Peposertib

Shows activity

Also known as:

M3814 MSC2490484A Nedisertib

Cancer types include:

gallbladder cancer pancreas cancer prostate cancer sarcoma

HealthScout AI Analysis

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Overview

Peposertib (M3814; MSC2490484A; nedisertib) is an oral, small-molecule inhibitor of DNA-dependent protein kinase (DNA-PK), developed primarily as a radiosensitizer and chemosensitizer. Early clinical studies as monotherapy and in combination with radiotherapy and/or systemic therapy have shown acceptable tolerability at certain doses but limited antitumor activity to date; several dose-finding studies have reported pharmacodynamic target engagement without clear efficacy signals. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Target: DNA-PK catalytic subunit (PRKDC), a key kinase in non-homologous end-joining double-strand break repair. Inhibition impairs DSB repair, enhancing cytotoxicity of ionizing radiation and DSB-inducing agents. (aacrjournals.org)
Preclinical: Peposertib potentiated radiotherapy across tumor models, increased persistent DSBs, and led to complete tumor regressions when combined with fractionated radiation in mice. It also enhanced chemosensitivity (e.g., to etoposide/paclitaxel) in NSCLC models and boosted p53-dependent cytotoxic signaling in leukemia models. (aacrjournals.org)

Efficacy

Monotherapy, first-in-human phase I (NCT02316197, advanced solid tumors): No objective responses; best overall response was stable disease in 12/31 patients (7 lasting ≥12 weeks). RP2D declared 400 mg BID. (pubmed.ncbi.nlm.nih.gov)
Head and neck/thoracic tumors with radiotherapy (Phase I, NCT02516813):
Arm A (palliative RT + peposertib): RP2D 200 mg once daily with RT; study focused on dose finding; efficacy not a primary endpoint.
Arm B (curative-intent RT + cisplatin + peposertib): 50 mg was tolerable but exposure was insufficient; RP2D not declared. No objective responses in Parts A/B; one partial response observed in a separate food‑effect part of the program. (pubmed.ncbi.nlm.nih.gov)
Locally advanced rectal cancer, neoadjuvant capecitabine-based chemoradiation + peposertib (Phase Ib, NCT03770689): Among 19 patients, clinical complete response at 8 weeks was 15.8% (3/19); two of the three cCR patients had residual tumor at surgery. Combined cCR/pathologic CR was 5.3% (1/19). Study closed without declaring MTD/RP2D, concluding no improvement in complete response rates at tolerable exposure. (aacrjournals.org)
Other ongoing/early reports: Phase I dose-escalation in newly diagnosed MGMT‑unmethylated glioblastoma (RT ± adjuvant temozolomide) and hypofractionated RT in locally advanced pancreatic cancer have reported interim dose-escalation summaries; mature efficacy results have not yet been reported publicly. (ascopubs.org)

Safety

Monotherapy (Phase I): Common treatment-related adverse events (AEs) included nausea, vomiting, fatigue, and pyrexia; grade 3 AEs most commonly maculopapular rash and nausea. One DLT at 300 mg BID (prolonged low-grade AEs); MTD not reached. (pubmed.ncbi.nlm.nih.gov)
With radiotherapy ± cisplatin (Head/Neck study): Most frequent AEs were radiation skin injury, fatigue, and nausea (palliative RT arm) and stomatitis, nausea, radiation skin injury, and dysgeusia (curative-intent chemoradiation arm). Combination with cisplatin was limited by insufficient peposertib exposure at tolerable doses. (pubmed.ncbi.nlm.nih.gov)
With neoadjuvant chemoradiation (Rectal cancer): DLTs occurred in 1/5 (100 mg), 1/6 (150 mg), and 3/6 (250 mg) evaluable patients; doses ≤150 mg once daily were tolerable with capecitabine-RT but did not achieve predicted efficacious exposure. (aacrjournals.org)

Active trials using Peposertib

Found 4 active trials using this drug:

A Phase 1 Study of Peposertib (M3814) and Low-Dose Liposomal Doxorubicin (Doxil®) in Patients With Metastatic Leiomyosarcoma and Other Soft Tissue Sarcomas

Sponsor: National Cancer Institute (NCI) (federal) Phase: 1 Start date: Feb. 6, 2024

HealthScout AI summary: Adults with metastatic or unresectable soft tissue sarcoma—emphasis on leiomyosarcoma—after prior therapy (including limited prior anthracycline) receive oral peposertib (DNA-PK inhibitor targeting NHEJ repair) continuously with low-dose pegylated liposomal doxorubicin every 28 days. Includes dose escalation across selected STS subtypes and a leiomyosarcoma expansion; requires biopsy-amenable disease, allows treated/stable CNS metastases, and excludes significant cardiac dysfunction and prior DNA-PK inhibitor exposure.

ClinicalTrials.gov ID: NCT05711615

A Phase 1/2 Study of M3814 (Peposertib) in Combination With Hypofractionated Radiotherapy for the Treatment of Locally Advanced Pancreatic Adenocarcinoma

Sponsor: National Cancer Institute (NCI) (federal) Phase: 1/2 Start date: Jan. 11, 2021

HealthScout AI summary: Adults with nonmetastatic, locally advanced pancreatic adenocarcinoma after 4–6 months of induction chemotherapy (FOLFIRINOX, NALIRIFOX, or gemcitabine/nab-paclitaxel), ECOG 0–2, and planned non-operative management receive hypofractionated radiotherapy with or without oral peposertib. Peposertib is a selective DNA-PK inhibitor and radiosensitizer given concurrently for 14 days to enhance radiation efficacy; phase 2 randomizes against placebo.

ClinicalTrials.gov ID: NCT04172532

A Phase I and Randomized Phase II Trial of Radium-223 Dichloride, M3814, &Amp; Avelumab in Advanced Metastatic Castrate-Resistant Prostate Cancer (mCRPC)

Sponsor: National Cancer Institute (NCI) (federal) Phase: 1/2 Start date: Oct. 14, 2020

HealthScout AI summary: Men with progressive mCRPC with bone-predominant disease (no visceral metastases), previously treated with AR-targeted therapy and/or taxane, are randomized to radium-223 alone versus radium-223 plus peposertib (M3814; oral DNA-PK inhibitor) versus radium-223 plus peposertib plus avelumab (anti–PD-L1). Key exclusions include active autoimmune disease requiring immunosuppression and concurrent abiraterone with radium-223; ECOG 0–1 (phase I) or 0–2 (phase II) required.

ClinicalTrials.gov ID: NCT04071236

A Phase I/II Study of Peposertib (M3814) and Avelumab in Combination With Hypofractionated Radiation in Patients With Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies

Sponsor: National Cancer Institute (NCI) (federal) Phase: 1/2 Start date: April 7, 2020

HealthScout AI summary: Adults with metastatic/unresectable solid tumors (phase I) and, in phase II, cholangiocarcinoma or gallbladder cancer after progression on gemcitabine/cisplatin plus durvalumab or pembrolizumab, eligible for palliative hypofractionated RT and with separate measurable non-irradiated disease. Treatment is hypofractionated RT plus avelumab (anti–PD-L1) with or without peposertib (M3814/nedisertib), an oral DNA-PK inhibitor and radiosensitizer given continuously each 28-day cycle.

ClinicalTrials.gov ID: NCT04068194