ALBERT

Description: Background DCDS4501A (DCDS), an anti-CD79b monoclonal antibody (Ab), is conjugated to the anti-mitotic agent MMAE. We previously determined a recommended Phase II dose (RP2D) of 2.4 mg/kg every 21 days (q21d), and clinical activity in R/R B-cell NHL at doses ≥ 1.8 mg/kg (Palanca-Wessels et al. ASH 2012). Here we update results from patients (pts) treated at 1.8 mg/kg and from the 2.4 mg/kg expansion cohort. Methods We evaluated ongoing safety, tolerability, pharmacokinetics (PK) and activity of DCDS with or without rituximab (RTX) at 375 mg/m2 q21d in pts with R/R DLBCL and indolent (i)NHL. Results Sixty pts were treated with DCDS (6 at 1.8 mg/kg, 45 at 2.4 mg/kg) and DCDS+RTX (9, DCDS at 2.4 mg/kg). Median age 68 yrs (range 20-86); 82% ECOG PS100-fold lower than acMMAE with an average Cycle 1 value of 5-9 ng/mL at the 2.4 mg/kg ADC dose level. Moderate accumulation of acMMAE and total Ab on the q21d dosing schedule was observed with no accumulation of free MMAE. Overall objective responses were observed in 27/51 (53%) DCDS and 7/9 (78%) DCDS+RTX pts. Objective (OR) and complete responses (CR) by histology were as follows: The median PFS for DLBCL patients treated with DCDS or DCDS + RTX was 149 days. The median PFS for iNHL patients treated with DCDS or DCDS + RTX was 241 days. Conclusions DCDS and DCDS+RTX were generally well-tolerated. Neutropenia and PN were the principal toxicities. PN was reversible in some patients with dose delays and reductions. Encouraging anti-tumor activity was observed in heavily pretreated pts with R/R NHL. Updated results from this Phase I study will be presented. An ongoing randomized Phase II study of DCDS+RTX versus a CD22-directed ADC (DCDT2980S) with the same linker-cytotoxic agent in patients with R/R DLBCL and follicular lymphoma will further assess the efficacy of DCDS in the treatment of NHL. Additional studies of DCDS combined with immunochemotherapy are being planned. Disclosures: Palanca-Wessels: Genentech, inc.: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate in r/r B-cell NHL. Salles:Genentech, inc.: Consultancy. Czuczman:Genentech, inc.: Consultancy, Honoraria. Flinn:Genentech, inc.: Research Funding. Sehn:Genentech, inc.: Consultancy, Honoraria, Research Funding. Tilly:Genentech, inc.: Honoraria. Advani:Genentech, inc.: Research Funding. Casasnovas:Genentech, inc.: Research Funding. Press:Genentech, inc.: Consultancy, Research Funding. Yalamanchili:Genentech, inc.: Employment. Kahn:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Chai:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Morschhauser:Genentech, inc.: Honoraria, Research Funding.

Description: Introduction. A substantial proportion of patients (pts) affected by Chronic Myeloid Leukemia (CML) achieve complete negativity in Q-RT-PCR. In this situation, as already demonstrated in other STOP trials, it is possible to safely discontinue imatinib treatment but it is still not clear how to discriminate subjects who will relapse. In fact even undetectable BCR-ABL may not equate to eradication of the disease because of the sensitivity of Q-RT-PCR. A new diagnostic method, the digital-PCR (dPCR), able to detect 1 BCR-ABL+ cell out of 107 cells, has been developed. Therefore, dPCR by assessing the presence of minimal residual disease with higher sensitivity, could potentially identify pts in whom CML has been eradicated. Aims. The ISAV study is aimed at validating the capability of dPCR to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR results and to evaluate relapse rate and timing of recurrence, survival and the impact of imatinib treatment on Quality of Life (QoL). Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (Chronic or Accelerated Phase) under imatinib therapy since more than 2 years and in complete molecular remission (CMR) were eligible. Patients had to be in CMR for at least 18 months (mts), with a minimum of 3 Q-RT-PCR performed at their own sites. After signing the informed consent, blood samples were obtained for dPCR and the pts discontinued imatinib therapy. Standard Q-RT-PCR is performed monthly (mts 1-6) and then bimonthly for 36 mts to assess the maintenance of the molecular remission. The loss of molecular remission is defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resume imatinib treatment at the same dosage used before interruption. Patients' QoL during imatinib discontinuation/resumption is evaluated through the EORTC QLQ-C30 questionnaire. Results. The study enrolled 112 pts with a median follow-up (FUP) time of 28.0 mts [95% CI: 25.5-30.1]. The 59.3% of pts were male and 37.0% were aged 65 or older; median duration of imatinib treatment was 103.1 mts with median duration of CMR of 25.7 mts before imatinib discontinuation. The cumulative probability of survival is 97.8% [95% CI: 91.4-99.5]. dPCR results showed that 23.1% of pts were positive and 75.9% negative, with a significant Negative Predictive Value ratio (dPCR/Q-RT-PCR) of 1.112 [95% CI: 1.009-1.225]. At 24 mts from imatinib discontinuation, 53 pts (49.1%, 95% CI: 39.3-58.9) of the 108 eligible pts relapsed and resumed imatinib; 73.6% of them relapsed in the first 9 mts and the last relapse occurred 21.8 mts after imatinib discontinuation. A loss of CCyR occurred in 13 pts (34.2% of those tested): 10/13 CCyR losses were recovered, the remaining 3 were not assessed for response. No case of CML progression or resistance to imatinib was observed. After the resumption of imatinib the median time to MMR/CMR was 1.9 [95% CI: 1.2-2.4] mts. Of the 55 not-relapsed pts, 42 (38.9% of the total) regained Q-RT-PCR positivity but never lost MMR. The median time to Q-RT-PCR positivity was 2.9 mts [95% CI: 2.0-3.1] in the relapsed pts and 4.5 mts [95% CI: 2.9-6.9] in pts who developed only PCR positivity. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR, Sokal score or duration of CMR was identified, while an inverse relationship between pts age and risk of relapse is evident. Moreover, age and dPCR results together can predict the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥ 45 years and with negative dPCR (36.1%). The analysis of QoL evidenced a statistically significant improvement in the general well-being and symptoms scales at 1 month after imatinib discontinuation and in particular nausea, diarrhea and fatigue (p

Description: Abstract 1942 Poster Board I-965 Introduction: The trial showing that the addition of rituximab to the CHOP regimen increases complete response (CR) rate and overall survival (OS) in elderly patients (pts) with diffuse large B-cell lymphoma (DLBCL) did not include pts over the age of 80 (Coiffier, 2002, NEJM). There is very limited data on octogenarians with DLBCL. These pts are often treated with reduced-dose therapeutic regimens, which may lead to a poorer OS (Meyer, 1995, J Clin Oncol). We were interested in examining the proportion of pts with DLBCL aged 80 and over in our institution; to characterize the determinants of their OS; to assess how many received standard therapy; and, to define which characteristics lead physicians to withhold therapy. Patients and method: A retrospective chart analysis was conducted of clinical and pathological data on all new cases of DLBCL from 2004 to 2008. Clinical data collected included International Prognostic Index (IPI), LDH, therapy received, and survival. Pathologic data included presence or absence of bcl-6 and/or bcl-2 expression, and proliferative fraction as determined by the level of Ki-67. This study received IRB approval. A Kaplan-Meier survival analysis was performed, Fisher's exact test was used to estimate p value for proportions, and confidence intervals were estimated for means. Results: We identified 54 new cases of DLBCL with a median age of 69.5 years. Fifteen pts (27.8%) were age 80 or older. Male to female ratio was 1:1.5. The average IPI was greater in pts above 80 than in pts below 80 years of age, 3.0 [95% confidence interval (CI), 2.17-3.83] vs. 1.9 [95% CI, 1.51-2.29 ], respectively. The LDH was high in 57.9% (22/38) of pts in the younger group vs. 69.2% (9/13) of pts in the older group (p=0.52). The presence of bcl-6 in the younger group versus the older group was 88.6% (31/35) and 84.6% (11/13), respectively (p = 0.65). The expression of bcl-2 in the younger group versus the older group was 55.9% (19/34) and 66.7% (8/12), respectively (p=0.73). The proportion of younger pts vs. older pts with high Ki67 (〉80%) was 45.7% vs. 53.8%, respectively (p= 0.75). Thirty six pts under age 80 received RCHOP compared to 7 pts 80 years and over (97.3% vs. 50%) (p=0.0006). There did not seem to be a correlation between IPI or co-morbidity and whether pts received treatment. However, therapy tended to be offered to outpatients but withheld from patients hospitalized at time of diagnosis. Chemotherapy had to be reduced or terminated due to poor tolerance in 1 patient in the younger cohort vs. 2 pts in the older cohort. Amongst the older group who did not receive RCHOP, 6 pts (85.7%) did not receive any chemotherapy, while 1 patient received 5 cycles of RCEPP. Kaplan Meier analysis for overall survival of pts under age 80 compared to over age 80 is shown below (HR = 7.0, 95% CI [2.0 – 24.2]), (p = 0.002). All pts above age 80 who did not receive any chemotherapy died vs. 25.0% (1/4) who received full dose RCHOP, vs. 66.7% (2/3) who received reduced RCHOP. The CR rate was 88.6% (31/35) for those aged under 80 vs. 75% (6/8) for those above age 80 (p=0.31), while the relapse rate was 11.4% (4/35) vs. 25% (2/8), respectively (p = 0.31). Conclusions: Though limited, these data reveal interesting findings about pts aged over 80 with DLBCL. With our aging population, more physicians will be faced with the question of how to treat the very elderly with this diagnosis. These pts had a poorer overall survival which, in large part, can be attributed to the fact that therapy was never administered. Age above 80 and hospitalization seemed to be the only clear reasons for withholding therapy. Elderly pts tended to have higher IPIs, but did not seem to have histologically more aggressive tumours. Interestingly, the pts over the age of 80 who died did tend to have more frequent expression of bcl-2. In contrast, all elderly pts who survived were bcl-6 positive. When standard therapy is given to pts over the age of 80, their response rates do not differ from those in younger pts. Further research into pts above 80 years of age with DLBCL is needed to confirm our findings. Nonetheless, our results raise questions about how we approach treatment of DLBCL in the very elderly and suggest that age alone should not prevent standard doses of therapy from being administered. 1. Kaplan-Meier survival curves for the two age groups: Disclosures: No relevant conflicts of interest to declare.

Description: Introduction. Despite years of translational research and discovery, outcomes in Acute Myeloid Leukemia remain poor. The MDM2 antagonist idasanutlin has shown promising clinical activity in solid tumors and acute leukemias. Idasanutlin enhances the activity of the tumor suppressor, p53, through antagonism of MDM2:p53 interaction. Such protein:protein disruption abolishes MDM2 targeting of p53 for ubiquitination and degradation. Subsequent stabilization of the p53 protein allows it to exert tumor suppressor transcriptional regulation and induction of apoptotic pathways. Identification of patients in whom functional p53 activation drives efficacy may translate into improved outcomes for patients treated with idasanutlin. Patients and Methods. Trial NP28679 (NCT01773408) is a Phase 1/1b study evaluating idasanutlin (as monotherapy or in combination with cytarabine) in relapsed or refractory AML patients, with clinical response as the primary endpoint. To identify biomarkers of response, patients' pre-treatment peripheral blood specimens were evaluated for MDM2 protein expression levels in leukemic blasts and leukemic stem cells. Association of MDM2 percent cell positivity with clinical outcomes was evaluated using intracellular flow cytometry gated on CD45dim leukemic blasts and CD45dim/CD117+/CD34+ leukemic stem cells. Results. We observed in a proof-of-principle training data set that MDM2 expression in leukemic blasts was associated with patients more likely to exhibit Complete Remission (CR, CRp, CRi) versus Progressive Disease (PD, HI, PR) [n=61; Wilcoxon p = .0041 (AUC = .74; 95%CI[.57, .91])] TP53 mutational status alone was not tightly associated with patient response (Fisher's Exact Test p = .19 [AUC = .60; 95%CI [.52,.67.])] When MDM2 protein expression and TP53 mutational status were analyzed as co-variates, an enhanced association with patient CR was observed (AUC = .76; 95% CI [.59, .93.]) A separate group of patients treated with an optimized idasanutlin formulation was utilized as a validation set. Association of CR with MDM2 expression in blasts was also shown in this separate patient population [n=24; Wilcoxon p = .0052 (AUC = .82; 95% CI [.64, 1.00.]) Comparable results were observed for proof-of-principle and validation set analyses of response association with MDM2 protein expression in AML patients CD45dim/CD117+/CD34+ stem cell subpopulations. Conclusions. In summary, training and validation sets reveal that MDM2 protein expression in leukemic blasts and stem cells are associated with idasanutlin-induced CR in patients with AML. We will continue to monitor this potentially predictive biomarker in future randomized clinical studies of idasanutlin. On a broader level, the data presented here support the concept that leukemic blasts may be "oncogene-addicted" to MDM2 in AML, i.e. that AML tumor cells may rely on a dominant oncogene for growth and survival, such that inhibition of the function of this specific oncogene is sufficient to halt the neoplastic phenotype. Thus, the concept of oncogene addiction may apply not only to mutated kinases but also to ubiquitin ligases such as MDM2. Disclosures Reis: Roche Pharma: Employment, Equity Ownership. Jukofsky:Roche Pharma: Employment, Equity Ownership. Chen:Roche Pharma: Employment, Equity Ownership. Martinelli:BMS: Speakers Bureau; MSD: Consultancy; Roche: Consultancy; ARIAD: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy. Zhong:Roche Pharma: Employment, Equity Ownership. So:Roche Pharma: Employment, Equity Ownership. Drummond:Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Assouline:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Hashemyan:Roche Pharma: Employment, Equity Ownership. Theron:Roche Pharma: Employment, Equity Ownership. Blotner:Roche Pharma: Employment, Equity Ownership. Rueger:Roche Pharma: Employment, Equity Ownership. Middleton:Roche Pharma: Employment, Equity Ownership. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Nichols:Roche Pharma: Employment, Equity Ownership. Chen:Roche Pharma: Employment, Equity Ownership. Pierceall:Roche Pharma: Employment, Equity Ownership.

Description: Abstract 2085 Poster Board II-62 Over the past 10 years, the incidence of acute myeloid leukemia (AML) has increased significantly with approximately 15 000 new cases annually. Standard induction chemotherapy consisting of cytarabine (Ara-C) and an anthracycline induces remission rates between 50% and 85%. Unfortunately, the majority of patients who achieve remission will relapse and die from their disease within 2 years, highlighting the need for novel therapeutic targets. The eukaryotic translation factor (eIF4E) is overexpressed in many human malignancies, including AML, and is associated with poor prognosis as well as clinical progression. Ribavirin, an anti-viral molecule, is classically used in the treatment of hepatitis C (with interferon), SARS, RSV, Lassa fever and influenza. Its structure physically mimics the m(7)G cap of mRNA, thus inhibiting eIF4E-induced export and translation of sensitive transcripts. We are carrying out the first clinical trial targeting eIF4E with ribavirin in AML patients. Clinical and molecular efficacy has been evaluated in 13 patients to date. The treatment was well tolerated by all patients with no marked toxicity observed. Importantly, no patients developed hemolytic anemia. We demonstrated that ribavirin effectively induces the relocalization of nuclear eIF4E to the cytoplasm and the reduction of eIF4E as well as its target proteins, including suppression of Akt activation. This led to dramatic clinical improvement, including one complete remission, two partial remissions, two blast responses and four patients with stable disease. Final response data will be presented along with translational correlates. Notably, lack of response or relapse after remission was associated with lack of molecular response in leukemic blasts. Despite the encouraging responses of patient on ribavirin, all patients acquired resistance to therapy and eventually relapsed. Hence, we sought novel therapies to combine with ribavirin in order to overcome resistance and maintain remissions. Using a cell line that overexpresses eIF4E, we screened a library of 5000 known drugs and searched for compounds that synergize with ribavirin to suppress tumor growth. We identified nearly 50 lead compounds, many of which are structurally related, with similar biological activity, and are currently used medically for indications other than cancer. Early clinical observations suggest that combinations of cytotoxic agents lead to substantially better clinical outcomes relative to monotherapies. Furthermore, various drugs that suppress the PI3/Akt pathway were found to sensitize leukemia cells to Ara-C. Thus, we combined Ara-C with ribavirin in vitro, and observed an improved reduction in colony growth of AML specimens. Combination therapy with ribavirin and Ara-C in patients with acute myelocytic leukemia is currently ongoing. Preliminary results will be presented. Disclosures: Borden: Translational Therapeutics: Equity Ownership.

Description: Background: Timely molecular monitoring is the cornerstone of chronic myeloid leukemia (CML) treatment guidelines. These guidelines are based on the design of clinical trials, but none have been validated prospectively. We hypothesized that timely molecular monitoring in routine patient care increases the likelihood of achieving major molecular response (MMR) in CML. Methods: We conducted a prospective cohort study using the Québec CML Registry, which comprises 713 patients from 16 hospitals. Patients with newly-diagnosed CML (2009-2014) and measurable disease by quantitative PCR were followed from tyrosine kinase inhibitor (TKI) initiation. Timely PCR (tPCR) was defined as a PCR performed at 2-4, 11-13, and 17-19 months. (Figure). Study outcome was the achievement of MMR at 25 months, defined as international scale ratio (IS) 50 CML patients) centers. Timely PCRs were performed in 76.3%, 69.5%, and 61.0% of patients at 2-4, 11-13, and 17-19 months, respectively. When compared with not performing tPCRs, performing one and two tPCRs were associated with achieving an MMR by 25 months (OR: 17.05, 95% CI: 5.18-56.09 and OR: 14.96, 95% CI 3.63-61.73, respectively, Table 2). The highest OR of achieving MMR was observed among those who underwent three tPCRs (OR: 24.02, 95% CI: 7.07-81.55). Conclusions: To our knowledge, this is the first study to assess clinical outcomes associated with timely molecular monitoring in early CML. While performing one and two tPCRs was associated with achieving MMR at 25 months, the point estimate for performing three tPCRs was the highest. These findings indicate that timely monitoring may allow for faster switching of TKI, which ultimately permits patients with early failure to "catch up." Alternatively, more regular testing may increase patient adherence to therapy. If replicated, these findings support routine and punctual monitoring of patients on TKI therapy. Disclosures Assouline: Pfizer: Speakers Bureau; BMS: Speakers Bureau.

Description: Purpose: MGCD0103 is an oral inhibitor of histone deacetylases (HDACs) with isotype-selective activity against HDAC-1, -2, -3, and -11. MGCD0103 exhibits significant biological activity in preclinical models of hematopoietic cancers. Although several HDAC inhibitors have shown promising clinical activity in patients (pts) with T-cell lymphoid malignancies, the clinical activity of HDAC inhibitors have not been previously examined in B-cell lymphoma. The purpose of this study was to examine the efficacy and tolerability of MGCD0103 as monotherapy for the treatment of relapsed or refractory follicular and diffuse large B-cell lymphoma. Methods : This was an open-label, multi-center, phase II trial in adults (≥18 years) with relapsed or refractory lymphoma. The trial contained 2 cohorts of pts with diagnoses of either diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Eligibility required the presence of ≥1 site of measurable disease (≥2.0 cm) and an ECOG performance status of 0 or 1. Oral MGCD0103 was initially dosed at 110 mg 3× per week in 4-week cycles, with escalation to 135 mg or reductions to 85 and 60 mg permitted based on patient tolerance. Pts enrolled later in the trial had starting doses of 85 mg, with escalation to 110 mg and reductions to 60 and 40 mg permitted. On day 1 of cycle 1, blood samples were collected for PK analysis before dosing and at 0.5, 1, 2, 4, 6, and 24 hours. Results: To date, 38 pts (mean age, 60.3 ± 13.0 yrs; male, n=18) have been dosed: 19 with DLCBL and 19 with FL, all of whom have received prior Rituxan. Nineteen of 24 pts (79%) who had tumor size reassessed by CT scan after treatment initiation exhibited some tumor reduction; 12 (50%) exhibited 〉30% reduction and 7 (29%) exhibited 〉40% reduction. Twenty-five pts (1 pt has not yet had disease reassessed) were formally evaluable for clinical response; 16 (64%) have completed ≥3 cycles (12 weeks) of treatment. A CR was observed in 1 pt with FL after 2 cycles. PRs were observed in 2 pts with DLBCL after 2 and 4 cycles respectively and 1 pt with FL after 6 cycles. Twenty pts required dose reductions for management of toxicities. In 35 pts evaluable for safety, the most common non-hematologic toxicities were fatigue (24 pts), nausea (22), diarrhea (17), anorexia and decreased appetite (12), vomiting (10), and weight loss (9). Grade 3 toxicities occurred in 10 pts; fatigue and weight decrease being the most common. There were no grade 4 non-hematological toxicities. Hematological toxicities were minimal, with 1 pt requiring dose modification for thrombocytopenia and 2 for neutropenia. Significant inhibition of HDAC activity in PBMCs was seen in the majority of pts evaluated. Population PK (N=16) revealed: Cmax 119 ± 73 ng/ml, AUC (0–24) 715 ± 495 ng*hr/ml. Conclusions: Interim results from this ongoing trial suggest that single-agent MGCD0103 demonstrates significant anti-cancer activity in relapsed or refractory non-Hodgkin’s lymphoma (DLCBL and FL subtypes) and has a manageable side effect profile.

Description: Key Points Panobinostat induces responses in 28% of patients with relapsed and refractory DLBCL that are typically durable off therapy. MEF2B mutations predicted for response whereas early increase in ctDNA abundance was a strong predictor of subsequent treatment failure.

Description: Introduction: Mantle cell lymphoma (MCL) is an aggressive disease that is incurable with conventional therapy and the outcome of which remains the poorest amongst B-cell lymphomas. Phosphoinositide-3 kinase (PI3K) pathway activation contributes to MCL pathogenesis, but early-phase studies of the PI3K-δ selective inhibitor idelalisib have reported lower responses in MCL compared with indolent non-Hodgkin lymphoma (NHL) subtypes (Kahl et al., Blood 123:3398-405, 2014; Gopal et al., NEJM 370:1008-18, 2014). In addition, although PI3K-δ is highly expressed in MCL, PI3K-α shows wide variation and expression increases with relapse (Iyengar et al., Blood 121;2274-84, 2013). Copanlisib is a novel pan-Class I PI3K inhibitor with potent preclinical inhibitory activity against both PI3K-α and PI3K-δ isoforms. Preliminary results from a phase 2a study of copanlisib in patients with relapsed/refractory NHL or chronic lymphocytic leukemia (CLL) have been reported (Dreyling et al., ASH 2013), with an expansion cohort in patients with aggressive lymphoma ongoing. We report here the final results of the MCL subset. Methods: Patients with histologically confirmed indolent and aggressive NHL and relapsed after, or refractory to, ≥2 prior lines of treatment were eligible. Copanlisib was administered at the starting dose of 0.8 mg/kg as a 1 hour intravenous infusion on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as assessed per independent radiologic review according to the response criteria for lymphoma (Cheson et al., JCO 17:1244, 1999). Secondary endpoints included progression-free survival (PFS) and duration of response (DOR), safety and tolerability. Results: As of February 28, 2015, of the 81 patients enrolled, a total of 11 patients with MCL were treated. Median age was 70 years (range 60-85), M/F= 8/3. The median number of prior lines of treatment was 3 (range 3-9) with a median time of 1.4 months since last systemic anti-cancer therapy. All patients previously received rituximab and 8 patients (73%) were refractory to the last therapy. The median duration of treatment was 17 weeks (range 3-59), corresponding to a median number of 4 cycles (range 1-15), with a close adherence to planned dose (median 92%). The most common drug-related adverse events (AEs) of all grades were hyperglycemia (8 patients, 73%), hypertension (6 patients, 55%), neutropenia (5 patients, 46%) and fatigue (4 patients, 36%). Grade 3-4 AEs occurring in 2 or more patients included: neutropenia (2 patients with grade 3, 18%; 3 patients with grade 4, 27%), hypertension (3 patients with grade 3, 27%), hyperglycemia (2 patients with grade 3, 18%), and fatigue (2 patients with grade 3, 18%). One grade 5 AE of acute respiratory failure, was assessed as drug-related by the investigator. Dose reductions and delays possibly due to study drug-related adverse events (AE) were reported in 2 (18%) and 6 (55%) patients, respectively. Two patients were discontinued from study treatment due to adverse events (lung infection and non-melanoma skin cancer). All 11 patients were included into efficacy assessment, although one clinical PD was not confirmed by radiologic measurement. The ORR as determined by independent radiologic review was 64% (2 CRu and 5 PRs). The median duration of response was 150 days (95% CI: 56, 434); 33% of responders had a DOR of at least 270 days. PFS ranged from 7 to 547 days [median 112 days (95% CI: 42, 377)]. Conclusions: Copanlisib was active as a single-agent, with an ORR of 64%, and had a manageable safety profile in patients with heavily pretreated, advanced refractory/relapsed MCL. These results support the potential role of inhibiting both PI3k-α and PI3K-δ in relapsed MCL. Based on these results, a phase 2 trial of copanlisib in ibrutinib-pretreated patients with MCL is under way (NCT02455297). Disclosures Cunningham: Astra Zeneca: Research Funding; Merrimack: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Merck Serono: Research Funding; Sanofi: Research Funding; Medimmune: Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding. Zinzani:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Assouline:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Mollica:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Giurescu:Bayer Pharma AG: Employment. Gorbatchevsky:Bayer HealthCare Pharmaceuticals: Employment. Neves:Bayer HealthCare: Employment. Lemos:Bayer HealthCare: Employment. Grunert:Bayer Pharma AG: Employment. Hiemeyer:Bayer Pharma AG: Employment. Childs:Bayer HealthCare Pharmaceuticals: Employment.