CAMBRIA2

Patients are eligible to be included in the study only if all of the following criteria apply:

Informed Consent

1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.

Age

2. Patient must be ≥ 18 years at the time of screening (or per national guidelines).

Patients and Disease Characteristics

3. Documented histologically confirmed ER+/HER2- early-stage resected invasive breast cancer with absence of any evidence of metastatic disease.

(a) Patients with multicentric and/or multifocal early invasive breast cancer whose histopathologically examined tumours all meet pathologic criteria for ER+ (ie, > 10% positive stained tumour cells), irrespective of PgR status, and HER2- are eligible.

(b) Patients with bilateral invasive breast cancer (diagnosed simultaneously or within 6 months of each other) are eligible if all lesions tested on both sides are ER+ (ie, > 10% positive stained cells) and HER2- AND adequate surgery has been performed in both breasts and any systemic treatment to either breast meets the inclusion criteria for the study.

4. Pre-, peri-, and post-menopausal women, and men are eligible if they meet at least 1 of the criteria below. Of note, pathological tumour and nodal staging should be used except for T4 tumours (for which either clinical or pathological stage is acceptable):

(a) T4 tumours (tumour of any size with direct extension to the chest wall and/or the skin - ulceration or macroscopic nodules), regardless of nodal status. (Note: Patients with inflammatory breast cancer are not eligible). Patients who received neoadjuvant therapy will be eligible if staged as T4 either clinically or pathologically.

(b) Tumour of any size with involvement in ≥ 2 ipsilateral lymph nodes. Note: For patients who have suspected involvement of locoregional lymph nodes, confirmation of nodal disease by pathology, cytology, IHC, and/or one step nucleic acid amplification is required. Patients with lymph nodes assessed by imaging only are not eligible. For this study, locoregional lymph nodes include ipsilateral lymph nodes (axillary, infraclavicular, supraclavicular, and internal mammary), but exclude intramammary lymph nodes. Patients with involvement of axillary lymph nodes contralateral to the side of the known breast cancer are not allowed.

(c) T1c-T3 N0 or involvement of 1 positive lymph node (pN1mi is allowed) if at least 1 of the following features is present:

   (i) Grade 3

   (ii) High risk of recurrence per genomic signature assessment (Oncotype DX ≥ 26 or MammaPrint High or Prosigna ROR High or EndoPredict High) from medical record if in compliance with local regulations and conducted in accordance with intended use 

   (iii) Centrally assessed Ki67 > 20% via an AstraZeneca-provided laboratory test using treatment-naïve archival sample where country- specific in vitro diagnostic approvals are available, as required. Note: Inclusion of patients with T1c-T2 N0 tumours will be capped at 20%.

5. Prior treatments and duration

(a) Patients must have undergone adequate (definitive) locoregional therapy (surgery with or without radiotherapy) for the primary breast tumour(s) with or without (neo) adjuvant systemic chemotherapy. Patients should be randomised within the first 12 weeks after radiation or the last chemotherapy dose (whichever is last).

(b) Patients may have received up to 12 weeks of ET either in the adjuvant or neoadjuvant setting prior to randomisation.

(c) In patients not receiving abemaciclib, adjuvant radiotherapy, when indicated, may be administered concomitantly to standard ET or camizestrant.

(d) In patients receiving abemaciclib, radiotherapy should be completed before randomisation and study treatment cannot start prior to 2 weeks from completion of radiation.

(e) Patients must be randomised within 12 months of definitive breast surgery.

6. Performance status ≤ 1 on the Eastern Cooperative Oncology Group (ECOG) scale (Oken et al, 1982).

7. Adequate bone marrow reserve and organ function.

Tumour Sample Requirements

8. All patients must provide an archival formalin-fixed paraffin-embedded (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. Note: Patients without tissue available may be eligible after consultation with the medical monitor and AstraZeneca.

Reproduction

9. 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 to prevent pregnancy during the study and for 28 days following the last dose of study treatment or must have evidence of nonchildbearing potential by fulfilling one of the following criteria at screening:

  (i) Natural cessation of regular menses for at least 12 consecutive months with no alternative pathological, medical (including prior chemotherapy), or physiological cause.

  (ii) Previous complete hysterectomy, bilateral surgical oophorectomy, or bilateral salpingectomy.

10. 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. 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 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.

Other Inclusion Criteria

11. The patient is able to swallow oral medications. 

Patients are excluded from the study if any of the following criteria apply:

Medical Conditions

1. Patients with inoperable locally advanced breast cancer, without known distant metastasis or distant metastatic (including contralateral axillary lymph nodes) disease.

2. Patients with pathological complete response (pCR) or residual cancer burden (RCB)-0 following treatment with neoadjuvant chemotherapy.

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’s 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.

4. Patients with a history of previous breast cancer are excluded except for ipsilateral ductal carcinoma in situ (DCIS, ypTis) treated by locoregional therapy alone ≥ 5 years ago at the time of randomisation as well as patients with a history of contralateral DCIS treated by locoregional therapy at any time.

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), or ongoing symptomatic hypotension, or ongoing asymptomatic hypotension with systolic BP < 90 mmHg.

(b) 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.

(c) Known left ventricular ejection fraction < 50% with heart failure NYHA Grade ≥ 2.

(d) Untreated electrolyte abnormalities with potential QT-prolonging effect including serum/plasma potassium, magnesium, and calcium below the institutional lower limit of normal.

Note: Correction of electrolyte abnormalities to within normal ranges can be performed during screening.

(e) Mean resting QTcF interval > 480 ms, obtained from ECG performed at screening.

(f) Resting heart rate consistently < 50 bpm for patients who are either taking heart rate reducing concomitant medications; or that have a history of stroke, or uncontrolled coronary heart disease, or dysrhythmia. Repeat measurements are permitted during the screening period.

(g) Uncontrolled hypertension (systolic BP > 160 and diastolic BP > 100 mmHg) despite optimal medical management. Hypertensive patients may be eligible, but BP must be adequately controlled at baseline.

(h) 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 treatment), severe aortic regurgitation (Grades 3 and 4), myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischaemic attack.

Prior/Concomitant Therapy

8. The patient is receiving concurrent exogenous reproductive hormone therapy (eg, birth control pills, hormone replacement therapy, Mirena intrauterine device (IUD), or megestrol acetate) or non topical hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy).

Note: Topical vaginal estrogen therapy is permitted if all non-hormonal options have been exhausted.

Note: Patients with Mirena IUD will be eligible if the device is removed within 8 weeks of randomisation.

9. Any concurrent anti-cancer treatment not specified in the protocol except for bisphosphonates (eg, zoledronic acid) or RANKL inhibitors (eg, denosumab).

10. Major surgical procedure or significant traumatic injury within 2 weeks of randomisation.

11. Patients treated:

(a) Within 2 weeks prior to first dose: medications or herbal supplements known to be strong inhibitors/inducers of cytochrome P450 (CYP) 3A4/5, sensitive CYP2B6 substrates and drugs which are substrates of CYP2C9 and/or CYP2C19 (eg, drugs with a narrow therapeutic index [eg, warfarin and other coumarin-derived vitamin K antagonist anticoagulants] and phenytoin).

(b) Within the timeframe indicated in the protocol with medications that are known to prolong the QT interval and have a known risk of TdP.

12. Previous treatment with camizestrant, investigational SERDs/investigational ER-targeting agents, or fulvestrant.

Prior/Concurrent Clinical Study Experience

13. Prior randomisation and withdrawal/discontinuation in the present study.

14. 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. Participation in other studies, including non-interventional clinical studies, is allowed following consultation with the medical monitor.

Other Exclusions

15. Patients with known hypersensitivity to active or inactive excipients of camizestrant or drugs with a similar chemical structure or class to camizestrant.

16. Currently pregnant (confirmed with positive serum pregnancy test) or breastfeeding.

17. 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).

18. 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. 

Research Nurse: Hilary Thatcher

Administrators: research.oncology@mbht.nhs.uk