First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas

Patnaik, Amita; Appleman, Leonard Joseph; Tolcher, Anthony W.; Papadopoulos, Kyriakos P.; Beeram, Muralidhar; Rasco, Drew W.; Weiss, Glen J.; Sachdev, Jasgit C.; Chadha, Manpreet K.; Fulk, Monica; Ejadi, Samuel; Mountz, James M.; Lotze, Michael T.; Toledo, Frederico G.S.; Chu, Edward; Jeffers, Michael; Peña, Carol; Xia, Chenghua; Reif, Stefanie; Genvresse, Isabelle; Ramanathan, Ramesh K.

doi:10.1093/annonc/mdw282

Cited by 193 publications

(201 citation statements)

References 40 publications

(55 reference statements)

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“…The mean terminal half-life was 52-h (40–67-h) and is in accordance with the known PK of copanlisib (range 16.9–72.7-h) [8]. The mean recovery of total radioactivity was about 86% within a collection interval of 20–34 days: about 64% in feces and about 22% in urine.…”

Section: Discussionsupporting

confidence: 79%

“…Three mild-to-moderate gastrointestinal adverse events related to copanlisib were reported, which are well-known effects of PI3K inhibitors [8]. …”

Section: Discussionmentioning

confidence: 99%

“…At the MTD dose of 0.8 mg/kg (approximately equivalent to 60 mg absolute dose), copanlisib as monotherapy demonstrated promising efficacy in patients with solid tumors and hematological malignancies [8]. …”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers

Gerisch

Schwarz

Lang

et al. 2017

Cancer Chemother Pharmacol

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PurposeTo determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib.MethodsA single dose of 12 mg copanlisib containing 2.76 MBq [14C]copanlisib was administered as a 1-h intravenous infusion to 6 volunteers with subsequent sampling up to 34 days. Blood, plasma, urine and feces were collected to monitor total radioactivity, parent compound and metabolites.ResultsCopanlisib treatment was well tolerated. Copanlisib was rapidly distributed throughout the body with a volume distribution of 1870 L and an elimination half-life of 52.1-h (range 40.4–67.5-h). Copanlisib was the predominant component in human plasma (84% of total radioactivity AUC) and the morpholinone metabolite M1 was the only circulating metabolite (about 5%). Excretion of drug-derived radioactivity based on all 6 subjects was 86% of the dose within a collection interval of 20–34 days with 64% excreted into feces as major route of elimination and 22% into urine. Unchanged copanlisib was the main component excreted into urine (15% of dose) and feces (30% of dose). Excreted metabolites (41% of dose) of copanlisib resulted from oxidative biotransformation.ConclusionsCopanlisib was eliminated predominantly in the feces compared to urine as well as by hepatic biotransformation, suggesting that the clearance of copanlisib would more likely be affected by hepatic impairment than by renal dysfunction. The dual mode of elimination via unchanged excretion of copanlisib and oxidative metabolism decreases the risk of clinically relevant PK-related drug–drug interactions.

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Section: Discussionsupporting

confidence: 79%

“…Three mild-to-moderate gastrointestinal adverse events related to copanlisib were reported, which are well-known effects of PI3K inhibitors [8]. …”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers

Gerisch

Schwarz

Lang

et al. 2017

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

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“…The first-in-human study showed promising results in the NHL cohort of nine patients, with a 77% ORR and manageable toxicities of hyperglycemia and hypertension [87], leading to multiple phase II studies. An open-label phase II trial of copanlisib (CHRONOS-1, NCT01660451) examined efficacy and safety in patients who failed at least two prior lines of therapy for indolent or aggressive NHL (part A) with a second portion of the study specifically devoted to patients with relapsed/refractory indolent lymphoma (part B).…”

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

“…Hyperglycemia is a known side effect of p110α inhibition. The hypertension is unexplained and is not a side effect commonly seen with other pan-PI3K inhibitors [87]. Both the hyperglycemia and hypertension are transient, resolving within 24 h of the infusion.…”

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Lampson

Brown

2017

Expert Opinion on Investigational Drugs

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Introduction Phosphatidylinositol-3-kinase (PI3K) inhibitors comprise a novel class of agents that are effective for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL). The demonstrated efficacy and subsequent FDA approval of the prototypical PI3Kδ inhibitor idelalisib has led to development of multiple compounds targeting this pathway. Areas Covered We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of tonic signaling from the B cell receptor, blockade of pro-survival signals from the microenvironment, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections and sepsis (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We then summarize PI3K inhibitors that have entered clinical trials for the treatment of lymphoma, focusing on agents with significant selectivity for PI3Kα and PI3Kδ. Expert Opinion PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, in comparison to other novel agents, idelalisib has infectious and autoimmune toxicities that have limited its use. Outside of clinical trials, the use of PI3K inhibitors should be restricted to CLL patients who have progressed on ibrutinib or iNHL patients who have progressed on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

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Pharmacologic Differentiation of Drugs Targeting the PI 3K‐ AKT ‐m TOR Signaling Pathway

Ahn¹,

Brown²,

Davids³

2023

Precision Cancer Therapies, Volume 1 ‐ Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

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First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas

Cited by 193 publications

References 40 publications

Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers

Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Pharmacologic Differentiation of Drugs Targeting the PI 3K‐ AKT ‐m TOR Signaling Pathway

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