Phase i study of the anti-CD22 antibody-drug conjugate pinatuzumab vedotin with/without rituximab in patients with relapsed/refractory B-cell non-hodgkin lymphoma

Ranjana H. Advani, Daniel Lebovic, Andy Chen, Mark Brunvand, Andre Goy, Julie E. Chang, Ephraim Hochberg, Sreeni Yalamanchili, Robert Kahn, Dan Lu, Priya Agarwal, Randall C. Dere, Hsin Ju Hsieh, Surai Jones, Yu Waye Chu, Bruce D. Cheson

Research output: Contribution to journalArticle

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Abstract

Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a proteasecleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients. Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the mostcommon grade≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. UnconjugatedMMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses. Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL.

Original languageEnglish (US)
Pages (from-to)1167-1176
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number5
DOIs
StatePublished - Mar 1 2017

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B-Cell Lymphoma
Non-Hodgkin's Lymphoma
Anti-Idiotypic Antibodies
Pharmaceutical Preparations
Neutropenia
Lymphoma, Large B-Cell, Diffuse
B-Cell Chronic Lymphocytic Leukemia
Safety
pinatuzumab vedotin
Rituximab
Antibodies
Peripheral Nervous System Diseases
Research Design
Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase i study of the anti-CD22 antibody-drug conjugate pinatuzumab vedotin with/without rituximab in patients with relapsed/refractory B-cell non-hodgkin lymphoma. / Advani, Ranjana H.; Lebovic, Daniel; Chen, Andy; Brunvand, Mark; Goy, Andre; Chang, Julie E.; Hochberg, Ephraim; Yalamanchili, Sreeni; Kahn, Robert; Lu, Dan; Agarwal, Priya; Dere, Randall C.; Hsieh, Hsin Ju; Jones, Surai; Chu, Yu Waye; Cheson, Bruce D.

In: Clinical Cancer Research, Vol. 23, No. 5, 01.03.2017, p. 1167-1176.

Research output: Contribution to journalArticle

Advani, RH, Lebovic, D, Chen, A, Brunvand, M, Goy, A, Chang, JE, Hochberg, E, Yalamanchili, S, Kahn, R, Lu, D, Agarwal, P, Dere, RC, Hsieh, HJ, Jones, S, Chu, YW & Cheson, BD 2017, 'Phase i study of the anti-CD22 antibody-drug conjugate pinatuzumab vedotin with/without rituximab in patients with relapsed/refractory B-cell non-hodgkin lymphoma', Clinical Cancer Research, vol. 23, no. 5, pp. 1167-1176. https://doi.org/10.1158/1078-0432.CCR-16-0772
Advani, Ranjana H. ; Lebovic, Daniel ; Chen, Andy ; Brunvand, Mark ; Goy, Andre ; Chang, Julie E. ; Hochberg, Ephraim ; Yalamanchili, Sreeni ; Kahn, Robert ; Lu, Dan ; Agarwal, Priya ; Dere, Randall C. ; Hsieh, Hsin Ju ; Jones, Surai ; Chu, Yu Waye ; Cheson, Bruce D. / Phase i study of the anti-CD22 antibody-drug conjugate pinatuzumab vedotin with/without rituximab in patients with relapsed/refractory B-cell non-hodgkin lymphoma. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 5. pp. 1167-1176.
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abstract = "Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a proteasecleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients. Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the mostcommon grade≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. UnconjugatedMMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses. Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL.",
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T1 - Phase i study of the anti-CD22 antibody-drug conjugate pinatuzumab vedotin with/without rituximab in patients with relapsed/refractory B-cell non-hodgkin lymphoma

AU - Advani, Ranjana H.

AU - Lebovic, Daniel

AU - Chen, Andy

AU - Brunvand, Mark

AU - Goy, Andre

AU - Chang, Julie E.

AU - Hochberg, Ephraim

AU - Yalamanchili, Sreeni

AU - Kahn, Robert

AU - Lu, Dan

AU - Agarwal, Priya

AU - Dere, Randall C.

AU - Hsieh, Hsin Ju

AU - Jones, Surai

AU - Chu, Yu Waye

AU - Cheson, Bruce D.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a proteasecleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients. Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the mostcommon grade≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. UnconjugatedMMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses. Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL.

AB - Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a proteasecleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients. Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the mostcommon grade≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. UnconjugatedMMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses. Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL.

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