone therapy (eg, birth control pills, hormone replacement therapy, hormonal IUD, or megestrol acetate) or non-topical hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy). Please refer to Appendix H 2. Note: topical vaginal estrogen therapy is permitted if all non-hormonal options have been exhausted.
Note: Patients with a hormonal IUD will be eligible if the device is removed within 8 weeks after randomisation.
10 Any concurrent anti-cancer treatment not specified in the protocol with the exception of bisphosphonates (e.g. zoledronic acid) or RANKL inhibitors (eg, denosumab).
11 Major surgical procedure or significant traumatic injury within 2 weeks of randomisation.
12 Patients treated:
(a)Within 2 weeks prior to first dose: medications or herbal supplements known to bestrong inhibitors/inducers of cytochrome P450 (CYP) 3A4/5, sensitive CYP2B6substrates and drugs which are substrates of CYP2C9 and/or CYP2C19 (eg, drugswith a narrow therapeutic index [ie, warfarin (and other coumarin-derived vitamin Kantagonist anticoagulants] and phenytoin) (see Appendix H 1).
(b)Within the timeframe indicated in Table 16 with medications that are known toprolong the QT interval and have a known risk of TdP (see Appendix H 1).
13 Previous treatment with camizestrant, investigational SERDs/investigational endocrine agents, or fulvestrant. Prior/Concurrent Clinical Study Experience 14 Previous randomisation in the present study. 15 Concurrent or prior participation in another therapeutic clinical trial with a study treatment or investigational medicinal device judged by AstraZeneca not to be medically or scientifically compatible with this study is not allowed (eg, CAMBRIA-2). Participation in other studies, including non-interventional clinical studies, is allowed following consultation with the medical monitor.
Other Exclusions
16 Patients with known hypersensitivity to active or inactive excipients of camizestrant or drugs with a similar chemical structure or class to camizestrant. In pre-/peri-menopausal female and male patients, known hypersensitivity to LHRH agonists or any of its excipients, that would preclude the patient from receiving any LHRH agonist.
Notes for patients who are receiving LHRH agonists:
Female patients with undiagnosed vaginal bleeding will be excluded.
17 Currently pregnant (confirmed with positive serum pregnancy test) or breastfeeding.
18 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).
19 Judgement 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.
