Gedatolisib Plus Fulvestrant With or Without Palbociclib vs Standard-of-Care for the Treatment of Patients With Advanced or Metastatic HR+/HER2- Breast Cancer (VIKTORIA-1)

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of metastatic or locallyadvanced breast cancer Adult females, pre- and/or post-menopausal, and adult males.Pre-menopausal (and peri-menopausal) women can be enrolled if amenable to treatmentwith an LHRH agonist. Patients are to have commenced concomitant treatment with LHRHagonist prior to or on Cycle 1, Day 1 and must be willing to continue on it for theduration of the study.

2. Negative pregnancy test for women of childbearing potential. Female subjects ofchildbearing potential must use an effective and/or acceptable contraceptive methodfrom screening until 1 year after the last dose of study treatment

3. Confirmed diagnosis of estrogen receptor positive and/or progesterone receptorpositive, as per American Society of Clinical Oncology/College of AmericanPathologists (ASCO-CAP) guidelines (2020), based on most recent tumor biopsyutilizing an assay consistent with local standards

4. Documented HER2 immunohistochemistry (IHC) negative as per ASCO-CAP 2018 guidance

5. Adequate archival or fresh tumor tissue for the analysis of PIK3CA mutational status

6. Subject must have documentation of radiological disease progression on or after thelast prior treatment and also have radiologically evaluable disease (measurableand/or non-measurable) according to RECIST v1.1, per local assessment. Subjects withbone only disease must have lytic or mixed lytic/blastic lesions that can beaccurately assessed; bone only blastic lesions with no soft tissue component is notallowed.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

8. Life expectancy of at least 3 months

9. Progressed during or after CDK4/6 inhibitor combination treatment with non-steroidalaromatase inhibitor (AI)

10. Adequate bone marrow, hepatic, renal and coagulation function

Exclusion Criteria:

1. History of malignancies other than adequately treated non-melanoma skin cancer,curatively treated in situ cancer of the cervix, or other solid tumors curativelytreated with no evidence of disease for ≥3 years

2. Prior treatment with a phosphoinositide 3-kinase (PI3K) inhibitor, a protein kinaseB (Akt) inhibitor, or a mechanistic target of rapamycin (mTOR) inhibitor

3. Prior treatment with chemotherapy and antibody drug conjugates for advanced diseaseis not permitted (prior adjuvant or neoadjuvant chemotherapy is permitted)

4. More than 2 lines of prior endocrine therapy treatment

5. Bone only disease that is only blastic with no soft tissue component

6. Subjects with type 1 diabetes or uncontrolled type 2 diabetes

7. Known and untreated, or active, brain or leptomeningeal metastases a. Subjects with previously treated central nervous system (CNS) metastases may beenrolled in the study if they meet the following criteria: do not require supportivetherapy with steroids; do not have seizures and do not exhibit uncontrolledneurological symptoms; stable disease confirmed by radiographic assessment within atleast 4 weeks prior to enrollment

8. Patients with advanced, symptomatic, visceral spread that are at risk oflife-threatening complication in the short-term

9. History of clinically significant cardiovascular abnormalities such as: Congestiveheart failure (New York Heart Association (NYHA) classification ≥ II within 6 monthsof study entry

10. Myocardial infarction within 12 months of study entry

11. History of any uncontrolled (or untreated) clinically significant cardiacarrhythmias, (e.g., ventricular tachycardia), complete left bundle branchblock, high grade AV block (e.g., bifascicular block, Mobitz type II and thirddegree AV block), supraventricular, nodal arrhythmias, or conductionabnormality in the previous 12 months

12. Uncontrolled hypertension defined by systolic blood pressure (SBP) ≥160 mmHgand/or diastolic blood pressure (DBP) ≥100 mmHg, with or withoutantihypertensive medication (initiation or adjustment of antihypertensivemedication[s] is allowed prior to screening)

13. Long QT syndrome, family history of idiopathic sudden death or congenital longQT syndrome, or any of the following:

• i. Risk factors for Torsades de Pointes (TdP) including uncorrectedhypokalemia or hypomagnesemia, or history of clinicallysignificant/symptomatic bradycardia
• ii. On screening, inability to determine the corrected QT interval usingFridericia's formula (QTcF) on the ECG (i.e., unreadable or notinterpretable) or QTcF >480 msec (determined by mean of triplicate ECGs atscreening)

10. Known hypersensitivity to the study drugs or their components

11. Pregnant or breast-feeding women

12. Concurrent participation in another interventional clinical trial

13. Subjects must agree not to participate in another clinical trial (other thanobservational) at any time during participation in VIKTORIA-1.