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Phase I single dose, two-period and two-sequence cross-over trial to evaluate the relative bioavailability of two oral pimasertib formulations in advanced cancer patients

Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

A phase I two-period two sequence cross-over study compared the bioavailability of two pimasertib (MSC1936369B/AS703026) formulations (capsule versus tablet) in advanced cancer patients.

Methods

Patients with advanced solid tumors were randomized to one of two treatment sequences utilizing pimasertib tablet (test; 3 × 20 mg, PO QD) and capsule (standard; 2 × 30 mg, PO QD). The trial comprised a screening and baseline period, two time periods or parts A and B, and a trial extension phase.

Results

N = 38 patients were randomized to two treatment sequences S1 and S2. PK parameters t 1/2, CL/f, and V z/f were within the same range for the two formulations. Tablet had bioavailability comparable to capsule based on the analysis of AUC0–t, however, tablet administration resulted in an increase of ~25% in C max versus capsule. Common predicted adverse events of pimasertib included ocular events, diarrhea and creatine phosphokinase elevation. Disease control rate was ~29% with 1 partial response and 4 of 10 patients with stable disease >4 months.

Conclusions

Pimasertib tablet was overall well tolerated, had a similar safety and efficacy profile to standard capsule formulation and had bioavailability comparable to capsule.

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Acknowledgements

The authors would like to thank the patients, the patients’ families and the study teams at the participating centers. This trial was sponsored by EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, a US-subsidiary of Merck KGaA, Darmstadt, Germany. EMD Serono has had no role in the writing of this article. EMD Serono has performed a scientific review of the publication, but the views and opinions described in the publication do not necessarily reflect those of EMD Serono. We wish to thank Lee Ann Dietz, RN (West Clinic) for help manage patients on trial.

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Correspondence to D. Mahadevan.

Ethics declarations

This study was funded by EMD Serono (Billerica, MA, USA). DM, MM, DR, EM, RSH, AK, SS and AN have no potential conflict of interest. No animal studies were involved. For human subjects who participated in this study signed an IRB approved (Western IRB and MD Anderson IRB) ICF for the study. All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration.

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Mahadevan, D., Mita, M., Richards, D. et al. Phase I single dose, two-period and two-sequence cross-over trial to evaluate the relative bioavailability of two oral pimasertib formulations in advanced cancer patients. Cancer Chemother Pharmacol 79, 681–688 (2017). https://doi.org/10.1007/s00280-017-3258-0

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  • DOI: https://doi.org/10.1007/s00280-017-3258-0

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