An Open-label, Phase 1 Study to Determine the Maximum Tolerated Dose of HLX07,in Patients With Advanced Solid Cancers

The role of EGFR in carcinogenesis led to the development and extensive evaluation of EGFR-blocking agents for cancer treatment. Two EGFR-targeted approaches have been explored: (a) small-molecule tyrosine kinase inhibitors targeting the intracellular EGFR tyrosine kinase domain and (b). mAbs targeting the EGFR extra-cellular domain.

Small-molecule tyrosine kinase inhibitors have been widely used in lung cancer with EGFR mutations. However, the results of using small molecule inhibitors for cancer with overexpressed wildtype EGFR have been unsatisfactory.

The best-studied of the anti-EGFR mAbs in cancer is cetuximab (Erbitux®), and panitumumab (Vectibix®). Necitumumab, another humanized anti-EGFR mAb is currently under investigation is multiple cancers. Both cetuximab and panitumumab have been approved in colorectal cancer and head/neck cancer.

Cetuximab is chimeric human-murine IgG1 mAb, and blocks ligand binding to EGFR, thereby diminishing receptor dimerization and autophosphorylation and inducing EGFR downregulation. The immunoglobulin IgG1 isotype of cetuximab may also engage hose immune functions such as antibody-dependent cellular cytotoxicity (ADCC). Cetuximab is approved to be used in combination with chemotherapy and has been shown to improve the survival of patients with advanced colorectal cancer. Cetuximab, when used in combination with radiotherapy has also improved response rate in patients with locally advanced head/neck cancer. However, the use of cetuximab has been associated with rare anaphylactic reactions, which is likely to be related to the specific glycosylation in the molecules and possibly its mouse/human chimeric structure.

Panitumumab is a human IgG2 mAb that targets EGFR. But unlike cetuximab, it mediates its effects through mechanisms other than ADCC, which has a different binding site on EGFR extracellular domain from that of cetuximab, is also approved for colorectal cancer and head/neck cancer. However, the side effects, especially skin reactions, is more pronounced in patients receiving panitumumab, which also limiting its clinical use.

Although cetuximab and panitumumab target EGFR, clinical studies of cetuximab and panitumumab have shown that the levels of EGFR expression in cancer cells do not affect the efficacy of the drug.So far there is unclear why it is so. However, several retrospective studies have shown that the presence of K-ras, and B-raf mutations predicts the poor response to either cetuximab or panitumumab. Likewise, there is no clear answer for such phenomenon. Therefore, in this study, the investigators will examine the expression of EGFR in the cancer cells of enrolled patients, but will not use its expression for enrollment. But, in this study, the investigators will exclude patients whose cancer cells harbor either K-ras, or B-raf mutations, since the investigators in vivo study also demonstrated that HLX07 is not effective in cancer cells with K-ras mutations.

HLX07 is an improved version of anti-EGFR monoclonal antibody. There are several important improvements in the development of HLX07. First, the investigators re-engineered the Fab portion of the antibody to modify the glycosylation pattern of this antibody- to make less immunogenic and have better binding affinity. Second, the investigators produced an antibody using CHO cell system, which lead to cleaner glycosylation profile and better yield. Therefore, the investigators expect that the results can provide a better and more affordable option for patients with advanced cancer.

The investigators in vitro and in vivo animal studies have demonstrated that the anti-cancer effect of HLX07 at the same dose level is either equal or superior to those of cetuximab. In the toxicokinetic studies on monkey, the toxicity profile of HLX07 was better than that of cetuximab. Therefore, the investigators are confident that HLX07 will be a better solution for patients who benefit from anti-EGFR monoclonal antibody therapy.

However, HLX07 has not been tested in human yet. Therefore, the investigators propose this first-in-human phase 1 study. In this study, the investigators intend to investigate the safety, and tolerability of HLX07 in humans, and hope to identify the maximum tolerated dose, and determine the recommended phase 2 dose in future study. At the same time, the investigators would like to gain information of the pharmacokinetics and pharmacodynamics of this drug and its potential immunogenicity.

To minimize the risk of patients who volunteer to receive this experimental drug, the investigators will choose 50 mg flat dose as the initial starting dose. The selection of starting dose is based on the repeat-dose toxicology study on monkey. In the 3-month repeat-dose study, the highest non-severely toxic dose (HNSTD) is weekly 60 mg/kg. The human equivalent dose for this HNSTD is 20 mg/kg. One-sixth of 20 mg/kg in an adult of 70 kilogram is 233 mg. In order to provide sufficient safety factor in the FIH study, the investigators will select 50 mg flat dose as the starting dose in this study.

To investigate the dose required to reach maximal effect, the investigators propose a dose escalation sequence. The purpose of the dose escalation is to obtain the pharmacokinetics and pharmacodynamics of HLX07 at different dose levels, and investigate its relationship with adverse reactions. Also, the investigators intend to identify the MTD and determine the dose required to reach 90% saturation of clearance. The information from the dose escalation is crucial to determine the optimal dose in future studies and potential indications for HLX07.