Carlos Becerra M.D.

Abramson, V. G., M. Oliveira, A. Cervantes, H. Wildiers, M. R. Patel, T. M. Bauer, P. L. Bedard, C. Becerra, S. Richey, M. C. Wei, E. Reyner, J. Bond, N. Cui, T. R. Wilson, H. M. Moore, C. Saura and I. E. Krop (2019). “A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer.” Breast Cancer Res Treat 178(1): 121-133.

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PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade >/= 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m(2) docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m(2) paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.

Abramson, V. G., M. Oliveira, A. Cervantes, H. Wildiers, M. R. Patel, T. M. Bauer, P. L. Bedard, C. Becerra, S. Richey, M. C. Wei, E. Reyner, J. Bond, N. Cui, T. R. Wilson, H. M. Moore, C. Saura and I. E. Krop (2019). “A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer.” Breast Cancer Res Treat Jul 31. [Epub ahead of print].

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PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade >/= 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m(2) docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m(2) paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.

Saif, M. W., L. Rosen, M. A. Rudek, W. Sun, D. R. Shepard, C. Becerra, F. Yamashita, P. Bebeau and R. Winkler (2019). “Open-label study to evaluate trifluridine/tipiracil safety, tolerability and pharmacokinetics in patients with advanced solid tumours and hepatic impairment.” Br J Clin Pharmacol 85(6): 1239-1246.

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AIMS: Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open-label, nonrandomized study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations. METHODS: Patients aged >/=18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m(2) orally twice daily on days 1-5 and 8-12 of each 28-day cycle. RESULTS: Twenty-four patients were enrolled to the normal hepatic function (n = 8) and mild (n = 10) and moderate (n = 6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least 1 adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, 5 of 6 patients experienced grade >/= 3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI area under the curve. CONCLUSIONS: FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment.

Shi, Y., W. Gao, N. K. Lytle, P. Huang, X. Yuan, A. M. Dann, M. Ridinger-Saison, K. E. DelGiorno, C. E. Antal, G. Liang, A. R. Atkins, G. Erikson, H. Sun, J. Meisenhelder, E. Terenziani, G. Woo, L. Fang, T. P. Santisakultarm, U. Manor, R. Xu, C. R. Becerra, E. Borazanci, D. D. Von Hoff, P. M. Grandgenett, M. A. Hollingsworth, M. Leblanc, S. E. Umetsu, E. A. Collisson, M. Scadeng, A. M. Lowy, T. R. Donahue, T. Reya, M. Downes, R. M. Evans, G. M. Wahl, T. Pawson, R. Tian and T. Hunter (2019). “Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.” Nature 569(7754): 131-135.

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Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology(1,2). The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance(3-7). Furthermore, PSC activation occurs very early during PDAC tumorigenesis(8-10), and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.

Saif, M. W., L. Rosen, M. A. Rudek, W. Sun, D. R. Shepard, C. Becerra, F. Yamashita, P. Bebeau and R. Winkler (2019). “Open-label study to evaluate trifluridine/tipiracil safety, tolerability and pharmacokinetics in patients with advanced solid tumours and hepatic impairment (PI: Dr Saif).” Br J Clin Pharmacol Jan 9. [Epub ahead of print].

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AIMS: Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open-label, non-randomised study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations. METHODS: Patients aged >/=18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m(2) orally twice daily on days 1-5 and 8-12 of each 28-day cycle. RESULTS: Twenty-four patients were enrolled to the normal hepatic function (n=8) and mild (n=10) and moderate (n=6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least one adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, five of six patients experienced grade >/=3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve (AUC) at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI AUC. CONCLUSIONS: FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment.