FDA Grants Fast Track Designation to CMG901 in Relapsed/Refractory Metastatic Gastric/GEJ Cancer

US FDA

The FDA has granted a fast track designation to the antibody-drug conjugate (ADC) CMG901 as a single-agent treatment for patients with unresectable or metastatic gastric and gastroesophageal junction (GEJ) cancer that is relapsed or refractory to approved therapies.¹

CMG901 is the first Claudin 18.2 ADC to receive an investigational new drug approval in the United States and China. The agent is comprised of a monoclonal antibody targeting Claudin 18.2, a cleavable linker, and a potent cytotoxic payload of monomethyl auristatin E.

The agent binds to Claudin 18.2–positive cells through its monoclonal antibody. Once bound, the agent is internalized in the lysosome through tumor cells. The cytotoxic payload is released, resulting in cell cycle arrest and apoptosis of cancer cells. The agent has been found to stimulate cellular and soluble immune effectors that stimulate antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity to eliminate the Claudin 18.2–positive cells.

Preclinical data have indicated that the agent can eliminate gastric cancer cells with better potency than zolbetuximab analog or the unconjugated antibody of CMG901; the agent was also found to have acceptable tolerability. The fast track designation was based on findings from phase 1 studies that evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the agent.

“The ongoing phase 1 trial of CMG901 demonstrated promising antitumor activity in [patients with] advanced gastric and GEJ adenocarcinoma,” Joy Yan, MD, PhD, chief medical officer of Keymed Biosciences, stated in a press release.

The safety and preliminary efficacy of CMG901 is currently under exploration in patients with advanced solid tumors, including gastric cancer, GEJ adenocarcinoma, and pancreatic cancer, as part of a phase 1 trial (NCT04805307).² In April 2022, the FDA granted CMG901 an orphan drug designation based on early data from this study.³

The open-label, multicenter phase 1 trial is comprised of 2 parts. In part A, which is the dose-escalation portion of the trial, investigators sought to determine the maximum tolerated dose (MTD) of CMG901 in patients with relapsed/refractory advanced solid tumors who do not have standard therapy available to them. In part B, or the dose-expansion portion of the trial, the preliminary antitumor activity and safety of CMG901 was evaluated in patients with Claudin 18.2–positive gastric cancer, GEJ cancer, and pancreatic cancer who are relapsed or refractory to approved treatments.

In part A, CMG901 was administered once every 3 weeks, with dose escalation carried out according to a modified 3+3 design. Accelerated dose titration was used for the first 2 dose levels of 0.3 mg/kg and 0.6 mg/kg. Then, traditional 3+3 dose escalation will be used for the following doses: 1.2 mg/kg, 1.8 mg/kg, 2.2 mg/kg, 2.6 mg/kg, and 3.0 mg/kg. Patients received intravenous (IV) CMG901 on day 1 of every 21-day cycle.

In part B, patients were administered intravenous CMG901 on day 1 of every 21-day cycle, based on the MTD that is determined in part A of the research. Patients continued study treatment in both parts until evidence of disease progression per investigator assessment, unacceptable toxicity, or other reasons for discontinuation.

The primary end points for part A of the trial include the number of participants who experience dose-limiting toxicities (DLTs) up to 21 days after the first dose of CMG901, as well as the incidence, severity, and outcome of treatment-emergent adverse effects (TEAEs). The primary objectives of part B include measuring objective response rate per RECIST v1.1 criteria and establishing the recommended phase 2 dose of the agent.

Secondary end points in both parts of the trial include area under the curve (AUC) to the last quantifiable concentration up to 21 days after the first dose of the investigative agent, and AUC for multiple doses. Other secondary objectives include disease control rate, duration of response, progression-free survival, Claudin 18.2 expression (part A only), ORR (part A only), and overall survival, as well as incidence, severity, and outcome of TEAEs (part B only).

“We look forward to working closely with the FDA to finish the design of the global pivotal trial in Claudin 18.2–positive advanced gastric and GEJ adenocarcinoma,” Yan added.

References

1. FDA granted CMG901 fast track designation for unresectable or metastatic gastric and gastroesophageal junction cancer which have relapsed and/or are refractory to approved therapies. News release. Keymed Biosciences. April 19, 2022. Accessed April 21, 2022. https://prn.to/3jXET0G
2. Safety, tolerability, pharmacokinetics, and preliminary efficacy, phase 1 study of CMG901. ClinicalTrials.gov. Updated December 9, 2021. Accessed April 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04805307?term=CMG901&draw=2&rank=1
3. CMG901 for the treatment of gastric cancer and gastroesophageal junction adenocarcinoma was granted the orphan-drug designation by the Food and Drug Administration of the United States. News release. Keymed Biosciences. April 12, 2022. Accessed April 21, 2022. https://prn.to/3vGqR9o