Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial

Gerald Falchook, Robert Coleman, Andrzej Roszak, Kian Behbakht, Ursula Matulonis, Isabelle Ray-Coquard, Piotr Sawrycki, Linda R. Duska, William Tew, Sharad Ghamande, Anne Lesoin, Peter E. Schwartz, Joseph Buscema, Michel Fabbro, Alain Lortholary, Barbara Goff, Razelle Kurzrock, Lainie P. Martin, Heidi J. Gray, Siqing Fu & 6 others Emily Sheldon-Waniga, Huamao Mark Lin, Karthik Venkatakrishnan, Xiaofei Zhou, E. Jane Leonard, Russell J. Schilder

Research output: Contribution to journalArticle

Abstract

Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.

LanguageEnglish (US)
JournalJAMA Oncology
Volume5
Issue number1
DOIs
StatePublished - Jan 1 2019

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Paclitaxel
Ovarian Neoplasms
Randomized Controlled Trials
Breast Neoplasms
Disease-Free Survival
Arm
MLN 8237
Breast
Pharmaceutical Preparations
Stomatitis
Poland
Neutropenia
Platinum
France

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer : A Randomized Clinical Trial. / Falchook, Gerald; Coleman, Robert; Roszak, Andrzej; Behbakht, Kian; Matulonis, Ursula; Ray-Coquard, Isabelle; Sawrycki, Piotr; Duska, Linda R.; Tew, William; Ghamande, Sharad; Lesoin, Anne; Schwartz, Peter E.; Buscema, Joseph; Fabbro, Michel; Lortholary, Alain; Goff, Barbara; Kurzrock, Razelle; Martin, Lainie P.; Gray, Heidi J.; Fu, Siqing; Sheldon-Waniga, Emily; Lin, Huamao Mark; Venkatakrishnan, Karthik; Zhou, Xiaofei; Leonard, E. Jane; Schilder, Russell J.

In: JAMA Oncology, Vol. 5, No. 1, 01.01.2019.

Research output: Contribution to journalArticle

Falchook, G, Coleman, R, Roszak, A, Behbakht, K, Matulonis, U, Ray-Coquard, I, Sawrycki, P, Duska, LR, Tew, W, Ghamande, S, Lesoin, A, Schwartz, PE, Buscema, J, Fabbro, M, Lortholary, A, Goff, B, Kurzrock, R, Martin, LP, Gray, HJ, Fu, S, Sheldon-Waniga, E, Lin, HM, Venkatakrishnan, K, Zhou, X, Leonard, EJ & Schilder, RJ 2019, 'Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial', JAMA Oncology, vol. 5, no. 1. https://doi.org/10.1001/jamaoncol.2018.3773
Falchook, Gerald ; Coleman, Robert ; Roszak, Andrzej ; Behbakht, Kian ; Matulonis, Ursula ; Ray-Coquard, Isabelle ; Sawrycki, Piotr ; Duska, Linda R. ; Tew, William ; Ghamande, Sharad ; Lesoin, Anne ; Schwartz, Peter E. ; Buscema, Joseph ; Fabbro, Michel ; Lortholary, Alain ; Goff, Barbara ; Kurzrock, Razelle ; Martin, Lainie P. ; Gray, Heidi J. ; Fu, Siqing ; Sheldon-Waniga, Emily ; Lin, Huamao Mark ; Venkatakrishnan, Karthik ; Zhou, Xiaofei ; Leonard, E. Jane ; Schilder, Russell J. / Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer : A Randomized Clinical Trial. In: JAMA Oncology. 2019 ; Vol. 5, No. 1.
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abstract = "Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75{\%}) patients had a documented PFS event; 52 (71{\%}) in the alisertib plus paclitaxel arm, and 55 (80{\%}) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80{\%} CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86{\%}) vs 14 (20{\%}) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77{\%}) vs 7 (10{\%}) neutropenia, 18 (25{\%}) vs 0 stomatitis, and 10 (14{\%}) vs 2 (3{\%}) anemia; 54 (74{\%}) vs 17 (25{\%}) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.",
author = "Gerald Falchook and Robert Coleman and Andrzej Roszak and Kian Behbakht and Ursula Matulonis and Isabelle Ray-Coquard and Piotr Sawrycki and Duska, {Linda R.} and William Tew and Sharad Ghamande and Anne Lesoin and Schwartz, {Peter E.} and Joseph Buscema and Michel Fabbro and Alain Lortholary and Barbara Goff and Razelle Kurzrock and Martin, {Lainie P.} and Gray, {Heidi J.} and Siqing Fu and Emily Sheldon-Waniga and Lin, {Huamao Mark} and Karthik Venkatakrishnan and Xiaofei Zhou and Leonard, {E. Jane} and Schilder, {Russell J.}",
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T1 - Alisertib in Combination with Weekly Paclitaxel in Patients with Advanced Breast Cancer or Recurrent Ovarian Cancer

T2 - JAMA oncology

AU - Falchook, Gerald

AU - Coleman, Robert

AU - Roszak, Andrzej

AU - Behbakht, Kian

AU - Matulonis, Ursula

AU - Ray-Coquard, Isabelle

AU - Sawrycki, Piotr

AU - Duska, Linda R.

AU - Tew, William

AU - Ghamande, Sharad

AU - Lesoin, Anne

AU - Schwartz, Peter E.

AU - Buscema, Joseph

AU - Fabbro, Michel

AU - Lortholary, Alain

AU - Goff, Barbara

AU - Kurzrock, Razelle

AU - Martin, Lainie P.

AU - Gray, Heidi J.

AU - Fu, Siqing

AU - Sheldon-Waniga, Emily

AU - Lin, Huamao Mark

AU - Venkatakrishnan, Karthik

AU - Zhou, Xiaofei

AU - Leonard, E. Jane

AU - Schilder, Russell J.

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N2 - Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.

AB - Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P =.14; 2-sided P value cutoff =.20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.

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