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. 2021 Apr 15;127(8):1301-1310. doi: 10.1002/cncr.33349. Epub 2020 Dec 8.

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.

Trial registration: ClinicalTrials.gov NCT02044120.

Keywords: Ewing sarcoma; irinotecan; niraparib; poly(adenosine diphosphate ribose) polymerase (PARP) inhibition; temozolomide.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alanine Transaminase / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Bone Neoplasms / drug therapy*
  • Drug Administration Schedule
  • Female
  • Humans
  • Indazoles / administration & dosage
  • Indazoles / adverse effects
  • Irinotecan / administration & dosage
  • Irinotecan / adverse effects
  • Irinotecan / therapeutic use
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neutropenia / chemically induced
  • Piperidines / administration & dosage
  • Piperidines / adverse effects
  • Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage*
  • Poly(ADP-ribose) Polymerase Inhibitors / adverse effects
  • Progression-Free Survival
  • Sarcoma, Ewing / drug therapy*
  • Temozolomide / administration & dosage
  • Temozolomide / adverse effects
  • Thrombocytopenia / chemically induced
  • Young Adult

Substances

  • Indazoles
  • Piperidines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Irinotecan
  • Alanine Transaminase
  • niraparib
  • Temozolomide

Associated data

  • ClinicalTrials.gov/NCT02044120