FDA Grants Orphan Drug Designation to Osemitamab for Pancreatic Cancer

The FDA has granted an orphan drug designation (ODD) to osemitamab (TST001) for the treatment of patients with pancreatic cancer, marking the second ODD for the agent following its initial designation in 2021 for use in those with gastric and gastroesophageal junction (GEJ) cancer.¹

Osemitamab is a high affinity humanized anti-Claudin18.2 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

Osemitamab is the second most advanced CLDN18.2-targeting antibody being developed globally. The agent, which is developed using Immune Tolerance Breaking Technology (IMTB) from Transcenta Holding Limited, kills CLDN18.2-expressing tumor cells through ADCC and CDC.

“Osemitamab (TST001) is currently being evaluated for the treatment of different Claudin18.2–positive indications,” Caroline Germa, MD, executive vice president, Global Medicine Development and chief medical officer of Transcenta, stated in a press release. “We believe it also has the potential to be transformative for advanced pancreatic adenocarcinoma who lack effective therapeutic options. We look forward to progressing our program in this indication.”

Previously, osemitamab has shown robust antitumor activity in preclinical models of Claudin18.2-expressing pancreatic cancer regardless of KRAS mutation status. Moreover, manufacturing with advanced bioprocessing technology led to reduced fucose content, resulting in enhanced natural killer cell–mediated ADCC with osemitamab.

Early efficacy data with the agent, which were presented at the 2022 International Gastric Cancer Congress, demonstrated a sustained partial response in a patient with Claudin18.2-low pancreatic cancer who progressed on several cycles of chemotherapy.

The agent is currently being evaluated in phase 1/2 trials in the United States (NCT04396821) and China (NCT04495296/CTR20201281).^2,3 Both trials will investigate the safety and preliminary efficacy of osemitamab in patients with advanced or metastatic solid tumors.

In the first trial, which has two parts, the agent will be tested as a single agent and in combination with nivolumab (Opdivo) or standard therapy. Part A, the dose-finding portion, will include 2 cohorts, in which osemitamab will be dosed every 2 or 3 weeks in a standard 3 + 3 design. Between 18 and 36 patients are planned to enroll in this portion.

Part B, the dose-escalation portion, will include 3 cohorts. Cohort A will enroll patients with previously untreated, unresectable, locally advanced or metastatic gastric/GEJ adenocarcinoma. Eligible patients will receive 2 mg/kg or 4 mg/kg of osemitamab every 2 weeks plus nivolumab and modified FOLFOX6. The first 6 patients at each dose level will not be selected based on CLDN18.2 tumor expression. A total of 12 to 42 patients will be enrolled in cohort A.

Cohort B will include patients with gastric/GEJ adenocarcinoma and radiologic progression following 1 or 2 prior lines of systemic therapy. Eligible patients will receive osemitamab in combination with nivolumab. Similarly, the first 3 to 6 patients of the safety run-in will not be selected based on CLDN18.2 expression. Patients with CLDN18.2 expression in tumor tissue tested by the central laboratory will be enrolled in the expansion phase of the trial. The safety run-in phase will follow a 3 + 3 design with osemitamab explored at 3 mg/kg and 6 mg/kg every 3 weeks plus nivolumab. Approximately 30 patients will be enrolled in cohort B, including the patients in the safety run-in phase.

In cohort C, patients with previously untreated, unresectable, locally advanced or metastatic histologically confirmed pancreatic adenocarcinoma will receive 2 mg/kg or 4 mg/kg of osemitamab every 2 weeks plus gemcitabine and albumin-bound paclitaxel. The first 6 patients at each dose level for the lead-in phase will not be enriched for CLDN18.2 expression. Between 12 and 42 patients will be enrolled in this cohort.

The second trial also consists of 2 parts, each including a dose-escalation and dose-expansion phase examining osemitamab monotherapy and osemitamab in combination with oxaliplatin and capecitabine; paclitaxel; gemcitabine and cisplatin; oxaliplatin, capecitabine, and nivolumab; and nivolumab. In dose-escalation, patients will be treated in a 3 + 3 design with once every 2-week or 3-week dosing.

After the maximum tolerated dose/recommended phase 2 dose is reached, three cohorts, including patients with gastric/GEJ and biliary tract cancer, may be included in the expansion plan. Here, between 60 and 120 patients with CLDN18.2 positivity will receive treatment. A total of 320 to 540 patients will be treated in total.

Preliminary data presented at the 2022 ESMO Congress showed that at a median follow-up of 65 days, the addition of osemitamab to capecitabine and oxaliplatin led to a partial response (PR) rate of 73.3% (n = 11) and a disease control rate of 100% (n = 15) per RECIST v1.1 criteria when administered as frontline therapy in patients with locally advanced or metastatic gastric/GEJ cancer.⁴

As of August 4, 2022, 51 patients had been enrolled and dosed, including 36 patients who received osemitamab plus CAPOX at 6 mg/kg every 3 weeks in the expansion phase. Notably, 6 of the 8 patients with medium or high Claudin18.2 expression, and 5 of the 5 patients with unknown Claudin18.2 expression, achieved PR.

Regarding safety, most treatment-emergent adverse effects were grade 1/2, and they included nausea, hypoalbuminemia, anemia, vomiting, and decreased platelet counts. Twelve (23.5%) patients experienced dose delay and five (9.8%) required dose reduction, but no patients needed to discontinue treatment due to treatment-related adverse effects.

References

1. Transcenta’s osemitamab (TST001) targeting Claudin18.2 granted orphan drug designation for treatment of pancreatic cancer. News release. Transcenta Holding Limited. March 29, 2023. Accessed April 10, 2023. https://www.transcenta.com/newsDet/id-121
2. A trial to evaluate safety and tolerability of TST001 in advanced or metastatic solid tumors. ClinicalTrials.gov. Updated January 20, 2023. Accessed April 10, 2023. https://clinicaltrials.gov/ct2/show/NCT04396821
3. A trial to evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of TST001 in advanced or metastatic solid tumors. Updated March 30, 2023. Accessed April 10, 2023. https://www.clinicaltrials.gov/ct2/show/NCT04495296
4. Transcenta releases encouraging interim safety and efficacy data of the TST001 (osemitamab) and chemotherapy combination expansion cohort for first line Claudin18.2 positive gastric cancer at ESMO Congress 2022. News release. BioSpace. September 13, 2022. Accessed April 10, 2023. https://www.transcenta.com/newsDet/id-97