Background: MP0274 is a four domain, trispecific, biparatopic, HER2-targeted Designed Ankyrin Repeat Protein (DARPin®) drug candidate. M0274 binds to domains II and IV of HER2 at different sites from trastuzumab and pertuzumab, and to human serum albumin for an extended half-life. MP0274 displays a unique mode of action in preclinical models by directly inducing apoptosis in HER2-addicted cancer cells. Compared to anti-HER2 monoclonal antibodies, preclinical studies revealed no additional safety signals and no maximum tolerated dose was reached.

Trial Design: This is a first-in-human study with 2 parts. The dose escalation part of the study, follows a classical 3+3 dose escalation approach, including one extra cycle for exploration of specific PK characteristics, and will establish the recommended dose (RD) for further development based on safety, pharmacokinetics (PK), and preliminary efficacy. The extension part is designed to confirm safety and further estimate efficacy at the RD in additional patients. MP0274 monotherapy will be administered as infusion over one hour every 3 weeks until disease progression.

Eligibility Criteria: The study population for this first-in-human study is HER2-positive cancer patients who have progressed after standard therapy for advanced disease. Inclusion/exclusion criteria are similar to those in studies with anti-HER2 antibodies.

Specific Aims: The primary objective is to assess safety and tolerability. Secondary objectives are PK, preliminary anti-tumor efficacy (RECIST), and characterization of immunogenicity. Biomarker evaluation include exploratory markers such as PIK3CA, BCL2, p53, PTEN and p21 in both tissue or plasma (ctDNA), investigation of drug induced apoptotic markers as well as additional translational research. This may help get a deeper insight into MP0274's mode of action and into potential resistance mechanisms. MP0274 may have the potential to be active against all HER2-dependent tumors including those that are resistant to trastuzumab and pertuzumab due to incomplete signaling inhibition or inadequate ADCC functionality. MP0274 could be a valid treatment option for HER2 positive cancers.

Statistical Methods: Due to being of non-comparative nature, no inferential statistical analysis will be applied in either the escalation or the expansion part of this study. Results will be listed and summarized by dose regimen using descriptive statistics. An interim evaluation of safety, tolerability and preliminary anti-tumor activity will be performed after 14 patients have been dosed at RD at least once and have completed end of Cycle 4. An interim analysis will be performed once all planned 29 patients have been dosed at RD at least once and completed end of Cycle 7 (pre-Cycle 8) tumor assessment. The final statistical analysis will occur after all patients have discontinued treatment for any reason and completed safety follow-up.

Present Accrual and target accrual: Currently recruitment is planned in UK, Germany, and Switzerland. Target accrual is 36 evaluable patients.

Citation Format: Baird R, Omlin A, Kiemle-Kallee J, Fiedler U, Zitt C, Feurstein D, Herbst J, Dawson K, vom Baur E, Stumpp M, Hermann F, Harstrick A, Schneeweiss A. MP0274-CP101: A phase 1, first-in-human, single-arm, multi-center, open-label, dose escalation study to assess safety, tolerability, and pharmacokinetics of MP0274 in patients with advanced HER2-positive solid tumors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-03-02.