FDA Lifts Partial Clinical Hold on NEON-2 Trial Evaluating Davoceticept Plus Pembrolizumab in Advanced Malignancies

FDA

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

The FDA removed the hold on the study, originally initiated in June 2021, after review of the Complete Response from Alpine Immune Sciences, Inc., which included a thorough review of the davoceticept safety database, plus a revised investigator brochure and study protocol. As previously disclosed, under the terms of the hold, patients previously enrolled continued to receive the study drug, but no new patients were eligible for enrollment until the partial clinical hold was lifted.

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

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.

NEON-2 is an open-label, cohort-based, dose-escalation and -expansion study.³

The study will enroll approximately 323 patients between the ages of 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 that is eligible for treatment with a PD-1/PD-L1 inhibitor; or that is refractory or resistant to standard therapy; or for which standard or curative therapy is not available.

Eligible patients must also have received at least 2 prior systemic anticancer therapies (lymphoma subjects only); protocol-defined measurable disease; 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 (except alopecia, hearing loss, grade ≤ 2 neuropathy, or endocrinopathy managed with replacement therapy); and adequate baseline hematologic, renal, and hepatic function.

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

The trial’s estimated primary completion date is August 2024.

References

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 24, 2022. https://bwnews.pr/3GjfQiX
2. 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 May 24, 2022. https://bit.ly/3HV7j59
3. ALPN-202 with PD-1 inhibition in advanced malignancies (NEON-2). ClinicalTrials.gov. Updated March 11, 2022. Accessed May 24, 2022. https://clinicaltrials.gov/ct2/show/NCT04920383