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First-in-human trial exploring safety, antitumor activity, and pharmacokinetics of Sym013, a recombinant pan-HER antibody mixture, in advanced epithelial malignancies

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Summary

Purpose. Sym013 contains six humanized monoclonal antibodies that bind to non-overlapping epitopes on three human epidermal growth factor receptors (HER1-3). Preclinical studies suggested Sym013 strongly suppresses growth of multiple epithelial tumors. This is a first-in-human study exploring safety and efficacy of Sym013 in patients with advanced epithelial malignancies. Methods. Dose escalation used single-patient cohorts until the stopping rule was met, followed by 3 + 3 design. Dose levels planned were: 1, 2, 4, 6, 9, 12, 15, and 18 mg/kg. Treatment cycles were 28 days with imaging every eight weeks. Serum samples were collected at multiple time points for assessment of pharmacokinetics and development of anti-drug antibodies. Results. Thirty-two patients were enrolled with multiple solid tumors, most common being colorectal cancer (CRC; 10/32, 31%). Due to mucositis, rash, and diarrhea at 4 mg/kg once-weekly, dosing was changed to biweekly (Q2W). Mandatory prophylaxis was added due to Grade 3 infusion-related reaction and oral mucositis at 9 mg/kg Q2W. The 15 mg/kg Q2W cohort was enrolling when the study was terminated for business reasons. Most common adverse events were skin (81%) and gastrointestinal (75%) disorders, including dermatitis/rash, stomatitis, and diarrhea. One patient with CRC achieved a partial response; 12 patients with varied malignancies had stable disease. Conclusion. During the conduct of the study, management of frequent infusion-related reactions, skin toxicities, and mucosal disorders, which are indicative of HER inhibition, necessitated multiple protocol amendments. The investigators, in concert with the Sponsor, agreed that achieving a tolerated regimen with acceptable target saturation was unlikely.

Trial registry: www.clinicaltrials.gov; NCT02906670 (September 20, 2016).

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Data availability

The datasets generated during the current study are available in the Clinicaltrials.gov repository, https://clinicaltrials.gov/ct2/show/results/NCT02906670?term=sym013-01&draw=2&rank=1

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Acknowledgements

The authors would like to thank the patients and their families for participating in this study. The authors would also like to thank the nurses and support staff at the participating study centers for their care of the patients and their dedicated attention to the conduct of this trial. In addition, special thanks to Rikke Hald and Andreas Rassov who developed the specific multiplex PK-assay to detect the six different mAbs in one sample.

Funding

This work was supported by Symphogen.

Author information

Authors and Affiliations

  1. Division of Hematology & Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    Jordan Berlin & Jennifer G. Whisenant

  2. Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, TN, 777 PRB 37232, Nashville, USA

    Jordan Berlin

  3. NEXT Oncology, San Antonio, TX, USA

    Anthony W. Tolcher

  4. Tessa Therapeutics, Singapore

    Cliff Ding & Ivan D. Horak

  5. Symphogen A/S, Ballerup, Denmark

    Debra L. Wood, Paul I. Nadler, Ulla Holm Hansen, Johan Lantto & Niels Jørgen Ø. Skartved

  6. Vaccibody, Norway

    Mikkel W. Pedersen

  7. START San Antonio, San Antonio, TX, USA

    Amita Patnaik

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  1. Jordan Berlin
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Contributions

Study conception and design were performed by Jordan Berlin, Ivan D. Horak, Cliff Ding, Johan Lantto, Niels Jørgen Ø. Skartved, Debra Wood, Paul I. Nadler, and Mikkel W. Pederson. Clinical study, including patient consent and data collection, was performed by Jordan Berlin, Anthony W. Tolcher, and Amita Patnaik. Clinical trial management was coordinated by Ulla Holm Hansen, Debra L. Wood, and Paul I. Nadler. Data review and analysis was performed by Cliff Ding, Debra L. Wood, and Ulla Holm Hansen. The first draft of the manuscript was written by Jennifer G. Whisenant and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jordan Berlin.

Ethics declarations

Ethics approval

All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments. The Institutional Review Boards at each participating center reviewed and approved the study protocol.

Informed consent

Written informed consent was obtained from all individual participants included in the study.

Consent to participate

Written informed consent was obtained from all individual participants included in the study.

Consent to publish

Not applicable.

Research involving Human Participants

All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments. The Institutional Review Boards at each participating center reviewed and approved the study protocol.

Conflict of interest

JB serves on the advisory board or is a consultant for FivePrime, Clovis, Ipsen, Bayer, Mirati, Puma, and Insmed. AWT serves on the advisory board for ADAGENE, Inc, ARO BIOTHERAPEUTICS, BIOINVENT, Boeringer Ingelheim International GmbH, Deka Biosciences, Eleven Bio, ELUCIDA, EMD SERONO/ MERCK KGaA, IMMUNOME, NBE THERAPEUTICS, Pelican, Pieris Pharma, PYXIS Oncology, Vincerx, and Zymeworks Biopharmaceuticals, Inc, and is a consultant for ABBVIE, Inc., AGENUS, Inc, ASANA BIOSCIENCES, ASCENTAGE, AxImmune, Bayer, GILDE HEALTHCARE PARTNERS, HBM PARTNERS, Immunomet Therapeutics, Inc., Karma Oncology B.V., Mekanistic Therapeutics, Menarini Ricerche, Mersana, NANOBIOTIX, Partner Therapetucs, Pfizer, PIERRE FABRE, RYVU THERAPEUTICS, Seattle Genetics, SOTIO Biotechnology Co., Spirea Limited Inc., Transcenta Therapeutics Inc., and Trillium Therapetics Inc.; all free for consulting and advisory boards memberships for AWT are paid to his institution of which he is president and co-founder. CD, IDH, and MWP were employees at Symphogen when this study was performed. JGW does not have any relevant disclosures. UHH and NJOS are employees at Symphogen but do not have any financial, economic, intellectual rights or other conflict of interest with the content in this paper. DW is a consultant/contractor for Symphogen A/S, Tessa Therapeutics, Iksuda Therapeutics, and Bristol Myers Squibb. PIN is a consultant/contractor for Symphogen A/S, Tessa Therapeutics, and Iksuda Therapeutics. AP serves as a consultant of advisor for Seattle Genetics, Silverback Therapeutics, Bayer, Daiichi Sankyo, Inc., Novartis, Gilead Sciences, HalioDx, Merck, and Shenzhen IONOVA Life Sciences Co., Ltd. On behalf of their institutions, JB, AWT, and AP received research funding from Symphogen.

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Berlin, J., Tolcher, A.W., Ding, C. et al. First-in-human trial exploring safety, antitumor activity, and pharmacokinetics of Sym013, a recombinant pan-HER antibody mixture, in advanced epithelial malignancies. Invest New Drugs 40, 586–595 (2022). https://doi.org/10.1007/s10637-022-01217-7

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