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. 2022 Jun;40(3):586-595. doi: 10.1007/s10637-022-01217-7. Epub 2022 Feb 3.

Abstract

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).

Keywords: HER1; HER2; HER3; Monoclonal antibody; Novel drug; Solid tumors.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / adverse effects
  • Antineoplastic Agents* / adverse effects
  • Diarrhea / chemically induced
  • Exanthema* / chemically induced
  • Humans
  • Maximum Tolerated Dose
  • Neoplasms* / metabolism
  • Neoplasms, Glandular and Epithelial* / chemically induced
  • Neoplasms, Glandular and Epithelial* / drug therapy

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents

Associated data

  • ClinicalTrials.gov/NCT02906670