Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ER+/HER2- Breast Cancer

Palbociclib (Ibrance®) is an orally active highly selective reversible inhibitor of cyclin-dependent kinase (CDK) 4 and CDK 6. Faslodex® (Fulvestrant) is a potent anti-estrogen drug that binds and degrades estrogen receptors (ERs). Interim results from the Phase 3 trial (Study PALOMA-3) have shown that combination of palbociclib and Faslodex increases progressive-free survival (PFS) from 3.8 to 9.2 months in patients with metastatic estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer that progressed during or after anti-endocrine therapy (Turner et al. 2015). The palbociclib/Faslodex combination was found to be well tolerated. Additionally, there is growing data indicating that this combination can be safely and effectively administered up front in anti-endocrine therapy-naive patients in the neoadjuvant setting. Gedatolisib (code name PF-05212384, formerly known as PKI-587) is an intravenous (IV) adenosine triphosphate (ATP) competitive, highly selective and potent inhibitor of pan-class I isoform phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3-K) and mammalian target of rapamycin (mTOR) (Fry et al. 2004). Preclinical and first-in-human studies have shown a manageable safety profile with predictable toxicity for this class of drugs. Activation of the PI3-K/Akt/mTOR/p-S6 pathway has been associated with endocrine resistance in ER+ breast cancer. There is ample evidence that inhibition of this pathway, in combination with anti-hormonal therapy, increases PFS (Baselga et al. 2012). There is also clinical evidence that combination therapy targeting all three pathways is feasible, safe and effective (Sweeney et al. 2014). The advantage of Gedatolisib is its potential to inhibit signaling through different PI3-K isoforms. Also important is the fact that once a week administration may be as effective, but less toxic, than chronic oral dosing. If hyperglycemia is a surrogate for effective PI3-K/Akt/mTOR/p-S6 inhibition, once weekly dosing of Gedatolisib would appear to accomplish equivalent degrees of hyperglycemia as chronically oral dosing and with less toxicity. Preoperative or neoadjuvant systemic chemotherapy, once reserved for patients with locally advanced breast cancer in whom the goal was to render large breast cancers operable, has become increasingly common due to the improvement in disease-free survival and overall survival. Historically, the endpoint of pathological Complete Response (pCR) in neoadjuvant therapy against ER+/HER2- breast cancer has been of limited value. However, new targeted agents, with higher response rates, have the potential to use pCR assessment as a strong clinical endpoint in drug development. Given the systemic response rate in previously treated Stage 4 breast cancer patients, the expectation will be a similar high rate of pathological improvement which can lead to greater use of targeted agents in the neoadjuvant setting. In addition to the potential of better pathological improvement, the advantage of clinical studies involving neoadjuvant therapy is that they can provide response information in patients that are treatment-naïve. This type of clinical trial can also be used to assess cellular and molecular changes with serial biopsies while on neoadjuvant therapy, which can aid in development of companion tissue and/or imaging biomarkers, and further the development of preclinical models. Accordingly, this investigation assesses the safety and efficacy of the combination of Gedatolisib, palbociclib and faslodex in the neoadjuvant setting in previously untreated patients with ER+/HER2- breast cancer. Being the first clinical trial using this combination in neoadjuvant setting, one of the main objectives for the current trial is to determine the Maximum Tolerated Dose (MTD) of Gedatolisib when used in combination with palbociclib and faslodex. Subsequent Phase II clinical trials will be conducted to assess the safety and efficacy of the Gedatolisib/palbociclib/faslodex combination, with the dose of Gedatolisib being the MTD determined from the current trial.