peposertib (M3814)

P1, N=29, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P1/2, N=90, Suspended, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=48, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=36, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting | Initiation date: May 2023 --> Feb 2024

P1/2, N=101, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=29, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1

P1, N=66, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1 | Initiation date: Nov 2023 --> Feb 2024

P1/2, N=90, Suspended, National Cancer Institute (NCI) | Phase classification: P2 --> P1/2

PRKDC inhibition with nedisertib sensitized glioblastomas to radiotherapy and extended survival in vivo, and single-cell RNA sequencing revealed hyperactivation of cell stress and cytokine signatures with combination treatment. In summary, we report in vivo perturb-seq as a platform for simultaneous discovery and functional interrogation of therapeutic vulnerabilities in glioblastoma, and show DNA-PK inhibition sensitizes glioblastomas to radiotherapy in vivo.

Both groups receive adjuvant temozolomide for 6-cycles. The initial safety data of peposertib plus radiation in newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors with DDR mutations, the gain of two ATM mutations in a recurrent tumor and the cases of scalp dermatitis suggest that peposertib is active and possibly potentiates the effect of radiation. Safety and survival data and correlations with genomics will be presented.

P2, N=90, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=29, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2023 --> Oct 2025 | Trial primary completion date: Oct 2023 --> Oct 2025

P1b, N=66, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting | Initiation date: May 2023 --> Nov 2023

In SSTR2-positive xenograft-bearing mice, the combination of nedisertib (a DNA-PK specific inhibitor) and LuTate produced a more robust control of tumour growth and increased survival compared to LuTate alone. DDR pathways are critical for sensing and repairing radiation-induced DNA damage, and our study shows that regulation of DDR pathways may be involved in both resistance and sensitivity to PRRT. Additionally, the use of a DNA-PK inhibitor in combination with LuTate PRRT significantly improves the efficacy of the treatment in pre-clinical models, providing further evidence for the clinical efficacy of this combination.

Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS.

Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg QD as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure.

The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.

This ongoing phase 1 dose escalation and dose expansion study is evaluating low dose liposomal doxorubicin combined with the DNA-PK inhibitor peposertib in LMS and select STS with embedded correlative studies to identify predictive biomarkers and explore mechanism of action. Note: Research support for correlative studies and peposertib supply were provided by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

P1, N=36, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1b, N=66, Suspended, National Cancer Institute (NCI) | Not yet recruiting --> Suspended

P1b, N=29, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

P1/2, N=39, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=36, Recruiting, National Cancer Institute (NCI) | N=66 --> 36

P1b, N=36, Recruiting, Telix International Pty Ltd | Not yet recruiting --> Recruiting

P1, N=66, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: Apr 2023 --> May 2025 | Trial primary completion date: Apr 2023 --> May 2025

P1b, N=36, Not yet recruiting, Telix International Pty Ltd

P1, N=42, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2023 --> Jul 2025 | Trial primary completion date: Jul 2023 --> Jul 2025

Accordingly, proliferation assays revealed that KIT mutant FDC-P1 cells were more sensitive to the DNA-PK inhibitors M3814 or NU7441, compared with empty vector controls. DNA-PK inhibition combined with inhibition of KIT signaling using the kinase inhibitors dasatinib or ibrutinib, or the protein phosphatase 2A activators FTY720 or AAL(S), led to synergistic cell death...Combined dasatinib and M3814 treatment also synergistically inhibited phosphorylation of the transcriptional regulators MYC and MYB. This study provides insight into the oncogenic pathways regulated by DNA-PK beyond its canonical role in DNA repair, and demonstrates that DNA-PK is a promising therapeutic target for KIT mutant cancers.

P1, N=42, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

In vivo efficacy was assessed in cell-line derived and patient-derived xenograft models. When administered in combination with doxorubicin, epirubicin, and etoposide, peposertib exhibited synergistic antiproliferative activity in TNBC cell lines in vitro. Our findings suggest that cotreatment with the DNA-PK inhibitor peposertib can enhance the efficacy of anthracycline/TOPO II-based chemotherapies.

Clonogenic survival assays were performed with either an ATR inhibitor (VX970), the selective DNA-PKcs inhibitor (M3814), or combination therapy. Our data demonstrates that dual targeting of ATR and DNA-PKcs is necessary in ATM-KO CRPC, as either kinase is independently capable of mediating DDR following IR. Our initial studies indicate that the RUVBL1 ATPase inhibitor Compound B may effectively block DDR in ATM-mutant CRPC, and could be utilized as a novel therapeutic strategy in this molecular subtype.

Peposertib radiosensitizes HNSCC tumors and leads to a better treatment response in dysfunctional p53 cells both in-vitro and in-vivo. Determination of the HPV and p53 status in a particular tumor might be necessary to effectively shape the intervention outcome when combining NHEJ targeting with radiation therapy.

P1b, N=66, Not yet recruiting, National Cancer Institute (NCI)

P1, N=48, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

In addition, the study will correlate clinical outcome with somatic tumor mutations and germline mutations. Clinical trial information: 04750954.

P1, N=42, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

Peposertib is an inhibitor of DNA-dependent protein kinase (DNA-PK), which is a key driver of nonhomologous end-joining (NHEJ)...Consequently, the combination of peposertib plus novobiocin resulted in synthetic lethality in TP53-deficient tumor cell lines, organoid cultures, and patient-derived xenograft models. Thus, the combination of a targeted DNA-PK/NHEJ inhibitor with a targeted POLθ/MMEJ inhibitor may provide a rational treatment strategy for TP53-mutant solid tumors.

This study demonstrates that EGFR signaling inhibits wt-p53 function in GBM by promoting an interaction between p53 and DNA-PKcs.

Our findings demonstrate a novel mechanism for the antitumoral immune effects of DNA-PK inhibitor and radiation that leads to increased sensitivity to anti-PD-L1 in poorly immunogenic pancreatic cancers. Implications: Our work nominates a novel therapeutic strategy as well as biomarkers of treatment resistance pertinent for future clinical trials combining M3814, radiation and αPD-L1 antibody in patients with pancreatic cancer.

In a genome-wide CRISPR knockout screen with the DNA-PK inhibitor M3814, we identify loss of POLQ, encoding polymerase theta, and other genes in the microhomology-mediated end-joining (MMEJ) pathway as key predictors of sensitivity to DNA-PK inhibition, whereas loss of TP53 conferred resistance to DNA-PK inhibition...Similarly, P53-deficiency which confers resistance to DNA-PK inhibition, also leads to a hyper-dependence on MMEJ and an upregulation of polymerase theta expression. Thus, a combination of DNA-PK and polymerase theta inhibitors may provide a precision treatment strategy for TP53-mutant solid tumors, known to account for 50% of newly diagnosed cancers.

P1, N=48, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022