Barrett H. Childs

Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma

Abstract Background Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms. Patients and methods This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. Results Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2–138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0–874) and 70 days (range 0–897), respectively; median duration of response was 390 days (range 0–825) and 166 days (range 0–786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression. Conclusion Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing. This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).

Abstract CT085: Phase III randomized, double-blind, controlled studies of the PI3K inhibitor copanlisib in combination with rituximab or rituximab-based chemotherapy in subjects with relapsed indolent B-cell non-Hodgkin's lymphoma (iNHL): CHRONOS-3 and CHRONOS-4

Background: Patients with newly diagnosed iNHL generally receive rituximab (R) either alone or given with an alkylating agent (bendamustine, ie R-B) or a chemotherapy combination containing an alkylating agent (CHOP, ie R-CHOP). Patients progressing after 6 months or more from last treatment are considered to be R-sensitive and candidates for re-treatment, whether with R treatment alone if ineligible for treatment with an alkylating agent or with a different R-chemotherapy treatment compared to initial treatment. Copanlisib is a novel pan-Class I PI3K inhibitor with potent preclinical inhibitory activity against both PI3K-δ and PI3K-α isoforms. Copanlisib has activity as monotherapy in patients with relapsed or refractory iNHL (Dreyling et al., ASH 2014). Therefore, in two separate phase III studies in the second line setting, we seek to evaluate the efficacy and safety of copanlisib in combination with R or R-based chemotherapy; namely CHRONOS-3, copanlisib plus R versus placebo plus R; and CHRONOS-4, copanlisib plus chemotherapy (R-B or R-CHOP) versus chemotherapy alone. The primary endpoints are progression-free survival. Methods: Patients must have histologically confirmed diagnosis of iNHL (including follicular lymphoma, marginal zone lymphoma (splenic, nodal, or extra-nodal), small lymphocytic lymphoma, or lymphoplasmacytoid lymphoma/Waldenstrom macroglobulinemia) and 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 For CHRONOS-3, patients will be randomized 2:1 to copanlisib (60 mg) or placebo administered intravenously on days 1, 8 and 15 of a 28-day cycle in combination with 375 mg/m2 of rituximab administered on days 1, 8, 15 and 22. Radiologic tumor assessment will be performed every 8, 12, or 24 weeks for years 1, 2, and 3, respectively. For CHRONOS-4, there will be an initial safety run-in with 45 mg copanlisib with either R-B or R-CHOP and if well tolerated, 60 mg, on days 1, 8, and 15 of a 28-day cycle with B iv 90 mg/m2 days 1 and 2, or on days 1 and 8 of a 21-day cycle with CHOP per standard dosing. After the run-in phase, patients eligible to receive R-B or R-CHOP will be randomized 1:1 to either copanlisib or placebo and receive up to 6 cycles of R-B or R-CHOP after which they will receive either copanlisib or placebo as monotherapy. Radiologic tumor assessment will be performed every 12 weeks for years 1 and 2, and every 24 weeks years 3-5. Citation Format: John F. Gerecitano, Pier L. Zinzani, HongXia Zheng, Rodrigo Ito, Paula Y. Tanaka, Katharina Mueller, Jason Yuan, Barrett H. Childs. Phase III randomized, double-blind, controlled studies of the PI3K inhibitor copanlisib in combination with rituximab or rituximab-based chemotherapy in subjects with relapsed indolent B-cell non-Hodgkin9s lymphoma (iNHL): CHRONOS-3 and CHRONOS-4. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT085.

Abstract CT084: A randomized, double-blind phase III study of phosphatidylinositol-3 kinase alpha/delta inhibitor copanlisib versus placebo in patients with rituximab-refractory indolent non-Hodgkin's lymphoma (iNHL): CHRONOS-2

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. A phase II study of copanlisib in patients with relapsed/refractory indolent or aggressive lymphoma reported promising activity in the indolent NHL group (Dreyling et al., ENA 2014). The objective of this 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: Patients meeting the following criteria are 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 Citation Format: Grzegorz S. Nowakowski, Igor Gorbatchevsky, Florian Hiemeyer, Lisa Cupit, Barrett H. Childs. A randomized, double-blind phase III study of phosphatidylinositol-3 kinase alpha/delta inhibitor copanlisib versus placebo in patients with rituximab-refractory indolent non-Hodgkin9s lymphoma (iNHL): CHRONOS-2. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT084.

Abstract 5252: Liquid biopsies to prospectively select patients with KRAS or NRAS mutant hepatocellular carcinoma (HCC) in two phase II studies with Refametinib

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: In a retrospective analysis performed in a phase II study evaluating efficacy and safety of the MEK-inhibitor refametinib plus sorafenib in Asian patients with HCC (Lim et al., Clin Cancer Res, in press), patients with mutant RAS appeared to exhibit a particularly robust clinical response to refametinib plus sorafenib compared to patients with wild-type RAS. To further investigate clinical activity of refametinib as monotherapy or in combination with sorafenib in HCC patients with mutant RAS, two Ph II studies for patients with unresectable HCC have been initiated; refametinib monotherapy ([NCT01915589][1]) and refametinib plus sorafenib combination therapy ([NCT01915602][2]). Since RAS mutations are very rare events in HCC and biopsies are not routinely taken in patients with underlying liver cirrhosis, only liquid biopsies seemed feasible for prospective patient selection. Therefore, Sysmex Inostics’ BEAMing (Beads, Emulsions, Amplification, and Magnetics) technology based on cell-free circulating DNA in plasma is used to select patients for KRAS/NRAS Mutation status prior to enrollment. Patients are eligible if they exhibit any one or multiple of 13 KRAS/NRAS mutations. Results: Between Sep 2013 and Nov 2014 more than 1000 plasma samples from patients with unresectable HCC enrolled in the refametinib monotherapy study or the refametinib plus sorafenib combination study, have been tested at a CLIA certified laboratory in Baltimore, MD. The turnaround time from shipping the plasma sample from the clinical trial site to the results reporting was 6-10 days. Out of 1004 samples from 116 trial sites in 18 countries, 47 (4.7%) have been reported to harbor a KRAS and / or a NRAS mut. The following mutations have been reported: KRAS\_G12A, KRAS\_G12C, KRAS\_G12D, KRAS\_G12R, KRAS_ G12S, KRAS\_G12V, KRAS\_G13D, NRAS\_Q61K, NRAS\_Q61L, NRAS\_Q61H, NRAS\_Q61R. The frequency of the mutant allele ranged from 0.02% to 9.75%. No obvious differences in the incidence of any of the mutations with regards to geography, demographic factors are other baseline characteristics have been observed. Conclusion: To our knowledge this is the largest dataset of KRAS and NRAS mutations in HCC. The observed prevalence of RAS mutations of approximately 5% across both trials is well in line with published data including the COSMIC database. Our data support that prospective selection of patients with HCC for KRAS or NRAS mutation is feasible with a turn-around time of 1-2 weeks depending on geographical region. These data further support the broad utility of such approaches for large randomized prospective studies in patients with specific tumor genetic profiles. The clinical outcome of the 2 clinical studies will help understand whether KRAS or NRAS can potentially be a predictive marker for response to refametinib in patients with HCC. Citation Format: Heiko Krissel, Andrea Hennig, Danny Zhang, Rodrigo Ito, Christine Gonschorek, Fabricio Souza, Martina Poethig, Kathleen Schostack, Joachim Reischl, Philipp Angenendt, Barrett H. Childs, Michael Teufel. Liquid biopsies to prospectively select patients with KRAS or NRAS mutant hepatocellular carcinoma (HCC) in two phase II studies with Refametinib. [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 5252. doi:10.1158/1538-7445.AM2015-5252 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01915589&atom=%2Fcanres%2F75%2F15_Supplement%2F5252.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01915602&atom=%2Fcanres%2F75%2F15_Supplement%2F5252.atom

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

INTEGRATED SAFETY DATA WITH COPANLISIB MONOTHERAPY FROM PHASE I AND II TRIALS IN PATIENTS WITH RELAPSED INDOLENT NON-HODGKIN'S LYMPHOMA

relapsed disease. Obinutuzumab has increased antibody dependent cellular cytotoxicity (ADCC) compared to rituximab in preclinical models and is approved for FL. We hypothesized that the immunologic properties of obinutuzumab and lenalidomide would be synergistic in relapsed FL. The studys objectives were to determine the MTD of lenalidomide with obinutuzumab and describe the efficacy of the combination. Methods: This open label phase I/II study enrolled relapsed/refractory Gr 1–3a FL. Exclusions included transformation, prior malignancy, and infection. Lenalidomide was given on D 2–22 with 1000 mg obinutuzumab on D1, 8, 15, and 22 of cycle 1 and monthly on D 1 for up to 12 cycles. Extended dosing with obinutuzumab was given every 2 months thereafter for up to 30 months total in patients (pts) who responded following doublet therapy. During phase I, three escalating dose levels were planned with 10, 15, and 20 mg of lenalidomide. Phase II planned to enroll 30 pts at MTD with efficacy and safety as primary endpoints. Results: All 36 pts with FL enrolled (6 in dose escalation and 30 at MTD), and all are eligible for efficacy and safety analysis. The median age was 65 with a median of 2 prior therapies. No DLTs were observed in phase I, and 20 mg of lenalidomide was used for the phase II dose. To date, the most common all grade non‐hematologic toxicities included fatigue (83%), diarrhea (67%), and rash (53%). Grade 3+ toxicities included neutropenia (23%), infection (11%), and fatigue (8%). The overall response rate was 100% with 78% (95% CI: 60.85–89.88%), of pts attaining complete remission (CR/Cru). At a median follow up of 14 months, 10 pts progressed. The estimated 24 month PFS is 61% (95% CI: 43–87%). Conclusions: Lenalidomide and obinutuzumab is highly active with durable remissions in relapsed FL, with all pts responding and 78% achieving CR. The majority of pts remain on therapy and the combination appeared safe. Correlatives are ongoing to identify biomarkers of response and frontline studies of the combination are currently enrolling.

Abstract CT149: Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: Primary results of the pivotal Chronos-1 study

Introduction: There are limited treatment options for patients with indolent B-cell lymphoma who have relapsed or are refractory to standard therapies. Copanlisib is an intravenously administered pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against PI3K-α and PI3K-δ isoforms. We report here the primary results from a pivotal phase II study (NCT01660451, part B). Methods: Patients with indolent B-cell non-Hodgkin lymphoma (4 subtypes: follicular [FL], marginal zone [MZL], small lymphocytic [SLL] and lymphoplasmacytoid/Waldenstrom macroglobulinemia [LPL-WM]) and relapsed after, or refractory to, ≥2 prior lines of treatment were eligible. Previous treatment had to include rituximab and an alkylating agent. Copanlisib (60 mg, I.V.) was intermittently administered on days 1, 8 and 15 of a 28-day cycle. The primary efficacy endpoint was objective tumor response rate (ORR) as assessed per independent radiologic review (Cheson et al., JCO 20:579, 2007). Results: The full analysis set comprised 142 patients, of which 141 patients had indolent lymphoma (FL/MZL/SLL/LPL-WM: 104/23/8/6). At the time of primary analysis, median duration of treatment was 22 weeks (range 1-105); 46 patients remained on treatment. The most common treatment-related AEs (all grade/grade 3+) were transient hyperglycemia (49%/40%) and hypertension (29%/23%). Other AEs of interest included neutropenia (25%/19%), diarrhea (18%/4%), lung infection (14%/11%), pneumonitis (7%/1.4%), and colitis (0.7%/0.7%). No colonic perforations occurred. There were two non-fatal opportunistic infections. Laboratory toxicities of interest were principally grade-1, including alanine aminotransferase (23% all-grade/19% grade-1) and aspartate aminotransferase (28%/25%). There were 6 deaths, 3 of which were attributed to copanlisib: lung infection, respiratory failure, and a thromboembolic event. The ORR was 59.2%, including 12.0% complete response (CR) and 47.2% partial response (PR), with stable disease in 29.6% of patients and progressive disease in 2.1% of patients. In the FL subset, the ORR was 58.7%, including 14.4% CR and 44.2% PR. In the MZL subset, the ORR was 69.6%, including 8.7% CR and 60.9% PR. The estimated Kaplan-Meier (KM) median duration of response in the full analysis set was 687 days (range 0-687) and 370 days (range 0-687) in the FL subset. The KM-estimate of median PFS was 340 days (range 0-736). Median overall survival had not yet been reached. Conclusions: Treatment of patients with relapsed or refractory indolent B-cell lymphoma with copanlisib resulted in durable tumor responses. Administration of copanlisib had a manageable safety profile, with low rates of severe hepatic enzymopathy, diarrhea or inflammatory events, as well as low rates of opportunistic infections, fatal infections or other fatal serious adverse events. Citation Format: Martin Dreyling, Armando Santoro, Luigina Mollica, Sirpa Leppa, George A. Follows, Georg Lenz, Won Seog Kim, Arnon Nagler, Panayiotis Panayiotidis, Judit Demeter, Muhit Ozcan, Marina Kosinova, Krimo Bouabdallah, Franck Morschhauser, Don A. Stevens, David Trevarthen, Marius Giurescu, Lisa Kupit, Shuxin Yin, Florian Hiemeyer, Jose Garcia-Vargas, Barrett H. Childs, Pier Luigi Zinzani. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: Primary results of the pivotal Chronos-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT149. doi:10.1158/1538-7445.AM2017-CT149

Abstract CT083: A pivotal randomized phase II study of anetumab ravtansine or vinorelbine in patients with advanced or metastatic pleural mesothelioma after progression on platinum/pemetrexed-based chemotherapy (NCT02610140)

Background: Mesothelioma is a rare but aggressive cancer with a 5-year survival rate less than 10%. Mesothelin is a protein normally present on mesothelial cells and overexpressed in the majority of mesotheliomas. Anetumab ravtansine (BAY 94-9343) is a novel fully human anti-mesothelin IgG1 antibody conjugated to ravtansine, an antitubulin cytotoxic agent. In a phase I study, anetumab ravtansine at 6.5 mg/kg on a q3w IV schedule was well tolerated and showed encouraging durable tumor responses in patients with previously treated mesothelioma. Design: A randomized, open-label, active-controlled, 2-arm, multicenter, phase II trial to evaluate the efficacy and safety of anetumab ravtansine at 6.5 mg Q3W versus vinorelbine 30 mg/m2 QW in patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin and who have progressed on first-line platinum/pemetrexed-based chemotherapy. Objectives: The primary objective is to test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS). The secondary objectives of this study include overall survival, patient-reported outcomes (PRO), tumor response, and safety. Exploratory objectives include immunogenicity of anetumab ravtansine, pharmacokinetics, and biomarkers of response. Methods: Biomarker sampling will be performed on all patients to measure tumor mesothelin expression levels at prescreening. Biomarker-positive patients with moderate (2+) and/or strong (3+) level in at least 30% of tumor cells will be randomized and start study treatment following progression after 1st line treatment of platinum/pemetrexed (with or without bevacizumab). Approximately 183 patients meeting eligibility criteria will berandomized in a 2:1 ratio to receive anetumab ravtansine or vinorelbine. Randomization will be stratified by geographic region (Rest of World v. Asia) and time to progression on 1st line treatment (? 6 months vs Results: This trial is open and currently accruing patients. Citation Format: Raffit Hassan, John J. Nemunaitis, Jan P. van Meerbeeck, Ross Jennens, George R. Blumenschein, Jr, Dean A. Fennell, Hedy L. Kindler, Silvia Novello, Cem Elbi, Annette Walter, Danila Serpico, Emma Fountain, Sandra Vingerhoedt, Christine Brown, Jonathan Siegel, Barrett H. Childs. A pivotal randomized phase II study of anetumab ravtansine or vinorelbine in patients with advanced or metastatic pleural mesothelioma after progression on platinum/pemetrexed-based chemotherapy (NCT02610140). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT083.

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