Combination treatment of copanlisib and gemcitabine in relapsed/refractory PTCL (COSMOS): an open-label phase I/II trial

H. Y. Yhim; T. Kim; S. J. Kim; H. J. Shin; Y. Koh; J. S. Kim; J. Park; G. S. Park; W. S. Kim; J. H. Moon; D. H. Yang

doi:10.1016/j.annonc.2020.12.009

Combination treatment of copanlisib and gemcitabine in relapsed/refractory PTCL (COSMOS): an open-label phase I/II trial

H. Y. Yhim, T. Kim, S. J. Kim, H. J. Shin, Y. Koh, J. S. Kim, J. Park, G. S. Park, W. S. Kim, J. H. Moon, D. H. Yang

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

Background: Current treatment options for peripheral T-cell lymphomas (PTCLs) in the relapsed/refractory setting are limited and demonstrate modest response rates with rare achievement of complete response (CR). Patients and methods: This phase I/II study (NCT03052933) investigated the safety and efficacy of copanlisib, a phosphatidylinositol 3-kinase-α/-δ inhibitor, in combination with gemcitabine in 28 patients with relapsed/refractory PTCL. Patients received escalating doses of intravenous copanlisib on days 1, 8, and 15, administered concomitantly with fixed-dose gemcitabine (1000 mg/m² on days 1 and 8) in 28-day cycles. Results: Dose-limiting toxicity was not observed in the dose-escalation phase and 60 mg copanlisib was selected for phase II evaluation. Twenty-five patients were enrolled in phase II of the study. Frequent grade ≥3 adverse events (AEs) included transient hyperglycemia (57%), neutropenia (45%), thrombocytopenia, (37%), and transient hypertension (19%). However, AEs were manageable, and none were fatal. The overall response rate was 72% with a CR rate of 32%. Median duration of response was 8.2 months, progression-free survival was 6.9 months, and median overall survival was not reached. Combination treatment produced a greater CR rate in patients with angioimmunoblastic T-cell lymphoma than those with PTCL-not otherwise specified (55.6% versus 15.4%, respectively, P = 0.074) and progression-free survival was significantly longer (13.0 versus 5.1 months, respectively, P = 0.024). In an exploratory gene mutation analysis of 24 tumor samples, TSC2 mutation was present in 25% of patients and occurred exclusively in responders. Conclusion: The combination of copanlisib and gemcitabine is a safe and effective treatment option in relapsed/refractory PTCLs and represents an important new option for therapy in this rare group of patients.

Original language	English
Pages (from-to)	552-559
Number of pages	8
Journal	Annals of Oncology
Volume	32
Issue number	4
DOIs	https://doi.org/10.1016/j.annonc.2020.12.009
Publication status	Published - 2021 Apr

Bibliographical note

Funding Information:
This work was supported by Bayer HealthCare Pharmaceuticals, Inc . (no grant number) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0021).

Funding Information:
We express our appreciation to the patients and their families, all study staff, and nurses for their effort in enrolling and managing patients. We thank Borum Sagong and Macrogen Incorporation for their support in gene mutational analyses. This work was supported by Bayer HealthCare Pharmaceuticals, Inc. (no grant number) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0021). D-HY reports receipt of institutional research funding from Bayer HealthCare Pharmaceuticals, Inc. All remaining authors have declared no conflicts of interest.

Publisher Copyright:
© 2020 European Society for Medical Oncology

All Science Journal Classification (ASJC) codes

Hematology
Oncology

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10.1016/j.annonc.2020.12.009

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@article{ba8d9f3d313943be953470b65a93b25f,

title = "Combination treatment of copanlisib and gemcitabine in relapsed/refractory PTCL (COSMOS): an open-label phase I/II trial",

abstract = "Background: Current treatment options for peripheral T-cell lymphomas (PTCLs) in the relapsed/refractory setting are limited and demonstrate modest response rates with rare achievement of complete response (CR). Patients and methods: This phase I/II study (NCT03052933) investigated the safety and efficacy of copanlisib, a phosphatidylinositol 3-kinase-α/-δ inhibitor, in combination with gemcitabine in 28 patients with relapsed/refractory PTCL. Patients received escalating doses of intravenous copanlisib on days 1, 8, and 15, administered concomitantly with fixed-dose gemcitabine (1000 mg/m2 on days 1 and 8) in 28-day cycles. Results: Dose-limiting toxicity was not observed in the dose-escalation phase and 60 mg copanlisib was selected for phase II evaluation. Twenty-five patients were enrolled in phase II of the study. Frequent grade ≥3 adverse events (AEs) included transient hyperglycemia (57%), neutropenia (45%), thrombocytopenia, (37%), and transient hypertension (19%). However, AEs were manageable, and none were fatal. The overall response rate was 72% with a CR rate of 32%. Median duration of response was 8.2 months, progression-free survival was 6.9 months, and median overall survival was not reached. Combination treatment produced a greater CR rate in patients with angioimmunoblastic T-cell lymphoma than those with PTCL-not otherwise specified (55.6% versus 15.4%, respectively, P = 0.074) and progression-free survival was significantly longer (13.0 versus 5.1 months, respectively, P = 0.024). In an exploratory gene mutation analysis of 24 tumor samples, TSC2 mutation was present in 25% of patients and occurred exclusively in responders. Conclusion: The combination of copanlisib and gemcitabine is a safe and effective treatment option in relapsed/refractory PTCLs and represents an important new option for therapy in this rare group of patients.",

author = "Yhim, {H. Y.} and T. Kim and Kim, {S. J.} and Shin, {H. J.} and Y. Koh and Kim, {J. S.} and J. Park and Park, {G. S.} and Kim, {W. S.} and Moon, {J. H.} and Yang, {D. H.}",

note = "Funding Information: This work was supported by Bayer HealthCare Pharmaceuticals, Inc . (no grant number) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0021). Funding Information: We express our appreciation to the patients and their families, all study staff, and nurses for their effort in enrolling and managing patients. We thank Borum Sagong and Macrogen Incorporation for their support in gene mutational analyses. This work was supported by Bayer HealthCare Pharmaceuticals, Inc. (no grant number) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0021). D-HY reports receipt of institutional research funding from Bayer HealthCare Pharmaceuticals, Inc. All remaining authors have declared no conflicts of interest. Publisher Copyright: {\textcopyright} 2020 European Society for Medical Oncology",

year = "2021",

month = apr,

doi = "10.1016/j.annonc.2020.12.009",

language = "English",

volume = "32",

pages = "552--559",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "4",

}

TY - JOUR

T1 - Combination treatment of copanlisib and gemcitabine in relapsed/refractory PTCL (COSMOS)

T2 - an open-label phase I/II trial

AU - Yhim, H. Y.

AU - Kim, T.

AU - Kim, S. J.

AU - Shin, H. J.

AU - Koh, Y.

AU - Kim, J. S.

AU - Park, J.

AU - Park, G. S.

AU - Kim, W. S.

AU - Moon, J. H.

AU - Yang, D. H.

N1 - Funding Information: This work was supported by Bayer HealthCare Pharmaceuticals, Inc . (no grant number) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0021). Funding Information: We express our appreciation to the patients and their families, all study staff, and nurses for their effort in enrolling and managing patients. We thank Borum Sagong and Macrogen Incorporation for their support in gene mutational analyses. This work was supported by Bayer HealthCare Pharmaceuticals, Inc. (no grant number) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0021). D-HY reports receipt of institutional research funding from Bayer HealthCare Pharmaceuticals, Inc. All remaining authors have declared no conflicts of interest. Publisher Copyright: © 2020 European Society for Medical Oncology

PY - 2021/4

Y1 - 2021/4

N2 - Background: Current treatment options for peripheral T-cell lymphomas (PTCLs) in the relapsed/refractory setting are limited and demonstrate modest response rates with rare achievement of complete response (CR). Patients and methods: This phase I/II study (NCT03052933) investigated the safety and efficacy of copanlisib, a phosphatidylinositol 3-kinase-α/-δ inhibitor, in combination with gemcitabine in 28 patients with relapsed/refractory PTCL. Patients received escalating doses of intravenous copanlisib on days 1, 8, and 15, administered concomitantly with fixed-dose gemcitabine (1000 mg/m2 on days 1 and 8) in 28-day cycles. Results: Dose-limiting toxicity was not observed in the dose-escalation phase and 60 mg copanlisib was selected for phase II evaluation. Twenty-five patients were enrolled in phase II of the study. Frequent grade ≥3 adverse events (AEs) included transient hyperglycemia (57%), neutropenia (45%), thrombocytopenia, (37%), and transient hypertension (19%). However, AEs were manageable, and none were fatal. The overall response rate was 72% with a CR rate of 32%. Median duration of response was 8.2 months, progression-free survival was 6.9 months, and median overall survival was not reached. Combination treatment produced a greater CR rate in patients with angioimmunoblastic T-cell lymphoma than those with PTCL-not otherwise specified (55.6% versus 15.4%, respectively, P = 0.074) and progression-free survival was significantly longer (13.0 versus 5.1 months, respectively, P = 0.024). In an exploratory gene mutation analysis of 24 tumor samples, TSC2 mutation was present in 25% of patients and occurred exclusively in responders. Conclusion: The combination of copanlisib and gemcitabine is a safe and effective treatment option in relapsed/refractory PTCLs and represents an important new option for therapy in this rare group of patients.

AB - Background: Current treatment options for peripheral T-cell lymphomas (PTCLs) in the relapsed/refractory setting are limited and demonstrate modest response rates with rare achievement of complete response (CR). Patients and methods: This phase I/II study (NCT03052933) investigated the safety and efficacy of copanlisib, a phosphatidylinositol 3-kinase-α/-δ inhibitor, in combination with gemcitabine in 28 patients with relapsed/refractory PTCL. Patients received escalating doses of intravenous copanlisib on days 1, 8, and 15, administered concomitantly with fixed-dose gemcitabine (1000 mg/m2 on days 1 and 8) in 28-day cycles. Results: Dose-limiting toxicity was not observed in the dose-escalation phase and 60 mg copanlisib was selected for phase II evaluation. Twenty-five patients were enrolled in phase II of the study. Frequent grade ≥3 adverse events (AEs) included transient hyperglycemia (57%), neutropenia (45%), thrombocytopenia, (37%), and transient hypertension (19%). However, AEs were manageable, and none were fatal. The overall response rate was 72% with a CR rate of 32%. Median duration of response was 8.2 months, progression-free survival was 6.9 months, and median overall survival was not reached. Combination treatment produced a greater CR rate in patients with angioimmunoblastic T-cell lymphoma than those with PTCL-not otherwise specified (55.6% versus 15.4%, respectively, P = 0.074) and progression-free survival was significantly longer (13.0 versus 5.1 months, respectively, P = 0.024). In an exploratory gene mutation analysis of 24 tumor samples, TSC2 mutation was present in 25% of patients and occurred exclusively in responders. Conclusion: The combination of copanlisib and gemcitabine is a safe and effective treatment option in relapsed/refractory PTCLs and represents an important new option for therapy in this rare group of patients.

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Combination treatment of copanlisib and gemcitabine in relapsed/refractory PTCL (COSMOS): an open-label phase I/II trial

Abstract

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