scholarly journals Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Ana C. Garrido-Castro ◽  
Cristina Saura ◽  
Romualdo Barroso-Sousa ◽  
Hao Guo ◽  
Eva Ciruelos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Clinical Benefit ◽  
Triple Negative ◽  
Pi3k Pathway ◽  
Pi3k Inhibitor ◽  
Class I ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3

Abstract Background Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer. Methods This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies. Results Fifty patients were enrolled. Median number of cycles was 2 (range 1–10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6–2.3). Median OS was 11.2 months (95% CI 6.2–25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease. Conclusions Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer. Trial registration NCT01790932. Registered on 13 February 2013; NCT01629615. Registered on 27 June 2012.

scholarly journals Dasatinib as a Single Agent in Triple-Negative Breast Cancer: Results of an Open-Label Phase 2 Study

2011 ◽  
Vol 17 (21) ◽  
pp. 6905-6913 ◽  
Author(s):  
Richard S. Finn ◽  
Carmelo Bengala ◽  
Nuhad Ibrahim ◽  
Henri Roché ◽  
Joseph Sparano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Study ◽  
Open Label Phase

scholarly journals Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3857
Author(s):  
Zhanfang Guo ◽  
Tina Primeau ◽  
Jingqin Luo ◽  
Cynthia Zhang ◽  
Hua Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Growth Response ◽  
Triple Negative ◽  
Pi3k Pathway ◽  
Pi3k Inhibitor ◽  
Pi3k Inhibitors ◽  
Patient Derived Xenograft ◽  
Phosphorylated Akt

PI3K pathway activation is frequently observed in triple negative breast cancer (TNBC). However, single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor, BKM120. Baseline and post-treatment PDX tumors were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive model. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increases in the levels of phosphorylated forms of Aurora kinases. Interestingly, increased AKT phosphorylation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.

Phase II trial of RAD001 plus carboplatin in patients with triple-negative metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11529-e11529
Author(s):  
Jasmeet Chadha Singh ◽  
Stacy Stein ◽  
Matthew Volm ◽  
Julia Anne Smith ◽  
Yelena Novik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Triple Negative Breast Cancer ◽  
Clinical Benefit ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Primary Objective ◽  
Grade 3 ◽  
Platinum Agents

e11529 Background: Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of RAD001 (oral mTOR inhibitor) and Carboplatin may have activity in triple-negative breast cancer. Methods: The primary objective of the study was to estimate the clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD) >6 months) and the toxicity of this combination in women with triple negative metastatic breast cancer who have had 0-3 prior chemotherapy regimens for metastatic disease. 25 subjects were to be entered into a single stage open label Phase II study. Prior Carboplatin is allowed. Treated brain metastasis are eligible. The null hypothesis that the clinical benefit rate is ≤10% could be rejected if number of CR/PR/SD >6 months was ≥6. Originally, intravenous Carboplatin AUC 6 was to be administered every 3 weeks along with daily 5mg of RAD001 with a 3 patient run-in and then 10 mg daily. Due to a surprising amount of thrombocytopenia with this combination, the dose of Carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001. Results: 18 patients have been recruited thus far. Median age is 59. There have been 1 CR, 4 PR’s and 2 SD's lasting > 6 months. One SD was achieved in a patient progressing on single agent Carboplatin at study entry. Median duration of CR+ SD +PR thus far is 13 weeks (range: 6-60 weeks). 5 patients had grade 3/4 thrombocytopenia and 4 patients had grade 3 neutropenia (no febrile neutropenia). However, since amendment of Carboplatin dose to AUC 4 the regimen has been well tolerated. 1 patient suffered from grade 3 dehydration. The estimated clinical benefit rate is 50% (95% C.I.: 24%, 76%). Median time to progression or death is 87.5 days from start of treatment; there is only 1 death to date on this study. Conclusions: The study has achieved it’s primary objective of demonstrating clinical benefit of RAD 001-Carboplatin combination in triple negative metastatic breast cancer. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment.

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