(T1330-02-09) Preliminary Phase 1a Clinical Results of Multispecific Antibody TAVO412 in Patients with Hard-to-Treat Solid Tumors

Purpose: TAVO412 is a multispecific anti-EGFR (dual epitopes), anti-cMET, and anti-VEGF antibody engineered with enhanced Fc functions and tumor microenvironment low pH enhanced target binding. This molecule is currently in the clinical development for difficult-to-treat solid tumors. Potential indications include non-small and small cell lung, gastric, pancreatic, triple negative breast, and other solid tumors. TAVO412 demonstrated target mediated drug disposition (TMDD) in the preclinical models. Predicted human PK was used to guide dose escalation in cancer patients. The preliminary PK and efficacy results from the Phase 1 clinical trial confirmed the model prediction and continuously guided safety and PK/PD based dose selection.

Methods: A two-compartment with parallel Michaelis-Menten non-linear clearance population PK model was based on monkey TAVO412 PK data, and allometric scaling was used to predict human PK prior to the clinical study. An open-label, non-randomized Phase 1 clinical study in patients with advanced or metastatic solid tumors who have received standards of care was conducted to evaluate the safety, tolerability, PK/PD, and preliminary efficacy of TAVO412. The study was conducted in 2 parts. The Part 1 study focused on dose escalation with a 3+3 design with the objectives of demonstrating safety, tolerability and PK. TAVO412, from 150 mg escalating to 1500 mg, was administered every two weeks in a 28-day cycle. Serum samples were collected at protocol-specified timepoints for PK, PD markers and anti-drug antibody analyses. Serum TAVO412 concentrations were quantified using a validated and specific ELISA-based assay. Tumor progression was evaluated at Week 8 and every 8 weeks thereafter or based on the investigator’s discretion. The PK, safety, and preliminary signals of efficacy were evaluated to support dose escalation and selection decisions.

Results: The dose escalation reached 1500 mg with no observed DLTs and MTD. TAVO412 showed a reasonable and tolerable safety profile in patients with hepatic, breast, colon, esophageal, and non-small cell cancers. All AEs were controllable. The Safety Review Committee has approved additional dose escalation to 1750 mg. Up to date in 19 evaluable patients who received TAVO412 in Cohorts up to the 1500 mg, 1 confirmed PR, 6 SDs, and 2 PDs were observed with the rest of patients not evaluable or to be evaluated. Preliminary PK results showed that the drug concentrations of TAVO412 in cancer patients followed typical TMDD non-linear PK profiles which were consistent with the prediction based on preclinical data using the population model. A similar non-linear PK model has been built to describe the clinical PK data that is fine-tuned with more incoming clinical data. The model simulation results, with preclinical PK and efficacy data, were used to guide dose escalation and selection for Part 2 of the study. The totality of the safety profiles, PK data, and preliminary efficacy signals of TAVO412 were used to determine the dose selections. More data will be presented at the meeting.

Conclusion: Clinical data of TAVO412 showed a reasonable and tolerable safety profile in patients with advanced or metastatic solid tumors. TAVO412 demonstrated non-linear PK profiles in cancer patients, which were consistent with the prediction based on the preclinical models. The predictability of previously reported non-linear PK mode has been confirmed. A clinical PK model is developed based on the preclinical model and will be used to develop PK/PD correlations.  The PK, safety, and preliminary efficacy data together will guide dose selections in Part 2 of the study.