Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients

ESMO Open ◽  
2021 ◽  
Vol 6 (5) ◽  
pp. 100231
M. Del Re ◽  
C. Omarini ◽  
L. Diodati ◽  
M. Palleschi ◽  
I. Meattini ◽  
2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3089-3089
Ateeq Ahmad ◽  
S. Sheikh ◽  
R. Nagarkar ◽  
J. K. Singh ◽  
S. Krishnan ◽  

3089^ Background: Endoxifen is an active metabolite of tamoxifen, a drug used in the treatment of breast cancer. To be clinically effective, tamoxifen must be converted to endoxifen by CYP2D6. Direct administration of endoxifen would not be subject to pharmacogenetic variations or drug-drug interactions. Our preclinical studies (Breast Cancer Treat 122, 579-584, 2010) have validated the concept of using endoxifen for the treatment of breast cancer. In human (Clin. Pharmacol. Ther. 88, 814-817, 2010), the single oral doses tested up to 4 mg of endoxifen were safe, well tolerated and bioavailable. Methods: A multiple-dose escalating study was conducted in 3 cohorts and each cohort had 6 patients (18 metastatic breast cancer patients). Endoxifen at 3 dose levels (2, 4, or 8 mg) was given once daily for 28 days. Routine laboratory tests, vital signs and electrocardiograms were measured throughout the study. Blood samples for PK analysis were collected after 28 days post dose. Endoxifen in plasma samples was determined using LC-MS/MS. Results: Endoxifen was found to be safe up to 8.0 mg. At steady state, it displays dose-proportional PK with respect to Cmax and AUC ( see Table below). Conclusions: Multiple daily endoxifen doses of 4.0-8.0 mg resulted in endoxifen exposures that would be sufficient for effective therapy. The favorable safety and multiple-dose PK profile of endoxifen warrants further evaluation of safety and efficacy of endoxifen in breast cancer patients. [Table: see text]

2014 ◽  
Vol 140 (9) ◽  
pp. 1557-1565 ◽  
Luca G. Campana ◽  
Sara Galuppo ◽  
Sara Valpione ◽  
Antonella Brunello ◽  
Cristina Ghiotto ◽  

2012 ◽  
Vol 98 (1) ◽  
pp. 39-44 ◽  
Stefania Gori ◽  
Jennifer Foglietta ◽  
Maria Grazia Mameli ◽  
Lucia Stocchi ◽  
Daniela Fenocchio ◽  

2013 ◽  
Vol 31 (26_suppl) ◽  
pp. 31-31 ◽  
Italia Grenga ◽  
Renee Nicole Donahue ◽  
Peter Sungwhan Kim ◽  
Brendan Dempsey ◽  
James L. Gulley ◽  

31 Background: Therapeutic vaccine is emerging as a potentially efficacious and safe treatment for cancer patients. However, markers are not available to identify patients more likely to benefit from this treatment. Aim of this retrospective study was to analyze before treatment immune subsets that correlated with clinical outcome in metastatic breast cancer patients treated with docetaxel alone or in combination with vaccine. Methods: We applied multi-color flow cytometry analysis of PBMCs harvested prior to treatment from patients (n=43) enrolled in a small randomized phase II study of docetaxel alone (n=20) or in combination with PANVAC-V (Vaccinia) and PANVAC-F (Fowlpox) encoding for the tumor-associated antigens CEA and MUC-1, along with a TRIad of COstimulatory Molecules (B7-1, ICAM-1, and LFA-3; called TRICOM) (n=23). Frequency of more than 200 immune sub-populations before treatment was measured by flow cytometry. Each of the resulting subsets was ranked in tertiles. For immune subsets that correlated directly with PFS, 2 points were assigned if the frequency fell in the highest tertile, 1 point if in the middle, and 0 if in the lowest tertile. For subsets that correlated inversely with PFS, the points were assigned in the opposite order. An immunoscore was calculated based on the sum of points assigned to each subset. Log-Rank analysis, with the cutoff based on the median of the immunoscores, was performed to evaluate differences in PFS between patients with a low and high immunoscore. Results: In vaccine plus docetaxel arm, 10 immune subsets from PBMCs before treatment correlated with PFS and were used for the calculation of the immunoscore. Patients with an immunoscore above the median showed a statistically significant longer PFS compared to those with lower score in vaccine plus docetaxel arm (p<0.001, HR=0.1466, 95% CI= 0.0478-0.4375) but not in docetaxel alone arm (p=0.097, HR=0.418, 95% CI=0.147-1.172). Conclusions: Calculation of an immunoscore from PBMCs before treatment based on flow cytometry screening of immune subsets may identify patients that will most likely benefit from vaccine combination immunotherapy.

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