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Ann Oncol. 2016 Oct;27(10):1928-40. doi: 10.1093/annonc/mdw282.

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.

Author information

1
South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio amita.patnaik@start.stoh.com.
2
University of Pittsburgh, Pittsburgh.
3
South Texas Accelerated Research Therapeutics (START) Center for Cancer Care, San Antonio.
4
Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale Cancer Treatment Centers of America, Goodyear.
5
Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale.
6
Bayer HealthCare Pharmaceuticals, Inc., Whippany, USA.
7
Bayer Pharma AG, Berlin, Germany.

Abstract

BACKGROUND:

To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL).

PATIENTS AND METHODS:

Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially.

RESULTS:

Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years.

CONCLUSION:

Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL.

CLINICALTRIALSGOV:

NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

KEYWORDS:

PI3K inhibitor; advanced cancer; copanlisib; non-Hodgkin's lymphoma

PMID:
27672108
PMCID:
PMC5035790
DOI:
10.1093/annonc/mdw282
[Indexed for MEDLINE]
Free PMC Article

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