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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
Author(s) -
Chugh Rashmi,
Ballman Karla V.,
Helman Lee J.,
Patel Shreyaskumar,
Whelan Jeremy S.,
Widemann Brigitte,
Lu Yao,
Hawkins Douglas S.,
Mascarenhas Leo,
Glod John W.,
Ji Jiuping,
Zhang Yiping,
Reinke Denise,
Strauss Sandra J.
Publication year - 2021
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.33349
Subject(s) - medicine , irinotecan , temozolomide , neutropenia , olaparib , parp inhibitor , gastroenterology , cohort , febrile neutropenia , sarcoma , dosing , surgery , oncology , chemotherapy , cancer , colorectal cancer , pathology , poly adp ribose polymerase , polymerase , biochemistry , chemistry , gene
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/m 2 every day on D2‐6 (arm 1) or NIR at 100 mg every day on D1‐7 plus IRN at 20 mg/m 2 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.