Phase i dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

R. D. Kim, Steven Robert Alberts, C. Peña, I. Genvresse, A. Ajavon-Hartmann, C. Xia, A. Kelly, J. E. Grilley-Olson

Research output: Contribution to journalArticle

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Abstract

Background:Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo.Methods:A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed.Results:Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8 mg kg -1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29).Conclusions:Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

Original languageEnglish (US)
Pages (from-to)462-470
Number of pages9
JournalBritish Journal of Cancer
Volume118
Issue number4
DOIs
StatePublished - Feb 20 2018

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gemcitabine
Cisplatin
Biliary Tract Neoplasms
Neoplasms
Phosphatidylinositol 3-Kinase
Maximum Tolerated Dose
Safety
2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo(1,2-c)quinazolin-4-yl)pyrimidine-5-carboxamide
Class I Phosphatidylinositol 3-Kinases
Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase i dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer. / Kim, R. D.; Alberts, Steven Robert; Peña, C.; Genvresse, I.; Ajavon-Hartmann, A.; Xia, C.; Kelly, A.; Grilley-Olson, J. E.

In: British Journal of Cancer, Vol. 118, No. 4, 20.02.2018, p. 462-470.

Research output: Contribution to journalArticle

Kim, R. D. ; Alberts, Steven Robert ; Peña, C. ; Genvresse, I. ; Ajavon-Hartmann, A. ; Xia, C. ; Kelly, A. ; Grilley-Olson, J. E. / Phase i dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer. In: British Journal of Cancer. 2018 ; Vol. 118, No. 4. pp. 462-470.
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title = "Phase i dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer",
abstract = "Background:Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo.Methods:A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed.Results:Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8 mg kg -1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86{\%}), hyperglycaemia (80{\%}) and decreased platelet count (80{\%}). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3{\%} (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12{\%} (one complete response and three partial responses all in patients with BTC (response rate 17.4{\%} in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41{\%} (12 out of 29).Conclusions:Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.",
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T1 - Phase i dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

AU - Kim, R. D.

AU - Alberts, Steven Robert

AU - Peña, C.

AU - Genvresse, I.

AU - Ajavon-Hartmann, A.

AU - Xia, C.

AU - Kelly, A.

AU - Grilley-Olson, J. E.

PY - 2018/2/20

Y1 - 2018/2/20

N2 - Background:Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo.Methods:A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed.Results:Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8 mg kg -1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29).Conclusions:Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

AB - Background:Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α/activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo.Methods:A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed.Results:Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8 mg kg -1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29).Conclusions:Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

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