Chugh, R;
Ballman, KV;
Helman, LJ;
Patel, S;
Whelan, JS;
Widemann, B;
Lu, Y;
... Strauss, SJ; + view all
(2020)
SARC025 arms 1 and 2: A phase 1 study of the poly(ADP‐ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma.
Cancer
10.1002/cncr.33349.
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Abstract
BACKGROUND: In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES. METHODS: Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2-6 [D2-6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re-escalation in cohort C. In arm 2, patients were assigned to NIR (days 1-7 [D1-7]) and escalating doses of IRN (D2-6). RESULTS: From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose-limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1-7 plus TMZ at 30 mg/m2 every day on D2-6 (arm 1) or NIR at 100 mg every day on D1-7 plus IRN at 20 mg/m2 every day on D2-6 (arm 2). One confirmed partial response was observed in arm 2; the median progression-free survival was 9.0 weeks (95% CI, 7.0-10.1 weeks) and 16.3 weeks (95% CI, 5.1-69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP-ribose) activity was 89% (range, 83%-98%). CONCLUSIONS: The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple-combination study of NIR, IRN, and TMZ has commenced.
| Type: | Article |
|---|---|
| Title: | SARC025 arms 1 and 2: A phase 1 study of the poly(ADP‐ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/cncr.33349 |
| Publisher version: | https://doi.org/10.1002/cncr.33349 |
| Language: | English |
| Additional information: | Copyright © 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
| Keywords: | Ewing sarcoma, irinotecan, niraparib, poly(adenosine diphosphate ribose) polymerase (PARP) inhibition, temozolomide |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10117417 |
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