397P - Phase 1 study of sorafenib and eribulin in patients with advanced, metastatic or refractory solid tumors

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Presenter Frederik Marmé
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors F. Marmé1, C. Gomez-Roca2, K. Graudenz3, F. Huang4, J. Lettieri5, C. Pena4, Z. Trnkova3, J. Eucker6
  • 1Translationale Gynäkologische Onkologie, Universitätsklinikum Heidelberg & Nationales Centrum für Tumorerkrankungen, D-69120 - Heidelberg/DE
  • 2Medical Oncology, Institut Claudius Regaud, Toulouse/FR
  • 3Clinical Pharmacology, Oncology, Bayer Pharma AG, Berlin/DE
  • 4Clinical Pharmacology, Oncology, Bayer Healthcare Pharmaceuticals, Whippany/US
  • 5Clinical Pharmacokinetics, Pharmacodynamics, Bayer Healthcare Pharmaceuticals, Whippany/US
  • 6Onkologie Und Hämatologie, Universitätsmedizin Berlin, Berlin/DE

Abstract

Background

Combining sorafenib (SOR), an oral multikinase inhibitor approved for hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma, with eribulin mesylate (ERI), a microtubule inhibitor approved for breast cancer (BC), may provide synergistic antitumor activities.

Methods

This phase 1b, open label, dose escalation study evaluated safety, pharmacokinetics (PK), maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), cardiac safety (QT/QTc), and preliminary efficacy of SOR + standard dose ERI (1.4 mg/kg IV on Days [D] 1 and 8 of each 21-day cycle [C]) in patients (pts) with advanced, metastatic, or refractory tumors. Starting SOR dose was 200 mg BID continuously starting on D11 of C1. SOR + ERI-related hematologic and nonhematologic dose limiting toxicities (DLT) were assessed in C2. If tolerable, SOR was escalated in new cohorts to 600 mg daily (200 mg AM/400 mg PM) and 400 mg BID. QT/QTc intervals and PK were evaluated respectively in C1 for single dose and C2 for multiple doses. Antitumor activity was assessed by RECIST v1.1. RP2D was confirmed in a MTD expansion cohort (minimum 12 pts).

Results

Of 40 pts treated, 5 received SOR 200 mg BID, 8 received 600 mg/d, and 27 received 400 mg BID (MTD), of whom 14 were in the expansion cohort. Of 12 cancer types reported, 62.5% of pts had BC. No DLT was reported in the 200-mg and 600-mg cohorts; 1 DLT (Grade 3 increased ALT) was reported in the 400-mg BID dose escalation cohort and 1 DLT (Grade 3 acute coronary syndrome) in the expansion cohort. Most common drug-related ≥Grade 3 TEAEs were hypophosphatemia (10%) and hypertension (10%) for SOR and neutropenia (25%) for ERI. No significant QT/QTc prolongation was observed; mean QTcF change from baseline was 11.44 ms with ERI alone and 8.25 ms with ERI + SOR. No drug interaction was observed; mean SOR AUC was 60.4 mg*h/L for SOR 400 mg BID + ERI and 56.7 mg*h/L for SOR 400 mg BID alone. Respective mean SOR Cmax were 6.8 and 7.7 mg/L. 8 pts had a partial response (5 confirmed, 3 unconfirmed).

Conclusions

SOR 400 mg BID + standard dose ERI was well tolerated and confirmed RP2D. Toxicities were in line with known SOR and ERI safety profiles. Thus, SOR + ERI would be appropriate to examine in larger studies.

Clinical trial identification

NCT01585870; EudraCT: 2011-005849-12

Legal entity responsible for the study

N/A

Funding

Pharmaceutical Division of Bayer

Disclosure

F. Marmé: Honoraria (presentations and advisory boards): Roche, Novartis, Amgen, AstraZeneca, Eisai, Genomic Health, Celgene. C. Gomez-Roca: Received consulting fees from Novartis and Sanofi. K. Graudenz, Z. Trnkova: Employee of Bayer Pharma AG. F. Huang, J. Lettieri, C. Pena: Employee of Bayer HealthCare Pharmaceuticals. J. Eucker: Consulting fees: Novartis, Amgen, Roche; Contracted research: Novartis.