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Clinical Trial
. 2024 Feb 16;30(4):695-702.
doi: 10.1158/1078-0432.CCR-23-1129.

A Phase Ib Study of the DNA-PK Inhibitor Peposertib Combined with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer

Paul B Romesser  1 , Jaume Capdevila  2 , Rocio Garcia-Carbonero  3 , Tony Philip  4 , Carlos Fernandez Martos  5 , Richard Tuli  6 , Almudena Rodriguez-Gutierrez  7 , Mirjam Kuipers  8 , Andreas Becker  8 , Anna Coenen-Stass  8 , Barbara Sarholz  8 , Xiaoli You  9 , Eric D Miller  10
Affiliations
Clinical Trial

A Phase Ib Study of the DNA-PK Inhibitor Peposertib Combined with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer

Paul B Romesser et al. Clin Cancer Res. .

Abstract

Purpose: Peposertib-an orally administered DNA-dependent protein kinase inhibitor-has shown potent radiosensitization in preclinical models. This dose-escalation study (NCT03770689) aimed to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of peposertib plus capecitabine-based chemoradiotherapy (CRT) and assessed its safety and efficacy in locally advanced rectal cancer.

Patients and methods: Patients were treated for 5 to 5.5 weeks with 50- to 250-mg peposertib once daily, capecitabine 825 mg/m2 twice daily, and radiotherapy (RT), 5 days per week. Following clinical restaging (8 weeks after CRT completion), patients with clinical complete response (cCR) could opt for surveillance. Total mesorectal excision was recommended upon incomplete response (IR).

Results: Nineteen patients were treated with peposertib at doses of 50 mg (n = 1), 100 mg, 150 mg, and 250 mg (n = 6 each). Dose-limiting toxicities occurred in one out of five (100 mg), one out of six (150 mg), and three out of six (250 mg) evaluable patients. Peposertib ≤150 mg once daily was tolerable in combination with CRT. After 8 weeks of treatment with peposertib and CRT, the cCR was 15.8% (n = 3). Among the three patients with cCR, two underwent surgery and had residual tumors. Among the 16 patients with IR, seven underwent surgery and had residual tumors; five of the remaining nine patients opted for consolidative chemotherapy. The combined cCR/pathologic complete response (pCR) rate was 5.3% (n = 1, 100 mg cohort).

Conclusions: Peposertib did not improve complete response rates at tolerable dose levels. The study was closed without declaring the MTD/RP2D.

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Figures

Figure 1. Patient disposition and patient flow during the study. aThree patients were initially treated with 150 mg. After DLT occurred in the 250-mg cohort, the dose was de-escalated and a further three were treated with 150 mg. bPatient declined surgery at week 15 in favor of consolidative chemotherapy and underwent surgery outside the protocol window. cOne patient was removed due to protocol nonadherence. Abbreviations: Cap, capecitabine; cCR, clinical complete response; CRT, chemoradiotherapy; DLT, dose-limiting toxicity; RT, radiotherapy.
Figure 1.
Patient disposition and patient flow during the study. aThree patients were initially treated with 150 mg. After DLT occurred in the 250-mg cohort, the dose was de-escalated and a further three were treated with 150 mg. bPatient declined surgery at week 15 in favor of consolidative chemotherapy and underwent surgery outside the protocol window. cOne patient was removed due to protocol nonadherence. Abbreviations: Cap, capecitabine; cCR, clinical complete response; CRT, chemoradiotherapy; DLT, dose-limiting toxicity; RT, radiotherapy.
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