Marius Giurescu

Phase-I study of sagopilone in combination with cisplatin in chemotherapy-naive patients with metastasised small-cell lung cancer

BACKGROUND Sagopilone (ZK219477) is a new and fully synthetic epothilone with activity against multi-drug resistant tumour cell lines. It has demonstrated clinical activity in several solid tumours like ovarian cancer and melanoma. Data about clinical efficacy of sagopilone in small-cell lung cancer are lacking. Here we report the first phase-I trial of sagopilone in combination with cisplatin in previously untreated metastatic small-cell lung cancer patients. METHODS Chemonaive patients with metastatic small-cell lung cancer (SCLC) received sagopilone in four different dosing schedules ranging from 12 to 22 mg/m(2) (on day 1 as 3-h infusion) followed by a fixed dose of cisplatin of 75 mg/m(2) as 1-h infusion on day 1. Chemotherapy was administered every 3 weeks to a maximum of six cycles. The primary objective was determination of dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) in this setting. Secondary objectives were assessment of objective response rates (ORR) as well as investigation of sagopilone pharmacokinetics. RESULTS Twenty-six patients received a total of 107 treatment cycles of the platinum-sagopilone doublet. The recommended phase-II dose (RD) and schedule was found to be 19 mg/m(2) sagopilone followed by 75 mg/m(2) cisplatin. Peripheral neuropathy turned out as dose-limiting toxicity when the combination was administered over a median of four cycles. Objective responses were observed in six out of seven SCLC patients (85.7%) treated with the RD. CONCLUSIONS Sagopilone and cisplatin can be safely combined in the first-line treatment of metastasised SCLC. This combination demonstrated preliminary efficacy and should be further evaluated within phase-II trials.

Abstract 5239: KRAS wild-type status as detected by circulating tumor DNA analysis may be a prognostic or predictive factor for clinical benefit in patients with unresectable, locally advanced or metastatic pancreatic cancer (PC) treated with the MEK inhibitor refametin

Background: Mutationally-activated KRAS is present in 90% of pancreatic ductal adenocarcinoma (PDAC) and may represent an early genetic driver, being commonly found in low-grade pancreatic lesions (Eser et al. 2014 BJC 111:817). Refametinib is a potent oral allosteric MEK 1/2 inhibitor with both single-agent activity and synergistic activity in combination with gemcitabine in preclinical models of pancreatic cancer (PC). A Phase 1B/2 study in patients with locally advanced, unresectable or metastatic PC and no prior systemic therapy was conducted and recently reported (Van Laethem et al., ASCO 2014; NCT01251640). We report here on the exploratory biomarker findings from this study. Methods: KRAS mutational analysis was conducted via liquid biopsy at baseline on circulating tumor DNA (ctDNA) by BEAMing (Sysmex-Inostics) as well as circulating micro RNA (miRNA) from plasma collected at baseline and post-dose and analyzed by qPCR using an Exiqon panel of 752 miRNAs and an innovative data preprocessing method for normalization and imputation of undetermined values. Tumor molecular characterization was performed on archival tumor tissue and included targeted tumor gene next-generation sequencing with FOUNDATION ONE and the analysis of Ki67 proliferation index. Results: Samples for biomarker analysis were obtained from 69 treated patients. Forty-six (67%) had detectable KRAS mutations by liquid biopsy. KRAS G12D, G12V and G12R were the most frequent mutations. Interestingly, KRAS wild-type patients had better efficacy outcomes compared to mutant KRAS patients (mut/WT, respectively): overall response rate 15%/30% (OR 2.4, p = 0.147), median progression-free survival (mPFS) 3.7/8.8 mo (HR 0.32, p = 0.001), and overall survival (OS) 7.1/18.2 mo (HR 0.28, p = 0.001). There was a trend correlating KRAS mutant allele frequency with response. The CA19.9 levels correlated with KRAS mutational status. Tumor exome sequencing was performed from 16 patients, 15 of which had a KRAS mutation (G12D or G12V). The discordancy rate compared to BEAMing KRAS data was 26% (4/15). Conclusions: The high prevalence of KRAS mutations in patients with PC has been confirmed using BEAMing technology. In this study, there was an association between improved mPFS and OS in KRAS WT patients. Together with lower baseline levels of CA19.9 in the KRAS WT cohort, we conclude that liquid biopsy may be an approach to identify prognostic or predictive markers in PDAC treated with refametinib and gemcitabine. This hypothesis is sustained by the finding that poor clinical response showed increasing allele frequency of mutant KRAS. These results require confirmation in a larger trial. Citation Format: Michael Teufel, Jean-Luc Van Laethem, Hanno Riess, Marius Giurescu, Vittorio L. Garosi, Anke Schulz, Richardus Vonk, Henrik Seidel, Joachim Reischl, Barrett H. Childs. KRAS wild-type status as detected by circulating tumor DNA analysis may be a prognostic or predictive factor for clinical benefit in patients with unresectable, locally advanced or metastatic pancreatic cancer (PC) treated with the MEK inhibitor refametin [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5239. doi:10.1158/1538-7445.AM2015-5239

Abstract CT215: CHRONOS-1: Open-label, uncontrolled phase II trial of intravenous phosphatidylinositol-3 kinase alpha/delta inhibitor copanlisib in patients with relapsed, indolent Non-Hodgkin's lymphomas (iNHL)

Background: Copanlisib is a novel pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with potent preclinical inhibitory activity against both PI3K-δ and PI3K-α isoforms. Results from a phase II study of copanlisib in 67 patients with relapsed/refractory indolent or aggressive lymphoma have been reported, with a promising overall response rate for 53% seen for patients in the indolent lymphoma group (Dreyling et al., ASH 2014; Dreyling et al., ENA 2014). Enrollment in an expansion cohort of 120 patients with indolent lymphoma has been initiated. The objective of the study is to evaluate the efficacy and safety of copanlisib in patients with indolent B-cell NHL relapsed after or refractory to standard therapy. Methods: In this study (NCT01660451), patients meeting the following criteria will be eligible for enrollment: histologically confirmed diagnosis of indolent B-cell NHL, with follicular lymphoma (FL) grade 1-2-3a, marginal zone lymphoma (MZL; splenic, nodal, or extra-nodal), small lymphocytic lymphoma (SLL) with absolute lymphocyte count The trial is currently enrolling patients. Citation Format: Martin Dreyling, Marius Giurescu, Julia Grunert, Felipe Fittipaldi, Lisa Cupit, Barrett H. Childs. CHRONOS-1: Open-label, uncontrolled phase II trial of intravenous phosphatidylinositol-3 kinase alpha/delta inhibitor copanlisib in patients with relapsed, indolent Non-Hodgkin9s lymphomas (iNHL). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT215. doi:10.1158/1538-7445.AM2015-CT215

Abstract CT221: CHRONOS-3: A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of phosphatidylinositol-3 kinase (PI3K) alpha/delta inhibitor copanlisib in combination with rituximab in patients with relapsed indolent B-c

Background: Copanlisib is a novel pan-Class I PI3K inhibitor with potent preclinical inhibitory activity against both PI3K-δ and PI3K-α isoforms. In a phase II study of copanlisib monotherapy in patients with relapsed/refractory indolent or aggressive lymphoma, an overall response rate of 53% was seen in patients with iNHL (Dreyling et al., ENA 2014). Rituximab in combination with chemotherapy is standard first-line therapy for indolent iNHL and is a therapeutic option for relapsed patients who cannot tolerate chemotherapy or who had a long response following the last rituximab-based therapy. The objective of this study is to evaluate the efficacy and safety of copanlisib in combination with rituximab versus placebo plus rituximab in patients with iNHL who relapsed after one or more lines of therapy, including rituximab and alkylating agents, and who are either unfit for chemotherapy or had a treatment-free interval of at least 12 months following last rituximab-based therapy. Methods: Patients must meet the following criteria: histologically confirmed diagnosis of iNHL, with follicular lymphoma (FL) grade 1-2-3a, marginal zone lymphoma (splenic, nodal, or extra-nodal), small lymphocytic lymphoma, or lymphoplasmacytoid lymphoma/Waldenstrom macroglobulinemia, and who have previously received at least one line of therapy including rituximab and alkylating agents. Patients must be not refractory to rituximab during any prior line of therapy (response Citation Format: Pier Luigi Zinzani, John F. Gerecitano, Marius Giurescu, Rodrigo Ito, Katharina Mueller, Barrett H. Childs. CHRONOS-3: A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of phosphatidylinositol-3 kinase (PI3K) alpha/delta inhibitor copanlisib in combination with rituximab in patients with relapsed indolent B-c [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT221. doi:10.1158/1538-7445.AM2015-CT221