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

Conditions: Breast Cancer

Summary: 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.

Eligibility criteria:
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.

Keywords: pi3k (phosphoinositide 3-kinase) mtor (mechanistic target of rapamycin) pi3k/mtor metastatic breast cancer (mbc) er+ (estrogen receptor positive) her2- (human epidermal growth factor receptor 2 negative)