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Poster display session

4219 - Evaluation of Drug-Drug Interactions (DDI) Between Tucatinib and Capecitabine (C) in Patients With Advanced HER2+ Metastatic Breast Cancer From a Phase 1b Study

Date

11 Sep 2017

Session

Poster display session

Presenters

Alex Vo

Citation

Annals of Oncology (2017) 28 (suppl_5): v74-v108. 10.1093/annonc/mdx365

Authors

A. Vo1, D. Leviten2, M. Insko3, T. Sierra2, A. Dozier2, L. Walker4, S. Peterson5

Author affiliations

  • 1 Dmpk, Cascadian Therapeutics, Inc., 98121 - Seattle/US
  • 2 Adme/pk, Cascadian Therapeutics, Inc., 98121 - Seattle/US
  • 3 Pk, Faraday Pharmaceuticals, Seattle/US
  • 4 Clinical Development, Cascadian Therapeutics, Inc., 98121 - Seattle/US
  • 5 Research And Development, Cascadian Therapeutics, 98121 - Seattle/US
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Resources

Abstract 4219

Background

Tucatinib is an orally bioavailable, potent HER2 selective tyrosine kinase inhibitor. Based on the combination activity with chemotherapy and trastuzumab (Tz) in preclinical HER2+ tumor models, tucatinib was evaluated in combination with C and Tz in a Phase 1b study in patients with HER2+ metastatic breast cancer (mBC).

Methods

A phase 1b 3 + 3 dose escalation study (ONT-380-005) was conducted to evaluate the safety and tolerability of tucatinib in combination with C and Tz. Tucatinib (300 mg PO BID), C (1000 mg/m2 PO BID 14 days of a 21-day cycle), and Tz (8 mg/kg IV loading; then 6 mg/kg IV once every 21 days), were administered to HER2+ mBC patients previously treated with Tz and T-DM1. Pharmacokinetic (PK) assessments were conducted on cycle 1 day 14 (+C) and on cycle 1 day 21 (-C). PK of C and its major catabolites/metabolites were also measured. In vitro assessments of the activation of C were determined in the presence of tucatinib. The enzymes evaluated were carboxyesterase (CES), cytidine deaminase (CDA), thymidine phosphorylase (TP), and dihydropyrimidinephosphorylase (DPD).

Results

Tucatinib did not inhibit conversion of C to 5’-DFCR in vitro; at 10 µM tucatinib reduced ∼30% of CES activity. Similarly, tucatinib did not have any significant effect on the activity of CDA, TP, or DPD. Results from in vitro inhibition studies suggested tucatinib does not have a measurable effect on the conversion of C to its active antimetabolite. The clinical PK of tucatinib was unchanged in the presence or absence of C. The PK of C and its catabolites/metabolites were also unaffected in the presence of tucatinib, and were consistent with reported literature.

Conclusions

The overall in vitro and clinical results indicate there is no evidence for DDI between tucatinib and C, including when the combination is given with Tz. The tucatinib-Tz-C triplet combination has been reported to be well tolerated and supports the evaluation of the efficacy of the combination regimen in an ongoing controlled, randomized, double-blinded registrational study (HER2CLIMB).

Clinical trial identification

ONT-380-005

Legal entity responsible for the study

Cascadian Therapeutics, Inc.

Funding

Cascadian Therapeutics, Inc.

Disclosure

A. Vo, D. Leviten, T. Sierra, A. Dozier, L. Walker, S. Peterson: Minor stockholder and employee of Cascadian Therapeutics, Inc. M. Insko: Minor stockholder of Cascadian Therapeutics, Inc., BLPH, and Faraday Pharmaceuticals Inc. Employee of Faraday Pharmaceuticals Inc.

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