Even with a clinical and biochemical profile compatible with menopause, switching from tamoxifen to an AI should be avoided in patients <48 with CIA.

BACKGROUND: The PI3K/AKT/mTOR (PAT) pathway alteration has been strongly implicated in breast cancer and may contribute to resistance to available therapy. PQR309 is an oral pan-PI3K and mTOR inhibitor that penetrates the blood-brain barrier. Experiments of eribulin in combination with PI3K inhibitors in luminal and TNBC pre-clinical models enhanced antitumor activity. TRIAL OBJECTIVES: The primary objectives of the study are: to identify the maximum tolerated dose (MTD), evaluate the efficacy, safety and tolerability as well as the pharmacokinetics (PK) of PQR309 in combination with eribulin. In addition, exploratory objectives include assessments of: PAT pathway alterations prior to treatment, pharmacodynamics (PD) activity of PQR309 in combination with eribulin and correlation of PAT pathway alterations and PD activity with PQR309 and eribulin PK. TRIAL DESIGN: This is an open label, non-randomized, multicenter phase 1/2b clinical trial (dose escalation followed by expansion part) of PQR309 p.o. in combination with the standard dose of eribulin mesylate (1.4 mg/m2) in patients with LAMBC until progression or unacceptable adverse events (AE). The dose escalation part of the study will first investigate PQR309 administered in a continuous daily (q.d.) and two intermittent treatment schedules in combination with standard administration of eribulin mesylate in patients with HER2 negative LAMBC following the “modified” 3 by 3 design. MTD is defined as the highest dose level at which ≤1 of 6 pts experiences dose-limiting toxicity (DLT) during the 1st cycle. After the MTD of PQR309 in combination with eribulin has been defined in all the three treatment schedules, one schedule will be selected, based on the overall evaluation of clinical data from the dose escalation part of the study, for further evaluation of efficacy in the expansion part of the study. The expansion part of the trial applies Simon's MiniMax two-stage design. At the first stage, &gt; 3 pts with TNBC with clinical benefit (CB) among 14 pts will be necessary to continue to the second stage. At the study end, &gt; 9 pts with CB out of 28 pts are required to reject the null hypothesis. With this design, there is an 80% probability of a positive finding if the true clinical benefit rate (CBR) is ≥ 43% and a 5% probability of a positive finding if the true CBR is ≤ 21%. ELIGIBILITY: Women with HER2- LAMBC with two to 5 prior chemotherapy regimens in advanced disease. Adequate organ function and performance status. Phase II specific selection criteria are: triple negative LAMBC and RECIST v1.1 evaluable disease. ACCRUAL: Approximately 60 patients will be enrolled in approximately 10 sites Recruitment opened in March 2016. TRIAL REGISTRATION: NCT02723877. Date of registration: 21/12/2015. First patient included: 04/04/2016. Citation Format: López-Miranda E, Gávila J, Pernas S, Saura C, Oliveira M, Serra V, Schmid P, Lord S, Paez D, Perez J, Llombart A, Petrovic K, Dimitrijevic S, Cortes J. PIQHASSO: Open label, non-randomized, multicenter phase 1/2b study investigating safety and efficacy of PQR309 and eribulin combination in patients (pts) with locally advanced (LA) or metastatic HER2 (-) and triple-negative breast cancer (TNBC) (study PQR309-007) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-06.

Despite best available therapy, triple-negative breast cancer (TNBC) continues to be associated with poorer outcomes when compared to other breast cancer subtypes and poses a serious therapeutic challenge. Therefore, novel and more efficacious therapies are in great need. It is widely accepted nowadays, that TNBC is not homogeneous, but comprised of a number of subpopulations very different in genetic make-up, oncogene dependence, and response to treatment. Among these, multiple core phosphatidylinositol-3-kinase (PI3K) pathway components are known to be altered in TNBC. The relevance of activating mutations in the PI3KCA gene or PTEN/INPP4B loss of protein expression on the virulence of breast cancer and response to PI3K inhibitors is yet to be elucidated. PI3K hyperactivity due to these alterations suggests that inhibitors of the PI3K pathway may be used to reverse resistance. BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor currently in clinical development. This non-randomized, two-stage, open-label, single-arm exploratory trial is designed to elucidate the preliminary therapeutic value of BKM120 in patients with metastatic TNBC and to identify subpopulations that may mostly benefit. Women 18 years and above with confirmed mTNBC who have received at least two prior chemotherapy regimens in the adjuvant or metastatic setting are eligible to participate. Availability of a tumor block from the primary tumor or accessible metastasis for biopsy is mandatory. The primary objective is to determine the clinical activity of BKM120 defined as the clinical benefit rate (CR, PR or SD for more than 4 months per RECIST 1.1). Secondary objectives are to determine progression-free survival, overall survival, safety profile, pharmacodynamic effects, and to identify biomarkers predictive of response. BKM120 will be administered orally at a 100-mg dose, once daily, in a continuous schedule. Treatment will continue until disease progression, unacceptable toxicity, or decision of the physician or the patient to terminate participation. Stage 1 will include up to 50 patients with an intermediate analysis after the enrollment of the first 29 subjects. If no sufficient activity is observed, the clinical trial will be terminated. If drug activity is observed, enrollment will continue up Stage 1 completion. After 50 patients are enrolled, a comprehensive analysis of molecular markers using technology and knowledge gathered in the Stand Up to Cancer Dream Team will take place. This analysis will be focused in identifying molecular markers predictive of response that would guide patient selection for Stage 2. Two clone investigator-initiated protocols (one for the US, one for Spain) are enrolling in parallel. A total of 110 patients will take part in this study in four sites in Spain and in 2 in the US: 50 patients in Stage 1 and 60 in Stage 2, exploring a maximum of 3 subgroups of 20 patients each. The trial is funded by a Stand Up to Cancer Dream Team Translational Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0209) and supported by Novartis. Patient enrollment started in June 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-06.

Background Stomatitis is the most common adverse event (AE) associated with mTOR inhibitors, including EVE. In the pivotal BOLERO-2 trial, stomatitis was reported for 59% vs 12% (Gr3, 8% vs &lt;1%) of pts with HR+, HER2– ABC who received EVE + EXE vs EXE alone. Of the limited real world evidence available, the BRAWO trial showed a stomatitis incidence of 39.8% (Gr3, 3.4%) in a similar pt population. Additional data are warranted to better understand the stomatitis incidence and time-course in order to minimize treatment discontinuations. Methods BALLET is a Phase 3b, European, multi-center, open-label, single-arm, expanded-access study that evaluated safety of EVE (10 mg/d) and EXE (25 mg/d) in 2131 postmenopausal women with HR+, HER2– ABC that progressed on prior NSAI treatment. Primary endpoint was safety; secondary endpoint was characterization of grade 3/4 AEs. In this exploratory analysis, we split the pts in two groups based on having experienced at least one all grade stomatitis event in the first 8 wks (cut-off chosen based on reports that 89.4% of stomatitis events occurred within 8 wks of EVE initiation [Rugo, ASCO 2014]) vs none. Results This subgroup analysis included 919 pts with stomatitis (43.1% of the full population). Baseline pt characteristics were comparable to the overall study population, except for more comorbidity (cardiovascular and metabolic disorder) in stomatitis subset. Pts with stomatitis had a longer EVE treatment duration vs pts who didn't (5.8 mo [95%CI, 5.0-6.2] vs 4.7 mo [95%CI, 4.4-5.3]; hazard ratio, 1.121 [95%CI, 0.97-1.28] censored by pts who switched to commercial drug). The relative risk of initial onset of stomatitis at 6 wks was ∼40%; median time to onset was 28 days. Majority of stomatitis events were of grade 1/2 severity (80%); grade 3/4 stomatitis was reported for 20% of pts. Most frequent reasons for treatment discontinuation in pts with stomatitis were reimbursement (37.6%), disease progression (35.0%), and AEs (16.2%). Most frequent AEs which led to treatment discontinuation in these pts were stomatitis in 3.7% (Grade 3/4, 2%), pneumonitis in 2.9% (Grade 3/4, 1.3%) and asthenia in 1.8% (Grade 3/4, 1%). Median EVE relative dose intensity in pts with stomatitis was 0.92. In the stomatitis subset, dose interruptions and reductions were required for 66.7% and 37.6% of pts, respectively; most frequent reasons for dose adjustments were AEs (65.9%) which included stomatitis (46.8%), asthenia (6.3%), and pneumonitis (5.3%). Median time to first dose modification in pts with stomatitis was 30 days; median duration of dose interruptions was 16 days. On-treatment deaths (4.4%) were due to progressive disease (2.1%), AEs (1.7%), and other reasons (0.5%). Conclusions These results confirmed the stomatitis time-course observed previously and that the majority of these events are of low grade. Stomatitis was the most common cause of dose reductions and interruptions due to AEs and was manageable with dose adjustments; there was a positive association between stomatitis and longer treatment duration. Therefore, proactive management, diligent monitoring and appropriate dose modifications, are recommended to keep pts on treatment. Citation Format: Ciruelos EM, Jerusalem G, Generali D, Lang I, Gavila JG, Michelotti A, Tjan-Heijnn VCG, Mariani G, Conte P, Beliera A, Camozzi M, Lorizzo K, Martin M. Stomatitis following everolimus (EVE) plus exemestane (EXE) in patients with hormone receptor-positive (HR+), HER2– advanced breast cancer (ABC) in the BALLET trial (CRAD001YIC04). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-10.

Background: Dysregulation of cyclin D-CDK4/6-Rb pathway is associated with endocrine resistance in hormone receptor–positive (HR+) breast cancer. Recently, a CDK4/6 inhibitor has shown unprecedented efficacy in metastatic disease, leading to its regulatory approval. Several others are currently in clinical development for the management of HR+ breast cancer in the early and advanced settings. However, it is vital to gain insights into the molecular and biological effects of this class of agents and could identify patients who can benefit the most, delaying or avoiding the use of chemotherapy.The neoadjuvant setting provides an ideal scenario to carry out these investigations. Hence, we propose to conduct an exploratory study to evaluate the biological effects and the efficacy of ribociclib in patients with primary luminal B tumors. We hypothesize that the combination of ribociclib plus letrozole may offer clinical benefit in the preoperative setting. Methods: This is a parallel, multicenter, two-arm, randomized exploratory study in postmenopausal women with primary operable HR+/HER2-negative Luminal B breast cancer designed to evaluate the clinical benefit of ribociclib plus letrozole. Eligibility includes stage I-III operable breast cancer, Luminal B by PAM50, ECOG 0-1. They will be randomized 1:1 to receive either six 28-days cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (2.5mg) or chemotherapy: four cycles of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 every 21 days) followed by weekly paclitaxel during 12 weeks. Baseline, Day 15 on-treatment, and surgical specimens will be collected for molecular characterization and evaluation of response (decrease in Ki67, change to ROR low disease) The primary endpoint is the rate of Residual Cancer Burden (RCB) per MD Anderson Cancer Center procedures. A rate of RCB 0 and 1 score at surgery, with a rank between 20% to 25% with 47 evaluable patients by group of treatment will offer a precision between 11.5% and 12.4%, respectively (95%CI). Ninety-four patients will be enrolled in 21 sites across Spain. The trial was activated in July 2017. As of June 2018, 78 patients have been recruited. Citation Format: Gavila J, Saura C, Oliveira M, Ciruelos E, Gonzalez X, de la Peña L, Bermejo de las Heras B, Muñoz M, Fernandez P, Villagrasa P, Ortega V, Lopez R, Celiz P, Pascual T, Prat A. CORALLEEN: A phase 2 clinical trial of chemotherapy or letrozole plus ribociclib as neoadjuvant treatment for postmenopausal patients with luminal B/HER2-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-05.