Phase 3 Study of Gedatolisib as First-Line Treatment for Patients With HR-Positive, HER2-Negative Advanced Breast Cancer (VIKTORIA-2)

This is a Phase 3, open-label, randomized, clinical trial evaluating the efficacy and safety of gedatolisib plus fulvestrant and CDK4/6 Inhibitors for the treatment of patients with locally advanced or metastatic HR+/HER2- advanced breast cancer.

This is a Phase 3, open-label, randomized clinical trial evaluating the efficacy and safety of gedatolisib plus fulvestrant combined with a CDK4/6 inhibitor (Investigator's choice of palbociclib or ribociclib) for the treatment of patients with advanced (inoperable) or metastatic hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer whose disease has progressed during or within 12 months of adjuvant treatment with endocrine therapy (either an AI or tamoxifen), and who have not received prior systemic therapy for ABC. Gedatolisib is an intravenously administered pan-PI3K/mTOR inhibitor. Palbociclib is a CDK4/6 inhibitor. Fulvestrant is a selective estrogen receptor degrader (SERD). Following completion of the safety run-in phase to determine the gedatolisib dose with ribociclib, subjects will be assigned to 1 of 2 cohorts based on their PIK3CA status and then randomized to either the investigational treatment arm (gedatolisib with fulvestrant and ribociclib or palbociclib) or standard-of-care control arm (fulvestrant and ribociclib or palbociclib).

Eligibility Criteria:
Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of metastatic or locally advanced HR+/HER2- breast cancer
2. Adult females, pre- and/or post-menopausal, and adult males. Pre-menopausal (and peri-menopausal) women can be enrolled if amenable to treatment with an LHRH agonist. Patients are to have commenced concomitant treatment with LHRH agonist prior to or on Cycle 1, Day 1 and must be willing to continue for the duration of the study.
3. Negative pregnancy test for females of childbearing potential. Female subjects who are not surgically sterile must use a medically effective contraceptive method from screening until 2 years after the last dose of study treatment.
4. Progression of disease during or within 12 months of completing (neo)adjuvant ET.
5. Adequate archival, fresh tumor tissue, or liquid biopsy for the analysis of PIK3CA mutational status.
6. Permitted prior therapies:

   1. (neo)adjuvant fulvestrant or any selective ER degrader only if the treatment duration \< 6 months
   2. (neo)adjuvant chemotherapy
   3. (neo)adjuvant CDK4/6 inhibitor, unless PD was on or within 6 months of discontinuation of CDK4/6i
7. Subject has radiologically measurable disease according to RECIST v1.1, per local assessment. Patients with evaluable bone-only disease are not eligible. Patients with bone-only disease that has lytic or mixed lytic/blastic lesions and at least one measurable soft tissue component per RECIST v1.1 may be eligible.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
9. Life expectancy of at least \>6 months.
10. Adequate bone marrow, hepatic, renal and coagulation function.

Exclusion Criteria:

1. Concurrent malignancies other than adequately treated non-melanoma skin cancer. Previous malignancies in remission but curatively treated with no evidence of disease progression and judged by local Investigator to be at low risk of impacting health or survival while on study.
2. Prior treatment with a phosphoinositide 3-kinase (PI3K) inhibitor, a protein kinase B (Akt) inhibitor, or a mechanistic target of rapamycin (mTOR) inhibitor
3. Prior treatment with systemic anticancer therapy for ABC
4. Subjects with type 1 diabetes
5. Known and untreated, or active, brain or leptomeningeal metastases
6. History of clinically significant cardiovascular abnormalities
7. History of drug-induced symptomatic interstitial lung disease (pneumonitis) or hepatitis