Phase II study of iniparib with concurrent chemoradiation in patients with newly diagnosed glioblastoma

Adult Brain Tumor Consortium

Research output: Contribution to journalArticle

Abstract

Purpose: Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM). Patients and Methods: Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi-institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy þ temozolomide þ iniparib (n ¼ 5) was followed by an efficacy study (n ¼ 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy þ daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide). Results: The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was 80% in 87% of participants. The mOS was 22 months [95% confidence interval (CI), 17–24] and the HR was 0.44 (95% CI, 0.35–0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27% of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia. Conclusions: Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.

Original languageEnglish (US)
Pages (from-to)73-79
Number of pages7
JournalClinical Cancer Research
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2019

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temozolomide
Glioblastoma
Radiotherapy
Survival
Confidence Intervals
Safety
Prodrugs
Gastritis
Exanthema
Drug-Related Side Effects and Adverse Reactions
Thrombocytopenia
iniparib
Cell Death
Survival Rate
Ions
Liver

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase II study of iniparib with concurrent chemoradiation in patients with newly diagnosed glioblastoma. / Adult Brain Tumor Consortium.

In: Clinical Cancer Research, Vol. 25, No. 1, 01.01.2019, p. 73-79.

Research output: Contribution to journalArticle

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title = "Phase II study of iniparib with concurrent chemoradiation in patients with newly diagnosed glioblastoma",
abstract = "Purpose: Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM). Patients and Methods: Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi-institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy {\th} temozolomide {\th} iniparib (n ¼ 5) was followed by an efficacy study (n ¼ 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy {\th} daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide). Results: The median age of the 81 evaluable participants was 58 years (63{\%} male). Baseline KPS was 80{\%} in 87{\%} of participants. The mOS was 22 months [95{\%} confidence interval (CI), 17–24] and the HR was 0.44 (95{\%} CI, 0.35–0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38{\%} and 25{\%}, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27{\%} of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia. Conclusions: Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.",
author = "{Adult Brain Tumor Consortium} and Jaishri Blakeley and Grossman, {Stuart A} and Chi, {Andrew S.} and Tom Mikkelsen and Rosenfeld, {Myrna R.} and Ahluwalia, {Manmeet S.} and {Burt Nabors}, L. and April Eichler and Ribas, {Ignacio Garcia} and Serena Desideri and Xiaobu Ye",
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T1 - Phase II study of iniparib with concurrent chemoradiation in patients with newly diagnosed glioblastoma

AU - Adult Brain Tumor Consortium

AU - Blakeley, Jaishri

AU - Grossman, Stuart A

AU - Chi, Andrew S.

AU - Mikkelsen, Tom

AU - Rosenfeld, Myrna R.

AU - Ahluwalia, Manmeet S.

AU - Burt Nabors, L.

AU - Eichler, April

AU - Ribas, Ignacio Garcia

AU - Desideri, Serena

AU - Ye, Xiaobu

PY - 2019/1/1

Y1 - 2019/1/1

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AB - Purpose: Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM). Patients and Methods: Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi-institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy þ temozolomide þ iniparib (n ¼ 5) was followed by an efficacy study (n ¼ 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy þ daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide). Results: The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was 80% in 87% of participants. The mOS was 22 months [95% confidence interval (CI), 17–24] and the HR was 0.44 (95% CI, 0.35–0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27% of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia. Conclusions: Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.

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