Top-line results from a phase I open-label, dose escalation monotherapy trial of KTN3379 (Kolltan Pharmaceuticals, Inc), a human monoclonal antibody that blocks the activity of ErbB3 in adult patients with advanced solid tumors, shows that the drug was well tolerated by the advanced cancer patients in the trial. No dose limiting toxicities were observed.
ErbB3 is a member of the epidermal growth factor receptor, or EGFR, family and believed to be an important receptor regulating cancer cell growth and survival. ErbB3 is expressed in many cancers including head and neck, breast, colorectal, lung, gastric, ovarian and melanoma. While there are several successful currently marketed products targeting two members of the EGFR family, there are none that directly target ErbB3.
Part I of the trial with KTN3379 was designed to evaluate the pharmacokinetic profile and safety of KTN3379 over several doses with the objective of defining a Phase II dose in patients with advanced malignancies.
In this dose escalation portion of the Phase I clinical trial, researchers identified a recommended Phase
II clinical trial dose and observed a linear and dose proportional pharmacokinetic (PK) profile. At some of the doses evaluated, KTN3379 blood levels exceeded the target exposure determined from experiments assessing antitumor activity in preclinical models.
In the part II of the clinical trial, the researchers evaluated the pharmacokinetic profile of KTN3379 in combination with other targeted agents to obtain preliminary evidence of antitumor activity in specific types of cancer. During this trial, patients continued to receive KTN3379 alone or in combination until disease progression or toxicity that necessitates discontinuation
All doses tested resulted in modulation of soluble ErbB3, a biomarker circulating in the patients’ blood. A maximum tolerated dose was not reached in this trial.
Three serious adverse events were experienced by patients, two of which were judged by the trial investigator to be related to the underlying cancer and one of which, severe diarrhea, was judged by the trial investigator to be related to KTN3379.
In late 2014, Kolltan plans to expand into the Phase Ib portion of the clinical trial of KTN3379 in combination with selected currently approved cancer drugs to evaluate KTN3379 in a variety of types of solid tumors.
The data from the dose escalation portion of the Phase 1 clinical trial have been selected for an oral presentation at the upcoming 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics being held in Barcelona, Spain, November 18-21, 2014. The oral presentation will describe results from the dose escalation portion of the Phase 1 clinical trial program that focused on PK, biomarkers and safety.
Additionally, the researchers, in collaboration with the laboratory of Joseph Schlessinger, Ph.D., Chair of the Department of Pharmacology, Director of the Cancer Biology Institute at Yale University and Kolltan Co-Founder, will present a KTN3379 preclinical poster at the same meeting. The poster depicts the elucidation of the x-ray crystal structure of KTN3379 bound to the extracellular domain of ErbB3, which revealed a unique binding site preventing ErbB3 activation that is dependent on ErbB3’s ligand, as well as ligand-independent activation. The novel binding of this antibody with ErbB3 and its dual mechanism of action suggest that KTN3379 has the potential to completely inactivate ErbB3 and potentially is applicable as a therapy for all tumor types in which ErbB3 plays a role.
“The identification of a Phase II dose for KTN3379 is an important step in advancing the clinical evaluation in several tumor types and different combinations with targeted therapies,” noted Jerry McMahon, PhD., President and Chief Executive Officer of Kolltan Pharmaceuticals.