A Study To Assess The Tolerability And Clinical Activity Of Gedatolisib In Combination With Palbociclib/Letrozole Or Palbociclib/Fulvestrant In Women With Metastatic Breast Cancer

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.