Phase I study of BIBF 1120 with docetaxel and prednisone in metastatic chemo-naive hormone-refractory prostate cancer patients

Abstract

Background:BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1–3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients.Methods:This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m−2, every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity.Results:Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ⩾50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone.Conclusion:Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m−2 of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.

Tolerability of Nintedanib (BIBF 1120) in Combination with Docetaxel: A Phase 1 Study in Japanese Patients with Previously Treated Non–Small-Cell Lung Cancer

“…This is consistent with findings from a phase I study of nintedanib/ docetaxel in patients with prostate cancer. 25 In the present study, we found no clear differences in PK data from patients with BSA less than 1.5 and BSA greater than or equal to 1.5. This could be due to the small sample size, so populationbased PK analyses of nintedanib are needed.…”

“…The mild-tomoderate gastrointestinal AEs and asymptomatic, reversible liver enzyme increases are consistent with the established safety/tolerability profile of nintedanib in NSCLC and other tumor types. 10,11,[21][22][23][24][25] AEs associated with many other VEGFtargeted tyrosine kinase inhibitors, such as grade 3-4 skin toxicities, hypertension, bleeding, perforation, thromboembolism, and proteinuria, 26 were either absent or infrequent in this study.…”

A Phase I Dose-Escalation Study of Afatinib Combined with Nintedanib in Patients with Advanced Solid Tumors

“…Nevertheless, both AUC and C max values of afatinib and nintedanib were comparable to those reported previously for each agent when administered as monotherapy or in combination [26][27][29][30][31][32][35][36][37]. These findings suggest that there were no pharmacokinetic interactions between afatinib and nintedanib in the applied dosing schedule.…”

Nintedanib: From Discovery to the Clinic

“…37 Inter-patient variability of PK parameters for nintedanib was moderate to high. 26,28,37 No PK interaction has been observed in phase I combination studies between nintedanib and the chemotherapeutic agents/regimens docetaxel, 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Cumulative recovery of excreted [ 14 C]-radioactivity revealed that urinary excretion for nintedanib is minor (approximately 0.7% over 72 hours) and that the major route of elimination is through metabolism, with metabolites excreted via the biliary system into the feces (93.4% over 120 hours). 26 Nintedanib metabolism in healthy humans occurs predominantly by cleavage of the methyl ester moiety to the carboxylate, which is then conjugated to glucuronic acid, yielding the 1-Oacylglucuronide.…”