FDA Clears IND of CLN-619 in R/R Multiple Myeloma

• CLN-619 is a monoclonal antibody that represents a new approach to targeting solid tumors and hematologic malignancies by binding to stress-induced ligands MICA and MICB.
• The mechanism of action of CLN-619 involves binding to MICA and MICB. By restoring the expression of these ligands on the tumor cell surface, CLN-619 enhances the interaction between MICA and NKG2D, promoting immune recognition of tumor cells.
• With the investigational new drug application clearance secured, the company plans to initiate a phase 1 dose-escalation and dose-expansion trial to evaluate CLN-619 in patients with relapsed/refractory multiple myeloma.

The FDA granted clearance to the investigational new drug application for CLN-619, a potential first-in-class humanized IgG1 monoclonal antibody, for patients with relapsed/refractory multiple myeloma.¹

CLN-619 works by binding to MICA and MICB, stress-induced ligands. These are expressed on various types of solid tumors and hematologic malignancies. Through restoring the expression of MICA and MICB on the surface of tumor cells, CLN-619 can improve the interaction between MICA and NKG2D. Further, the agent can induce antibody-dependent cellular toxicity, which then helps promote antitumor activity through multiple immune-mediated mechanisms.

“Multiple myeloma remains incurable, and most patients experience sequential relapses. The response to treatment is typically shorter with each relapse, so novel treatments are still needed,” said Jeffrey Jones, MD, MPH, MBA, chief medical officer, Cullinan Oncology, in a press release. “Multiple myeloma is another example of a malignancy where MICA/B shedding from tumor cells allows for immune evasion. As we shared at [Society of Immunotherapy for Cancer] 2023, CLN-619 restores MICA/B expression on tumor cells, enabling immune recognition.”

With this investigational new drug application cleared, the company plans to initiate a phase 1 dose-escalation and dose-expansion trial to evaluate CLN-619 in patients with relapsed/refractory multiple myeloma.

“This phase 1 trial will assess CLN-619 in patients with multiple myeloma, and, given the safety profile shown to date for CLN-619, we believe there is an opportunity to combine the monoclonal antibody with multiple standard therapies,” said Jones in the press release.

Red blood cells: © vipman4 - stock.adobe.com

About an Ongoing Phase 1 Study of CLN-619

In an ongoing phase 1 study (NCT05117476), experts are exploring CLN-619 as a monotherapy, as well as in combination with pembrolizumab (Keytruda), for the treatment of patients aged 18 years and older with solid tumors.²

In the first arm, module A in the dose-escalation portion, patients with advanced solid tumors will be enrolled in dose-escalation cohorts and treated with CLN-619. Following this, the module A cohort expansion arm will extend the investigation to patients with select solid tumor types, where CLN-619 will be administered at a dose selected from the escalation arm. In module B, patients with advanced solid tumors will receive CLN-619 alongside pembrolizumab in the dose-escalation cohorts. Finally, in the module B combination cohort expansion arm, patients with specific tumor types will undergo treatment with CLN-619 and pembrolizumab at doses determined from the escalation phase.

Each of these arms aim to evaluate the safety, efficacy, and potential synergistic effects of CLN-619 both as a monotherapy and in combination with pembrolizumab across diverse patient populations.

The primary end point of the dose-escalation portion of the trial is to investigate the number of treatment-emergent adverse events. For the dose-expansion part of the study, primary end points include best overall response rate (ORR), ORR, duration of response, disease control rate, overall survival, and clinical benefit rate. Secondary end points for all cohorts of the trial will assess pharmacokinetics.

In the module A cohort expansions, patients must have histologically or cytologically confirmed metastatic or locally advanced, unresectable non-small cell lung cancer (NSCLC; expansion A1) or histologically or cytologically confirmed metastatic or locally advanced, unresectable cervical cancer (expansion A2). In the module B expansion cohorts, patients must have histologically or cytologically confirmed metastatic or locally advanced, unresectable NSCLC (expansion B1), histologically or cytologically confirmed metastatic or locally advanced, unresectable head and neck squamous cell carcinoma (expansion B2), and histologically or cytologically confirmed metastatic or locally advanced, unresectable urothelial carcinoma (expansion B3).

All patients must have an ECOG performance status of 0 or 1, an estimated life expectancy of at least 12 weeks, have completed prior palliative radiotherapy at least 14 days prior to dosing on C1D1, and adequate liver and kidney function. Further, any toxicities related to prior treatment should be resolved to grade 1 or less.

“With clinical studies in both solid tumors and hematologic malignancies, we look forward to assessing the full potential of CLN-619 to address multiple areas of unmet clinical need,” added Jones in a press release.¹

REFERENCES:

1. Cullinan Oncology announces U.S. FDA clearance of investigational new drug application for novel MICA/B antibody, CLN-619, for relapsed/refractory multiple myeloma. News release. Cullinan Oncology, Inc. March 1, 2024. Accessed March 5, 2024. https://tinyurl.com/4xjbfkv2

2. A study of CLN-619 alone and in combination with pembrolizumab in advanced solid tumors. ClinicalTrials.gov. Updated December 13, 2023. Accessed March 5, 2024. https://clinicaltrials.gov/study/NCT05117476