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Proffered paper session - Developmental therapeutics

5879 - First-in-Human, First-in-Class study of the CD44v6 inhibitor AMC303 as monotherapy in patients with advanced epithelial tumors

Date

21 Oct 2018

Session

Proffered paper session - Developmental therapeutics

Topics

Clinical Research;  Translational Research

Tumour Site

Presenters

Emiliano Calvo

Citation

Annals of Oncology (2018) 29 (suppl_8): viii133-viii148. 10.1093/annonc/mdy279

Authors

E. Calvo1, P.G. Aftimos2, A. Azaro3, M.J. de Miguel4, C. Jungels5, J. Zeron-Medina Cuairan6, P.G. Nuciforo7, P. Ehmer8, A. Martin9, H.K. Bender10, K. Dembowsky10

Author affiliations

  • 1 Start Phase I, Hospital Madrid Norte San Chinarro Centro Integral Oncologico Clara Campal, 28050 - Madrid/ES
  • 2 Phase I Unit, Institute Jules Bordet, 1000 - Brussels/BE
  • 3 Oncology Department, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 4 Start-madrid Phase 1 Unit, Hospital Madrid Norte San Chinarro Centro Integral Oncologico Clara Campal, 28050 - Madrid/ES
  • 5 Medical Oncology, Institute Jules Bordet, 1000 - Brussels/BE
  • 6 Medical Oncology, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 7 Molecular Oncology, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 8 Clinical Pharmacokinetics, Pharmacelsus GmbH, Saarbrücken/DE
  • 9 Research, amcure GmbH, 76344 - Eggenstein-Leopoldshafen/DE
  • 10 Clinical Development, amcure GmbH, 76344 - Eggenstein-Leopoldshafen/DE
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Abstract 5879

Background

CD44v6 is an isoform of the CD44 family of transmembrane glycoproteins. High CD44v6 expression in epithelial cancer correlates with tumor growth, invasion, metastasis, and recurrence. CD44v6 is a co-receptor of the receptor tyrosine kinases c-Met, RON and VEGFR-2. Inhibition of CD44v6 blocks RTK activation and intracellular signaling processes. AMC303 is a highly selective inhibitor of CD44v6 with strong in vivo and in vitro anti-tumor activity.

Methods

This is a Phase I/Ib open label, non-randomized, multi-center study for patients with resistant advanced cancer (NCT03009214) with dose escalation based on a 3 + 3 design for all-comers (Part 1) and tumor type specific expansion cohorts at the Recommended Phase 2 Dose (RP2D) (Part 2). AMC303 was given IV, 0.1-20 mg/kg, in 30-60min. Tumor assessment (RECIST1.1) was performed every 6 weeks. A comprehensive biomarker program with paired tumor biopsies and plasma samples was established.

Results

26 patients with a total of 11 different cancer types were treated in 6 dose levels with colorectal cancer as most frequent type. AMC303 infusions were very well tolerated, most drug-related AEs were grade 1 and 2 (in 46% of patients). No related SAEs were reported. Most frequently reported related events were infusion related reactions and hypersensitivity (grade 1-2, in 22% of patients), followed by nausea, diarrhoe and fatigue. MTD was not achieved. PK analysis revealed a linear dose-exposure relationship, t1/2 of 4-7h, CL of 40-60 mL/h/kg. 81% of patients received at least 6 weeks of therapy. No objective responses were observed in this unselected patient population during the dose escalation phase. More than 70% of tumors were CD44v6 positive by IHC, and 50% exhibited strong to moderate expression with no change after 3 weeks. Biomarker analyses by IHC (Ki67, S6, c-Met, Akt, MAPK), protein profiling of tumor lysates and plasma revealed up- and down-regulation of several biomarkers at 3 weeks. The optimal biological dose was established as 10 mg/kg based on PK/PD data.

Conclusions

AMC303 was demonstrated to be well-tolerated with a favorable PK profile. Part 2 is designed to test anti-tumor activity, including patients with high expression of CD44v6 in specific tumor types.

Clinical trial identification

NCT03009214.

Legal entity responsible for the study

Amcure GmbH.

Funding

Amcure GmbH.

Editorial Acknowledgement

Disclosure

P. Ehmer: Employee: Pharmacelsus GmbH. A. Martin, H.K. Bender, K. Dembowsky: Employee: Amcure GmbH. All other authors have declared no conflicts of interest.

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