FDA Places Partial Clinical Hold on Phase 1 Trial of Davoceticept/Pembrolizumab in Advanced Malignancies


A phase 1 study of davoceticept and pembrolizumab for advanced malignancies received a partial clinical hold from the FDA following a patient death.

The FDA placed a partial clinical hold on the phase 1 NEON-2 study (NCT04920383) assessing the use of davoceticept (ALPN-202) plus pembrolizumab (Keytruda) in adult patients with advanced malignancies, according to a press release from Alpine Immune Sciences.1

The hold was implemented following a grade 5 adverse effect (AE) in 1 patient who had choroidal melanoma and previously underwent treatment with nivolumab (Opdivo) and ipilimumab (Yervoy). The patient received 1 dose of davoceticept and pembrolizumab each. The death is thought to be due to cardiogenic shock likely related to immune-mediated myocarditis or potential infection, according to the treating physicians.

“Patient safety remains, as always, our top priority,” Mitchell H. Gold, executive chairman and chief executive officer at Alpine, said 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.”

Patients who have already enrolled on the NEON-2 trial can continue undergoing treatment, but no additional patients can enroll until the partial clinical hold is lifted. Notably, the hold will not impact the phase 1 NEON-1 trial (NCT04186637) assessing single-agent davoceticept in patients with advanced cancer.

Davoceticept is a CD28 costimulator and dual checkpoint inhibitor. As PD-1/PD-L1 inhibitors can fail to yield anti-tumor activation without proper T-cell activation, davoceticept can mediate PD-L1–dependent CD28 costimulation plus PD-L1 and CTLA-4 inhibition.2

The agent appeared well-tolerated in rats and cynomolgus monkeys, with the monotherapy appearing superior to PD-L1 alone. Investigators did not observe evidence of cytokine release syndrome or systemic agonism across all dose levels up to 150 mg/kg in rats or 200 mg/kg in monkeys. Clinically significant colitis or immune-related AEs did not occur.

The trial enrolled adult patients with solid tumors and lymphoma. Patients had to be refractory or resistant to standard therapies including checkpoint inhibitors, and have measurable disease. An ECOG performance status of 0 to 2 and adequate hematological, renal, and hepatic function were also required. A 3+3 dose escalation design was used in part A of the study, with doses including 1 µ/kg to 10 µ/kg, 0.1 µ/kg to 10 µ/kg, and 0.2 µ/kg to 20 µ/kg. The expansion cohort, which included 15 patients, included patients who were PD-1 refractory and biomarker selected where applicable.

The study's end points included safety, overall response rate, duration of response, disease control rate, progression-free survival, and overall survival.


  1. 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. March 7, 2022. Accessed March 9, 2022. https://bwnews.pr/3Mw7SWq
  2. 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/3pR6unH
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