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


The FDA has lifted the partial clinical hold on the phase 1 NEON-2 trial of davoceticept plus pembrolizumab in adult patients with advanced solid tumors or lymphoma.

The FDA has removed the partial clinical hold on the phase 1 NEON-2 trial (NCT04920383) investigating the use of the first-in-class conditional CD28 costimulator and dual checkpoint inhibitor, davoceticept (ALPN-202) in combination with pembrolizumab (Keytruda) in adult patients with advanced solid tumors or lymphoma, according to Alpine Immune Sciences, Inc.1

The hold on the study, which was originally initiated in June 2021, was lifted after review of the complete response from the company. This review consisted of an in depth review of the safety database of davoceticept, in addition to a revised investigator brochure and study protocol.

Patients who were previously enrolled in the trial continued to receive the study drug, but no new patients were eligible for enrollment until the partial clinical hold was lifted, as previously disclosed under the terms of the hold.

In March 2022, the partial clinical hold was placed on the trial after the report of a grade 5 serious adverse effect (AE) that occurred in a patient with choroidal melanoma in the trial. This patient had received prior treatment with nivolumab (Opdivo) and ipilimumab (Yervoy), and received a single dose of each agent in the NEON-2 trial. According to the treating physician assessment, the fatality of the patient was attributed to cardiogenic shock which was possibly associated with immune-mediated myocarditis or potential infection.

The ongoing phase 1 NEON-1 study (NCT04186637), a monotherapy dose-escalation and -expansion trial in patients with advanced malignancies, which has completed dose escalation and is currently enrolling its expansion cohorts, was not included in the hold.

Prior preclinical studies of davoceticept have shown superior efficacy in tumor models compared with checkpoint inhibition alone.

The open-label, cohort-based, dose-escalation and -expansion phase 1 NEON-2 trial, will enroll approximately 323 patients aged between 18 and 80 years with pathologically confirmed, locally advanced or metastatic unresectable solid tumor, or Hodgkin or non-Hodgkin lymphoma, including transformed lymphoma, of an acceptable histology.

Further, patients must either have a diagnosis that is eligible for treatment with a PD-1/PD-L1 inhibitor, that is refractory or resistant to standard therapy, or for which standard or curative therapy is not available.

Other enrollment criteria includes that patients with lymphoma must have received at least 2 prior systemic anticancer therapies, and all patients must have protocol-defined measurable disease, have an available tumor biopsy representative of current disease, an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, recovery to grade 1 or lower non-laboratory toxicity resulting from prior anticancer therapy prior to the first dose of ALPN-202, and adequate baseline hematologic, renal, and hepatic function.

Prior to the studies halt, patients who met all of the criteria were actively being recruited at sites throughout Massachusetts, Michigan, Tennessee, and Texas.

The primary end point of the trial is to measure the type, incidence, and severity of AEs as assessed by the Common Terminology Criteria for Adverse Events, with the secondary end point consisting of objective response as assessed by RECIST v1.1 criteria for solid tumors, or Lugano classification for lymphoma.

The estimated primary completion date for the trial is August 2024.

  1. Alpine Immune Sciences announces FDA removes partial clinical hold on NEON-2 clinical trial of davoceticept (ALPN-202) in combination with pembrolizumab. News release. Alpine Immune Sciences, Inc.; May 24, 2022. Accessed May 26, 2022. https://yhoo.it/3PIu69o
  2. ALPN-202 with PD-1 inhibition in advanced malignancies (NEON-2). ClinicalTrials.gov. Updated March 11, 2022. Accessed May 26, 2022. https://clinicaltrials.gov/ct2/show/NCT04920383

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