Capivasertib + CDK4/6i + Fulvestrant for Advanced/Metastatic HR+/HER2- Breast Cancer (CAPItello-292) (CAPItello-292)

A Phase Ib/III, Open-label, Randomised Study of Capivasertib Plus CDK4/6 Inhibitors and Fulvestrant Versus CDK4/6 Inhibitors and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer (CAPItello-292)

A Phase Ib/III Open-label, Randomised Study of Capivasertib plus CDK4/6 Inhibitors and Fulvestrant versus CDK4/6 Inhibitors and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer (CAPItello-292)

This Phase Ib/III study (CAPItello-292) aims to evaluate the efficacy, safety and the degree of added benefit of capivasertib combined with CDK4/6i and fulvestrant in participants with locally advanced (inoperable) or metastatic HR+/HER2- breast cancer. Although the dosing regimens of capivasertib + fulvestrant and of CDK4/6i + fulvestrant are established separately, the dose and schedule for the triplet combinations (capivasertib + CDK4/6i + fulvestrant) need to be confirmed. Therefore, the initial dose finding Phase Ib part of the study will determine the recommended Phase III doses (RP3D) of the triplet combinations. The Phase III part of the study will evaluate the efficacy, safety and the degree of added benefit of the triplet combinations of capivasertib and fulvestrant with investigator's choice of CDK4/6i (either palbociclib or ribociclib at safe and tolerable doses, once identified) in comparison with a control arm (fulvestrant + investigator's choice of CDK4/6i [palbociclib or ribociclib]) in a ER+ HER2- maC high risk population that did not receive prior endocrine therapy in the advanced setting.

Phase Ib: Open, Parallel groups allowed, recruiting up to approx. 222 participants. Phase III: open-label, randomised, recruiting approx. 628 participants.

Capivasertib Plus Fulvestrant and Investigator's choice of CDK4/6i (palbociclib or ribociclib) (Ph III)

Phase Ib: Capivasertib 320 mg/ 400 mg administered PO BD 4 days on /3 days off per week for 4 weeks (28 days cycle) Phase III: : Capivasertib, administered PO BD 4 days on / 3 days off per week for 4 weeks (28 days cycle) at the dose confirmed in the phase Ib portion

Phase Ib and Phase III: 500 mg (2 injections of 250 mg) on Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter

Phase Ib: 100 mg/ 125 mg. Once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete 28-day cycle Phase III: Administered once daily for 21 days of 28-day cycle, at the dose of 125 mg.

Phase Ib: 200 mg/ 400 mg/ 600 mg. Once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete 28-day cycle Phase III: Administered once daily for 21 days of 28-day cycle, at the dose confirmed in the phase 1b portion.

Phase Ib: 50 mg/ 100 mg/ 150 mg. Twice daily for 28 consecutive days to comprise a complete 28-day cycle

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.

Data will include clinical observations, ECG parameters, clinical chemistry and haematology and vital signs assessed as the number of participants with treatment-related adverse events.

Data will include clinical observations, ECG parameters, clinical chemistry and haematology and vital signs assessed as the number of participants with treatment-related adverse events.

Progression Free Survival (PFS) is defined as time from randomization until progression per RECIST v1.1. as assessed by BICR or death due to any cause. RECIST related endpoints such as PFS, ORR, DoR, CBR will be collected

Objective Response Rate (ORR) is defined as the proportion of patients with measurable disease at baseline who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by the investigator at local site per Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

Clinical Benefit Rate (CBR) 24 weeks is defined as the percentage of patients who have a CR or PR or who have SD per RECIST v1.1 as assessed by the investigator at local site for at least 23 weeks after date of first dose.

Duration of Response (DoR) will be defined as the time from the date of first documented confirmed response until date of documented progression per RECIST v1.1 as assessed by the investigator at local site or death due to any cause.

Progression Free Survival (PFS) is defined as time from date of first dose until progression per RECIST v1.1. as assessed by the investigator at local site or death due to any cause.

Progression Free Survival (PFS) - time from randomisation until progression per RECIST v 1.1 as assessed by BICR or death due to any cause.

Progression Free Survival (PFS2) - time from randomisation to the earliest of the progression event, after first subsequent therapy or death.

Objective Response Rate (ORR) - the proportion of patients who have a complete or partial response), as determined by BICR per RECIST v1.1.

Duration of Response (DoR) - the time from the date of first documented response until the date of progression per RECIST v1.1 as assessed by BICR, or death due to any cause.

Clinical Benefit Rate (CBR) at 24 weeks-the % of patients who have a CR or PR or who have SD per RECIST v1.1 as assessed by BICR for at least 23 weeks after randomisation.

Phase III: 9. Participant-reported overall side effect bother in participants in the capivasertib arm relative to control arm

Proportion of participants experiencing different levels of overall treatment tolerability as measured by the Patient Global Impression-Treatment Tolerability (PGI-TT).

Data will include clinical observations, ECG parameters, clinical chemistry / haematology / glucose metabolism parameters and vital signs assessed as the number of participants with adverse events.

Data will include clinical observations, ECG parameters, clinical chemistry / haematology / glucose metabolism parameters and vital signs assessed as the number of participants with serious adverse events.

Key inclusion criteria for both phases: Adult females (pre-/peri-/ and post-menopausal), and adult males. Histologically confirmed HR+/ HER2- breast cancer determined from the most recent tumour sample (primary or metastatic) per the American Society of Clinical Oncology and College of American Pathologists guideline. To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without co-expression of progesterone receptor. Eligible for fulvestrant therapy and at least one of the following: palbociclib, ribociclib, or abemaciclib, as per local investigator assessment. Previous tolerance to specific CDK4/6 inhibitors and dose levels required. Adequate organ and bone marrow functions. Consent to provide a mandatory FFPE tumour sample. Inclusion criteria only for phase III: 1. Previous treatment with an ET (tamoxifen, AI, or oral SERD) as a single agent or in combination, with: a. radiological evidence of breast cancer recurrence or progression while on, or within 12 months of, completing a (neo)adjuvant ET regimen Key exclusion criteria for both phases: History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. Radiotherapy within 2 weeks prior to study treatment initiation. Major surgery or significant traumatic injury within 4 weeks of the first dose of study treatment. Persistent toxicities (CTCAE Grade >1) caused by previous anticancer therapy, excluding alopecia. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss or peripheral sensory neuropathy) after consultation with the AstraZeneca study physician. Spinal cord compression, brain metastases or leptomeningeal metastases unless these lesions are definitively treated (eg. radiotherapy, surgery) and clinically stable off steroids for management of symptoms for at least 4 weeks prior to study treatment initiation. Any of the following cardiac criteria at screening: (a). Mean resting corrected QT interval (QTcF): (i) Participants to be treated with palbociclib:: QTcF ≥ 470 ms obtained from the average of 3 consecutive (triplicate) ECGs (ii) Participants to be treated with ribociclib: QTcF ≥ 450 ms obtained from the average of 3 consecutive (triplicate) ECGs (iii) Participants to be treated with abemaciclib (Phase Ib only): QTcF ≥ 470 ms obtained from the average of 3 consecutive (triplicate) ECGs (b). Any clinically important abnormalities in cardiac rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third-degree heart block) (c). Any factors that increase the risk of QTc prolongation or risk of arrhythmic events (d). 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 New York Heart Association (NYHA) grade ≥ 2 (e). Uncontrolled hypotension (f) uncontrolled hypertension (g). Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher) uncontrolled or high grade or symptomatic arrhythmia and atrial fibrillation Any of these clinically significant abnormalities of glucose metabolism at screening: . diabetes mellitus type I or type II requiring insulin treatment . HbA1c ≥ 8.0% (63.9 mmol/mol) Previous allogeneic bone marrow transplant or solid organ transplant. Key exclusion criteria for the phase III only: Any prior treatment with, AKT, PI3K or mTOR inhibitors. Prior treatment with CDK4/6 inhibitors in the metastatic setting (prior CDK4/6 inhibitors permitted in the adjuvant setting provided there was a CDK4/6i treatment free interval of at least 12 months). More than 1 line of chemotherapy for metastatic disease

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