This is a multicenter, open label, Phase 1b study in patients with mBC. This study will have a dose escalation to identify the maximum tolerated dose (MTD) of the combination of gedatolisib plus palbociclib/fulvestrant and gedatolisib plus palbociclib/letrozole and expansion to estimate the objective response rate (OR) of the combination of gedatolisib plus palbociclib/letrozole or palbociclib/fulvestrant.

This is a multicenter, open label, continuous Phase 1b study in patients with MBC. This study will have a dose escalation and expansion. The dose escalation will identify the maximum tolerated dose (MTD) of the combination of gedatolisib plus palbociclib/fulvestrant and gedatolisib plus palbociclib/letrozole. The expansion will estimate the objective response rate (OR) of the combination of gedatolisib plus palbociclib/letrozole and the combination of gedatolisib plus palbociclib/fulvestrant.

Inclusion Criteria:

• Women 18 years of age or older, who are either: Postmenopausal or Pre/perimenopausal women with medically-induced menopause by treatment with agents to induce chemical menopause.

• Histologically or cytologically proven diagnosis of breast cancer with evidence of metastasis.

• Documentation of estrogen receptor positive ((ER+), human epidermal growth factor receptor 2 (HER2 negative (HER2-)) tumor.

• Dose Escalation Portion: Patients must satisfy one of the following criteria:

  • Letrozole combination cohort (L): metastatic breast cancer (MBC) with progression who are candidates for a letrozole-containing regimen, with palbociclib.
  • Fulvestrant combination cohort (F): MBC with progression who are candidates for a fulvestrant containing regimen, with palbociclib.

• Dose Expansion Portion: Patients must satisfy one of the following criteria:

  • Arm A: MBC with progression and no prior endocrine based systemic therapy in the metastatic setting;
  • Arm B: MBC with progression during or following one prior endocrine based systemic therapy in the metastatic setting, with no prior therapy with any cyclin-dependent kinase (CDK) inhibitor;
  • Arm C/Arm D: MBC with progression during or following one or two prior endocrine based systemic therapies in the metastatic setting, and following prior therapy with a CDK inhibitor.

• Measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.

• Bone only patients during dose escalation portion.

• Availability of archival tumor biopsy sample or willing to provide fresh biopsy if not available.

• Eastern Cooperative Oncology Group [ECOG] performance must be 0 or 1.

• Adequate bone marrow, renal and liver function.

Exclusion Criteria:

• Prior treatment with a mechanistic target of rapamycin (mTOR) inhibitor or phosphoinositide 3-kinase (PI3K) inhibitor.
• More than 1 line of prior chemotherapy in the treatment of metastatic or locally advanced/recurrent disease.
• Bone only patients during expansion/efficacy portion.
• Patients with advanced/metastatic disease who have symptomatic visceral spread, and who have life threatening complications needing immediate therapy, such as massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver replacement with tumor.
• Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases.
• Active bacterial, fungal or viral infection.
• Uncontrolled or significant cardiovascular disease.
• Radiation therapy within 4 weeks of investigational product.
• Cytotoxic chemotherapy within 4 weeks of investigational product (6 weeks for mitomycin C or nitrosoureas) if immediate prior regimen was administered on an every 3 4 week schedule or 2 weeks of investigational product if immediate prior regimen consisted of weekly therapy.
• Any other anti cancer agents (eg, hormonal, biological, investigational) within 5 times the half life prior to investigational product.
• Impairment of gastro intestinal (GI) function or GI disease.
• Pregnant female patients; breastfeeding female patients; and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in this protocol for the duration of the study and for 90 days.

Celcuity will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions.