FDA Places Partial Clinical Hold on NEON-2 Trial Evaluating Davoceticept/Pembrolizumab in Advanced Cancers

The FDA has placed a partial clinical hold on the phase 1 NEON-2 trial (NCT04920383) examining the combination of davoceticept (ALPN-202) and pembrolizumab (Keytruda) in patients with advanced solid tumors or lymphoma.¹

The decision follows a report of a grade 5 serious adverse effect that occurred on the trial. The patient who died had choroidal melanoma and had received prior treatment with the immunotherapy agents nivolumab (Opdivo) and ipilimumab (Yervoy). This patient was administered a single dose of each agent on NEON-2. Their death was attributed to cardiogenic shock, which was thought to be associated with immune-mediated myocarditis or potential infection per treating physician assessment.

“Patient safety remains, as always, our top priority,” Mitchell H. Gold, executive chairman and chief executive officer of Alpine Immune Sciences, Inc., stated in a press release. “We appreciate the dialogue with FDA and look forward to working diligently with FDA, Merck, the study Safety Monitoring Committee, and the study investigators to further understand this unfortunate event. Given the strong scientific rationale for the combination of davoceticept and pembrolizumab to benefit treatment-refractory patients, we are hopeful that the study will soon be resumed after appropriate safety review, and with appropriate safety precautions in place.”

The first-in-class conditional CD28 costimulator and dual checkpoint inhibitor, davoceticept, has been shown to have superior efficacy vs checkpoint inhibition alone when examined in tumor models.

In nonclinical studies, the agent was found to be well tolerated in rats and cynomolgus monkeys, with a maximum tolerated dose not reached.² When given at all dose levels up to 160 mg/kg in rats or 200 mg/kg in monkeys, investigators did not observe any evidence of cytokine release syndrome or systemic agonism. Moreover, when used in cynomolgus monkeys, the agent was not found to result in significant colitis or immune-related toxicities that have been reported with dual checkpoint blockade.

NEON-2 enrolled patients with pathologically confirmed, locally advanced or metastatic unresectable solid tumors, or Hodgkin or non-Hodgkin lymphoma of an acceptable histology, who were eligible to receive a PD-1/PD-L1 inhibitor, had disease that was refractory or resistant to standard treatment, or who does not have standard or curative therapy available to them.³

Patients needed to be between 18 years and 80 years at the time of screening, they must have received at least 2 prior systemic anticancer therapies, they had to have measurable disease, an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and acceptable hematologic, renal, and hepatic function at baseline.

Patients could not have a history of a grade 3 or higher immune-related toxicity, nor could they have active or prior pneumonitis or interstitial lung disease. Other exclusion criteria included having active central nervous system metastases, previously having undergone an organ allograft or allogeneic hematopoietic stem cell transplantation, having received select protocol-restricted therapy, or having any active, known, or suspected autoimmune disease, among others.

NEON-2 has an estimated enrollment of 323 participants; the trial began dosing patients in June 2021. The primary outcome measure for the research is to evaluate the type, incidence, and severity of adverse effects (AEs) experienced with the regimen, and a secondary outcome measure is to determine best observed objective responses as assessed by RECIST criteria for solid tumors, or Lugano criteria for lymphoma.

The ongoing, open-label, dose-escalation and -expansion phase 1 NEON-1 trial (NCT04186637) is evaluating davoceticept at several dose levels and regimens in adult patients with advanced solid tumors or lymphoma, who are refractory or resistant to standard treatment, including checkpoint inhibitors.

To be eligible for participation, patients needed to have measurable disease, an ECOG performance status of 0 to 2, and acceptable hematologic, renal, and hepatic function.²

In part A of the trial, which utilizes a 3+3 design, intravenous davoceticept is being evaluated at starting doses of 1 µg/kg (n = 1) and 10 µg/kg (n = 1) given once weekly. The agent will also be evaluated at 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10.0 mg/kg, and 20.0 mg/kg given once weekly (n = 3 to approximately 6). Lastly, the drug will be evaluated at 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10.0 mg/kg, and 20 mg/kg given every 3 weeks (n = 3 to approximately 6).

Part B of the trial is comprised of expansion cohorts (n = 15/cohort), which will evaluate the use of davoceticept in specific PD-1–refractory indications and/or populations, and potentially biomarker-selected populations.

The end points of this trial include safety, specifically dose-limiting toxicities, AEs, immunogenicity, and cytokines; efficacy, in the form of objective response rate, duration of response, disease control rate, progression-free survival, and overall survival; and pharmacokinetics and pharmacodynamics, specifically target saturation, immunophenotyping, and ex-vivo costimulatory capacity analysis.

Completion of the dose-escalation and initiation of the expansion cohorts is anticipated in the first half of 2022, according to Alpine Immune Sciences, Inc.

References

• Alpine Immune Sciences reports FDA partial clinical hold on NEON-2 trial of davoceticept (ALPN-202) in combination with pembrolizumab. News release. Alpine Immune Sciences, Inc.; March 7, 2022. Accessed March 8, 2022. https://bit.ly/3HV7j59
• Yang J, Means G, Tercero A, et al. NEON-1: a first-in-human phase I open-label study of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies. Presented at: 2020 AACR Virtual Annual Meeting; April 24-29, 2020; virtual. Abstract #9972. https://bit.ly/34odyR5
• ALPN-202 with PD-1 inhibition in advanced malignancies (NEON-2). ClinicalTrials.gov. Updated November 9, 2021. Accessed March 8, 2022. https://clinicaltrials.gov/ct2/show/NCT04920383