A phase I dose-escalation study of veliparib combined with carboplatin and etoposide in patients with extensive-stage small cell lung cancer and other solid tumors

Florence Atrafi, Harry J.M. Groen, Lauren Averett Byers, Elena Garralda, Martijn P. Lolkema, Randeep S. Sangha, Santiago Viteri, Young Kwang Chae, D. Ross Camidge, Nashat Y. Gabrail, Beibei Hu, Tian Tian, Silpa Nuthalapati, Elizabeth Hoening, Lei He, Philip Komarnitsky, Antonio Calles

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Abstract

Purpose: This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors. Patients and Methods: The 3 þ 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m 2 on days 1–3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity. Results: Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively. Conclusions: Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC.

Original languageEnglish (US)
Pages (from-to)496-505
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2019

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Carboplatin
Small Cell Lung Carcinoma
Etoposide
Neoplasms
Disease Progression
Pharmacokinetics
veliparib
Polyneuropathies
Poisons
Neutropenia
Nausea
Area Under Curve
Fatigue
Appointments and Schedules
Maintenance
Safety
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase I dose-escalation study of veliparib combined with carboplatin and etoposide in patients with extensive-stage small cell lung cancer and other solid tumors. / Atrafi, Florence; Groen, Harry J.M.; Byers, Lauren Averett; Garralda, Elena; Lolkema, Martijn P.; Sangha, Randeep S.; Viteri, Santiago; Chae, Young Kwang; Ross Camidge, D.; Gabrail, Nashat Y.; Hu, Beibei; Tian, Tian; Nuthalapati, Silpa; Hoening, Elizabeth; He, Lei; Komarnitsky, Philip; Calles, Antonio.

In: Clinical Cancer Research, Vol. 25, No. 2, 15.01.2019, p. 496-505.

Research output: Contribution to journalArticle

Atrafi, F, Groen, HJM, Byers, LA, Garralda, E, Lolkema, MP, Sangha, RS, Viteri, S, Chae, YK, Ross Camidge, D, Gabrail, NY, Hu, B, Tian, T, Nuthalapati, S, Hoening, E, He, L, Komarnitsky, P & Calles, A 2019, 'A phase I dose-escalation study of veliparib combined with carboplatin and etoposide in patients with extensive-stage small cell lung cancer and other solid tumors', Clinical Cancer Research, vol. 25, no. 2, pp. 496-505. https://doi.org/10.1158/1078-0432.CCR-18-2014
Atrafi, Florence ; Groen, Harry J.M. ; Byers, Lauren Averett ; Garralda, Elena ; Lolkema, Martijn P. ; Sangha, Randeep S. ; Viteri, Santiago ; Chae, Young Kwang ; Ross Camidge, D. ; Gabrail, Nashat Y. ; Hu, Beibei ; Tian, Tian ; Nuthalapati, Silpa ; Hoening, Elizabeth ; He, Lei ; Komarnitsky, Philip ; Calles, Antonio. / A phase I dose-escalation study of veliparib combined with carboplatin and etoposide in patients with extensive-stage small cell lung cancer and other solid tumors. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 2. pp. 496-505.
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abstract = "Purpose: This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors. Patients and Methods: The 3 {\th} 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m 2 on days 1–3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity. Results: Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39{\%}), fatigue (39{\%}), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44{\%}) and 16 of 25 (64{\%}) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46{\%}) and 5 of 6 (83{\%}) of all enrolled and ED SCLC patients, respectively. Conclusions: Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC.",
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T1 - A phase I dose-escalation study of veliparib combined with carboplatin and etoposide in patients with extensive-stage small cell lung cancer and other solid tumors

AU - Atrafi, Florence

AU - Groen, Harry J.M.

AU - Byers, Lauren Averett

AU - Garralda, Elena

AU - Lolkema, Martijn P.

AU - Sangha, Randeep S.

AU - Viteri, Santiago

AU - Chae, Young Kwang

AU - Ross Camidge, D.

AU - Gabrail, Nashat Y.

AU - Hu, Beibei

AU - Tian, Tian

AU - Nuthalapati, Silpa

AU - Hoening, Elizabeth

AU - He, Lei

AU - Komarnitsky, Philip

AU - Calles, Antonio

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Purpose: This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors. Patients and Methods: The 3 þ 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m 2 on days 1–3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity. Results: Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively. Conclusions: Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC.

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