- 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
- Histologically or cytologically proven diagnosis of breast cancer with evidence of
- 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
- 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: MBC with progression during or following one or two prior endocrine based
systemic therapies in the metastatic setting, and following prior therapy with a
- Measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST)
- Bone only patients during dose escalation portion.
- Availability of archival tumor biopsy sample or willing to provide fresh biopsy if not
- Eastern Cooperative Oncology Group [ECOG] performance must be 0 or 1.
- Adequate bone marrow, renal and liver function.
- 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
- 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