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01.07.2014 | Clinical Trial Report

Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors

verfasst von: Monica Mita, Michael Gordon, Lee Rosen, Nirmal Kapoor, Gavin Choy, Sanjeev Redkar, Pietro Taverna, Aram Oganesian, Amarpal Sahai, Mohammad Azab, Robert Bristow, Anthony W. Tolcher

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2014

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Abstract

Purpose

Amuvatinib is an oral multi-kinase inhibitor that suppresses RAD51, inhibits mutant c-KIT and platelet-derived growth factor receptor alpha, and has synergistic activity with DNA-damaging agents and topoisomerase inhibitors such as etoposide, doxorubicin, and topotecan. We conducted a phase 1B study to estimate the maximum tolerated dose (MTD) levels of amuvatinib with standard chemotherapy regimens and to define the safety profiles of specific amuvatinib + standard regimens.

Methods

Five therapies each co-administered with amuvatinib 100–800 mg/day every 21 days were evaluated in treatment-naïve or moderately pre-treated subjects: paclitaxel IV followed by carboplatin IV; carboplatin IV followed by etoposide; topotecan IV; docetaxel IV; and erlotinib by mouth.

Results

Among 97 treated subjects, no treatment arm reached the MTD. Dose-limiting toxicities included febrile neutropenia and diarrhea. No pharmacokinetic interactions of amuvatinib with any cancer regimens occurred. Of 12/97 (12 %) partial responses overall, 11 were seen in the amuvatinib and paclitaxel/carboplatin or carboplatin/etoposide arms and most commonly in the neuroendocrine (NE), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) tumors. Forty-four subjects (45 %) had stable disease. Adverse events reflected combination treatment and were primarily non-hematologic (fatigue, alopecia, diarrhea, nausea, anorexia) and hematologic (neutropenia, anemia, thrombocytopenia, leukopenia). Pharmacodynamic effects as measured by decreased levels of RAD51 and increased residual DNA damage (53BP1 foci) were seen in skin punch biopsies.

Conclusion

Amuvatinib was well tolerated, modulated RAD51, and showed antitumor activity when combined with paclitaxel/carboplatin and carboplatin/etoposide in NE, NSCLC, and SCLC tumors.

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Titel: Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors
verfasst von: Monica Mita
Michael Gordon
Lee Rosen
Nirmal Kapoor
Gavin Choy
Sanjeev Redkar
Pietro Taverna
Aram Oganesian
Amarpal Sahai
Mohammad Azab
Robert Bristow
Anthony W. Tolcher
Publikationsdatum: 01.07.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2014
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-014-2481-1

Springer Medizin

Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors