Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma

Kevin R. Kelly, Jonathan W. Friedberg, Steven I. Park, Kevin McDonagh, John Hayslip, Daniel Persky, Jia Ruan, Soham D Puvvada, Peter Rosen, Swaminathan Padmanabhan Iyer, Alexandra Stefanovic, Steven H. Bernstein, Steven Weitman, Anand Karnad, Gregory Monohan, Ari VanderWalde, Raul Mena, Monika Schmelz, Catherine S Perry, Susan Groshen & 5 others Karthik Venkatakrishnan, Xiaofei Zhou, Emily Sheldon-Waniga, E. Jane Leonard, Daruka Mahadevan

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Abstract

Purpose: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab vincristine in patients with relapsed/ refractory aggressive B-NHL. Patients and Methods: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 þ 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/ BCL2 IHC was performed on available archival tissue. Results: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n ¼ 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). Conclusions: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

Original languageEnglish (US)
Pages (from-to)6150-6159
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2018

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Aurora Kinase A
Vincristine
B-Cell Lymphoma
Non-Hodgkin's Lymphoma
Lymphoma, Large B-Cell, Diffuse
Rituximab
MLN 8237
Neutropenia
Drug-Related Side Effects and Adverse Reactions
B-Lymphocytes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma. / Kelly, Kevin R.; Friedberg, Jonathan W.; Park, Steven I.; McDonagh, Kevin; Hayslip, John; Persky, Daniel; Ruan, Jia; Puvvada, Soham D; Rosen, Peter; Iyer, Swaminathan Padmanabhan; Stefanovic, Alexandra; Bernstein, Steven H.; Weitman, Steven; Karnad, Anand; Monohan, Gregory; VanderWalde, Ari; Mena, Raul; Schmelz, Monika; Perry, Catherine S; Groshen, Susan; Venkatakrishnan, Karthik; Zhou, Xiaofei; Sheldon-Waniga, Emily; Jane Leonard, E.; Mahadevan, Daruka.

In: Clinical Cancer Research, Vol. 24, No. 24, 15.12.2018, p. 6150-6159.

Research output: Contribution to journalArticle

Kelly, KR, Friedberg, JW, Park, SI, McDonagh, K, Hayslip, J, Persky, D, Ruan, J, Puvvada, SD, Rosen, P, Iyer, SP, Stefanovic, A, Bernstein, SH, Weitman, S, Karnad, A, Monohan, G, VanderWalde, A, Mena, R, Schmelz, M, Perry, CS, Groshen, S, Venkatakrishnan, K, Zhou, X, Sheldon-Waniga, E, Jane Leonard, E & Mahadevan, D 2018, 'Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma', Clinical Cancer Research, vol. 24, no. 24, pp. 6150-6159. https://doi.org/10.1158/1078-0432.CCR-18-0286
Kelly, Kevin R. ; Friedberg, Jonathan W. ; Park, Steven I. ; McDonagh, Kevin ; Hayslip, John ; Persky, Daniel ; Ruan, Jia ; Puvvada, Soham D ; Rosen, Peter ; Iyer, Swaminathan Padmanabhan ; Stefanovic, Alexandra ; Bernstein, Steven H. ; Weitman, Steven ; Karnad, Anand ; Monohan, Gregory ; VanderWalde, Ari ; Mena, Raul ; Schmelz, Monika ; Perry, Catherine S ; Groshen, Susan ; Venkatakrishnan, Karthik ; Zhou, Xiaofei ; Sheldon-Waniga, Emily ; Jane Leonard, E. ; Mahadevan, Daruka. / Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 24. pp. 6150-6159.
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title = "Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma",
abstract = "Purpose: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab vincristine in patients with relapsed/ refractory aggressive B-NHL. Patients and Methods: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 {\th} 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/ BCL2 IHC was performed on available archival tissue. Results: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n ¼ 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89{\%} of patients, the most common was neutropenia (47{\%}). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45{\%}) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). Conclusions: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.",
author = "Kelly, {Kevin R.} and Friedberg, {Jonathan W.} and Park, {Steven I.} and Kevin McDonagh and John Hayslip and Daniel Persky and Jia Ruan and Puvvada, {Soham D} and Peter Rosen and Iyer, {Swaminathan Padmanabhan} and Alexandra Stefanovic and Bernstein, {Steven H.} and Steven Weitman and Anand Karnad and Gregory Monohan and Ari VanderWalde and Raul Mena and Monika Schmelz and Perry, {Catherine S} and Susan Groshen and Karthik Venkatakrishnan and Xiaofei Zhou and Emily Sheldon-Waniga and {Jane Leonard}, E. and Daruka Mahadevan",
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TY - JOUR

T1 - Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma

AU - Kelly, Kevin R.

AU - Friedberg, Jonathan W.

AU - Park, Steven I.

AU - McDonagh, Kevin

AU - Hayslip, John

AU - Persky, Daniel

AU - Ruan, Jia

AU - Puvvada, Soham D

AU - Rosen, Peter

AU - Iyer, Swaminathan Padmanabhan

AU - Stefanovic, Alexandra

AU - Bernstein, Steven H.

AU - Weitman, Steven

AU - Karnad, Anand

AU - Monohan, Gregory

AU - VanderWalde, Ari

AU - Mena, Raul

AU - Schmelz, Monika

AU - Perry, Catherine S

AU - Groshen, Susan

AU - Venkatakrishnan, Karthik

AU - Zhou, Xiaofei

AU - Sheldon-Waniga, Emily

AU - Jane Leonard, E.

AU - Mahadevan, Daruka

PY - 2018/12/15

Y1 - 2018/12/15

N2 - Purpose: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab vincristine in patients with relapsed/ refractory aggressive B-NHL. Patients and Methods: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 þ 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/ BCL2 IHC was performed on available archival tissue. Results: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n ¼ 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). Conclusions: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

AB - Purpose: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab vincristine in patients with relapsed/ refractory aggressive B-NHL. Patients and Methods: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 þ 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/ BCL2 IHC was performed on available archival tissue. Results: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n ¼ 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). Conclusions: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

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U2 - 10.1158/1078-0432.CCR-18-0286

DO - 10.1158/1078-0432.CCR-18-0286

M3 - Article

VL - 24

SP - 6150

EP - 6159

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 24

ER -