Investigational Drug
Peposertib
TrialFetch AI Analysis
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Overview
Peposertib (M3814; also called nedisertib or MSC2490484A) is an investigational oral cancer drug. Human results come mainly from small, early-phase studies, often combining it with radiation or other treatments. These studies have not established that adding peposertib improves outcomes. (pmc.ncbi.nlm.nih.gov)
Mechanism of action
Peposertib inhibits DNA-dependent protein kinase (DNA-PK), which helps repair DNA double-strand breaks. Blocking that repair may make tumors more sensitive to radiation and DNA-damaging drugs. (pubmed.ncbi.nlm.nih.gov)
Efficacy
- Alone: In a phase 1 study of 31 people with advanced solid tumors, there were no complete or partial responses. Twelve people (39%) had stable disease, including seven whose disease remained stable for at least 12 weeks. (pmc.ncbi.nlm.nih.gov)
- With other treatments: A study combining peposertib with avelumab, with or without radiation, found no objective responses in its two main dose-escalation groups. In a rectal-cancer study combining it with chemoradiation, 1 of 19 patients (5.3%) met the study’s combined clinical/pathologic complete-response endpoint; the investigators concluded that response rates did not improve at tolerable doses. (pmc.ncbi.nlm.nih.gov)
- A 2026 conference abstract reported partial responses in 5 of 24 evaluable patients (20.8%) given peposertib with lutetium-177 DOTATATE for neuroendocrine tumors. Without a comparison group, that result cannot establish peposertib’s contribution. (aacrjournals.org)
Safety
Nausea, vomiting and fatigue were common peposertib-related effects in the monotherapy study; seven of 31 patients (23%) had grade 3 peposertib-related adverse events. Combination treatment can be harder to tolerate: in the rectal-cancer study, dose-limiting toxicities occurred in 3 of 6 evaluable patients at the highest dose. A later analysis of six patients from that study found severe late rectal toxicity in three, all of whom had entered watch-and-wait surveillance. These small studies cannot reliably define the frequency of uncommon harms. (pmc.ncbi.nlm.nih.gov)
Further reading
- First-in-human monotherapy study
- Rectal-cancer combination study
- 2026 neuroendocrine-tumor conference abstract
Last updated: Sep 2026
Active trials using Peposertib
Found 3 active trials using this drug:
TrialFetch AI summary: Adults with previously treated metastatic or unresectable leiomyosarcoma or selected other soft tissue sarcomas receive oral peposertib plus low-dose intravenous pegylated liposomal doxorubicin; the expansion cohort is limited to measurable leiomyosarcoma. Peposertib inhibits DNA-dependent protein kinase, potentially impairing repair of doxorubicin-induced DNA damage.
ClinicalTrials.gov ID: NCT05711615
TrialFetch AI summary: For adults with nonmetastatic, locally advanced pancreatic adenocarcinoma after 4–6 months of induction chemotherapy, this study evaluates five-fraction hypofractionated radiotherapy with oral peposertib or placebo. Peposertib inhibits DNA-dependent protein kinase to impair repair of radiation-induced DNA damage.
ClinicalTrials.gov ID: NCT04172532
TrialFetch AI summary: Adults with progressive, bone-predominant mCRPC after an androgen-receptor pathway agent or taxane, and no visible visceral metastases, receive radium-223 alone or with peposertib, with or without avelumab. Peposertib is an investigational DNA-dependent protein kinase inhibitor intended to impair DNA repair; avelumab blocks PD-L1.
ClinicalTrials.gov ID: NCT04071236
