Monotherapy Arm Research Articles

Abstract 1594: Enhancement of the anti-tumor activity of CEA TCB via combination with checkpoint blockade by PD-L1 and interleukin-2 variant immunocytokine

Abstract Cancer immunotherapy represents a promising therapeutic approach to extend the overall survival of cancer patients. However, several mechanisms within the tumor microenvironment orchestrate the suppression of host immune response requiring combination strategies to prolong the durability of effect. Among suppressive pathways, up-regulation of PD-1 ligand (PD-L1) and its interaction with PD-1 receptor plays a key role in suppression of T-cell activity, a mechanism also called adaptive immune resistance. Therefore, approaches able to inhibit the tumor immune suppressive mechanisms along with those expanding the frequency of intra-tumor T-cells and enhancing/prolonging their functionality are required. CEA TCB (RG7802, RO6958688) is a novel T cell bispecific antibody targeting carcinoembryonic antigen (CEA) on tumor cells and CD3 on T cells, currently being investigated as single agent and in combination with atezolizumab in Phase 1/1b studies in patients with advanced and/or metastatic CEA-expressing tumors (NCT02324257; NCT02650713). CEA TCB treatment leads to increased intra-tumoral T cell infiltration and T-cell activation along with up-regulation of PD-1/PD-L1 suppressive pathway. Here we show that combination of CEA TCB with PD-L1 blocking antibody in vitro enhances T cell activation as detected by increased CD3 signaling and secretion of pro-inflammatory cytokines. Combination in vivo performed in both stem cell humanized NOG mice (HSC mice engrafted with MKN45) and fully immunocompetent human CEA transgenic C56BL/6 mice (hCEA Tg mice engrafted with MC38-hCEA) demonstrated significantly improved anti-tumor activity of combination as compared to activity of single agents, yielding to increased number of tumor-free animals. Randomization of animals that progressed to CEA TCB monotherapy revealed that combination of CEA TCB with PD-L1 blocking antibody is required to control tumor outgrowth, as tumors treated with corresponding monotherapy arms progressed to treatment. Efficacy of CEA TCB was also potentiated when administered in combination with a half-life-extended IL-2 variant (untargeted (IgG-IL2v) or fibroblast-activating protein-targeted IL-2 variant (FAP-IL2v)), resulting in stronger tumor growth inhibition in MKN45-bearing HSC mice or prolonged survival in PanCO2-hCEA-bearing hCEA Tg C56BL/6 mice. Synergy likely reflects ability of IL2v to enhance anti-tumor efficacy by increasing number of effector T cells in tumors. In conclusion, CEA TCB treatment leads to intra-tumoral T cell infiltration and T-cell activation. This is accompanied by up-regulation of PD-1/PD-L1 suppressive pathway, which can be overcome by combination therapy with a PD-L1 inhibitor. In vivo efficacy of CEA TCB is further potentiated when administered in combination with immunotherapies that increase the pool of available tumor-infiltrating effector cells. Citation Format: Marina Bacac, Sara Colombetti, Linda Fahrni, Tanja Fauti, Valeria Nicolini, Johannes Sam, Petros Papastogiannidis, Marine Le Clech, Xavier Miot, Inja Waldhauer, Karolin Rommel, Christian Gerdes, Christian Klein, Pablo Umaña. Enhancement of the anti-tumor activity of CEA TCB via combination with checkpoint blockade by PD-L1 and interleukin-2 variant immunocytokine [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 1594. doi:10.1158/1538-7445.AM2017-1594

Abstract 163: Evaluation of ETS2101 and its combination with anti-mCTLA4 monoclonal antibody on CD4 and CD8 TILs in a subcutaneous colorectal cancer model of CT-26

Abstract ETS2101, (HU-211, Dexanabinol) is a synthetic cannabinoid with limited affinity to cannabinoid receptors 1 and 2 (CB1 and CB2), reducing its psychotropic potential in comparison to other molecules in the cannabinoid class. ETS2101 has been found to have effects on immune cell function in vitro. The presence of Tumor Infiltrating Lymphocytes (TILs) has been previously shown to correlate with better patient outcomes during various antitumor therapies in a multitude of cancers. This study utilized immunohistochemistry (IHC) combined with digital image analysis to quantify CD4+ and CD8+ TILs within CT-26 tumors treated with ETS2101 in combination with a checkpoint inhibitor, anti-mCTLA4. A CT-26 colon carcinoma tumor line was implanted s.c. into immune-competent mice. Ten days post implantation groups were treated with ETS2101 administered at 200 mg/kg QD in combination with anti-mCTLA-4 administered as 10 mg/kg i.p. BiW. Thirty seven days post treatment, tumors were collected and IHC was performed for CD4+ and CD8+ TILs on FFPE tumor sections (n=12-15 per group). Whole slide images were generated per IHC section and customized algorithms developed within the Indica Labs HALO platform to classify viable tumor present across each section and to quantify CD4+ or CD8+ stain area within the viable tumor region of interest (ROI). Anti-mCTLA4 monotherapy resulted in regression of 44% tumors (7% CR) and anti-mCTLA4 + ETS2101 combination therapy resulted in regression of 74% tumors (36% CR). There was a significant increase in CD8+ % staining of viable tumor observed following anti-mCTLA4 monotherapy treatment versus control (2.16% v. 1.16%, P<0.0027) and anti-mCTLA4 + ETS2101 combination therapy (2.18% v. 1.10%, P<0.0019) compared to control. A similar trend was observed for CD4+ % staining of viable tumor with a significant increase observed following anti-mCTLA4 monotherapy treatment versus control (1.82% v. 0.49%, P<0.0083) and anti-mCTLA4 + ETS2101 combination therapy (1.93% v. 0.41%, P<0.0028) compared to control. Although, there was no significant difference between anti-mCTLA4 monotherapy treatment and anti-mCTLA4 + ETS2101 combination therapy for either marker alone, following treatment with the combination a statistically significant relationship between best overall response and the ratio of CD8+:CD8+ TILs was observed (P=0.0186). In summary, there was an observed difference in the number of mice exhibiting a partial/complete regression in tumor volume for the combination arm 74% (36% CR) versus the antibody monotherapy arm 44% (7% CR). A statistically significant relationship (p=0.0186) was observed between the best overall tumor response and the ratio of CD8+:CD4+ TILs. IHC combined with image analysis can be utilized to evaluate therapeutic response on TILs within the context of their tumor microenvironment. Citation Format: Lorcan Sherry, Mark Anderson, John Waller, Adam Sardar, Victoria Flores, Daniel Hynes. Evaluation of ETS2101 and its combination with anti-mCTLA4 monoclonal antibody on CD4 and CD8 TILs in a subcutaneous colorectal cancer model of CT-26 [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 163. doi:10.1158/1538-7445.AM2017-163

Phase I/II study of durvalumab (anti–PD-L1 antibody) as monotherapy and in combination in patients with lymphoma or chronic lymphocytic leukemia.

TPS7574 Background: The PD-1/PD-L1 pathway is an important immune checkpoint used by tumor cells to evade immune cell detection and inhibit antitumor responses. PD-1/PD-L1 expression in multiple hematologic malignancies may provide an effective target for enhancing anticancer immune response. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal Ab that selectively blocks PD-L1 binding to PD-1 and CD80, and has shown preliminary evidence of antitumor activity across multiple tumor types. Study objectives are to evaluate durvalumab monotherapy and combinations to determine dose and safety, as well as identify histologies and combinations that show the best complementary antitumor signals for future study. Methods: This is a phase I/II open-label, global, multicenter study of durvalumab as a monotherapy and in combination in relapsed/refractory B-cell lymphoma or CLL (MEDI4736-NHL-001; EUDRA CT 2015-003516-21; NCT02733042). Patients must have histologically-confirmed FL, MCL, splenic or nodal MZL, T-cell/histiocyte rich BCL, PMBCL, ALK+ large BCL, transformed large BCL, Richter’s transformation, DLBCL (NOS), CLL/SLL, or classical HL during the dose-finding part. Inclusion criteria are ECOG PS 0-2, and ≥1 prior antilymphoma therapy. Up to 253 patients may enroll in 4 treatment arms, which include fixed-dose durvalumab 1500 mg Q4W monotherapy or combinations with lenalidomide/rituximab, ibrutinib, or bendamustine/rituximab. The study has 3 parts: dose finding, dose confirmation, and dose expansion. The monotherapy arm does not have a dose finding or expansion part; upon progression, patients may receive combination therapy or involved-field radiation to a single nodal site (evaluating for systemic abscopal antitumor effect). Primary endpoints are safety, identification of recommended phase II dose (phase I, 3+3 design), and overall response rate (ORR; phase II); secondary endpoints include DOR, PFS, and PK/PD. ORR is measured by 2014 IWG criteria for lymphoma or modified 2008 iwCLL criteria for CLL; safety is assessed per NCI CTCAE v4.03 criteria. Recruitment is ongoing, with a target enrollment of 253 patients across 60-80 centers globally. Clinical trial information: NCT02733042.

Perioperative trastuzumab and pertuzumab in combination with FLOT versus FLOT alone for HER2 positive resectable esophagogastric adenocarcinoma: Petrarca—A phase II trial of the German AIO.

TPS4133 Background: Neoadjuvant or perioperative chemotherapy has become a standard of care for locally advanced, resectable gastric cancer and adenocarcinoma of the GEJ. However, patient’s outcome is still unsatisfactory and 5-year survival, even in prospective trials, has been below 40%. Targeting HER2 with Trastuzumab and Pertuzumab prolonged survival in patients with HER2-positive advanced breast cancer as did Trastuzumab in patients with HER2-positive advanced gastric cancer. This provides a rationale for the evaluation of anti-HER2 treatment for resectable patients. Methods: This is a prospective, multicenter, randomized, investigator initiated phase II trial. Patients with HER2-positive locally advanced adenocarcinoma of the stomach and GEJ (i.e. ≥cT2 any N or any T N-positive) with exclusion of distant metastases are enrolled. HER2 status is centrally assessed. Patients are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m²) followed by surgery and 4 additional cycles of FLOT (arm A); or the same therapy in combination with Trastuzumab 8/6 mg/kg and Pertuzumab 840 mg every 3 weeks pre- and postop, followed by a total of 9 additional cycles of Trastuzumab/Pertuzumab monotherapy (arm B). Primary endpoint of the phase II part (n = 100) of the trial is to show numerical improvement of the rate of pathological complete remission to approx. 25% with antibodies compared to approx. 16% with FLOT alone as assessed by a centralized pathology. Main secondary endpoints are safety and tolerability. Once results from phase II become available, study transition into phase III will be evaluated based on de facto results and current medical standards. Recruitment has already started; by February 2017 a total of 19 patients have been randomized. EudraCT: 2014-002695-86 Clinical trial information: NCT02581462.

Dose escalation results of a phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in patients (Pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML).

7027 Background: The ubiquitin ligase MDM2 inhibits the tumor suppressor p53. In preclinical AML models, MDM2 inhibitors have antitumor activity as monotherapy that is synergistic when combined with MEK inhibitors. This open-label phase 1b study assessed the maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity of the investigational oral, selective MDM2 inhibitor AMG 232 as monotherapy or combined with the MEK kinase inhibitor trametinib in pts with r/r AML. Methods: Pts with r/r AML received AMG 232 for 7 days every 2 weeks (7 days on/7 days off) at 60, 120, 240, 480, and 960 mg PO QD as monotherapy (Arm 1) or combined with trametinib 2 mg PO QD (Arm 2). Primary endpoints were the incidence of adverse events (AEs), dose-limiting toxicities (DLTs), and PK. Additional endpoints included best response (revised IWG) and serum MIC-1 level (increased MIC-1 suggests p53 activation). p53 target gene ( P21, BAX, and PUMA) expression in bone marrow was assessed by microarray. Results: In total, 35 pts (Arm 1, n = 26; Arm 2, n = 9; median age, 68 y; range, 26–86) were treated. Arm 1 enrolled AMG 232 at 60 mg (n = 4), 90 mg (n = 4), 180 mg (n = 5), 240 mg (n = 3), and 360 (n = 10). Twenty-two (85%) pts in Arm 1 had treatment-related AEs; the most common were nausea (n = 14), diarrhea (n = 14), and vomiting (n = 6). No DLTs occurred; one pt is still on treatment. The MTD was determined as 360 mg based on tolerance of gastrointestinal toxicity. Arm 2 enrollment is ongoing at a fixed AMG 232 dose of 60 mg plus trametinib (n = 9). AMG 232 plasma exposure increased with dose escalation; PK was unaffected by trametinib. Trametinib PK was as expected. Increases from baseline (BL) to day 10 in serum MIC-1 were dose dependent. Evidence of increased P21, BAX, and PUMA expression (BL to day 7 or 8) was seen (n = 3). One pt (Arm 2) had complete remission (CR); three pts (Arm 1) achieved CRi/MLFS. Median response duration was 66 days [range, 21–377+]). Conclusions: AMG 232 monotherapy was tolerable in pts with r/r AML at doses up to 360 mg on a 7 days on/7 days off schedule with expected PK, on-target biological effects, and early evidence of antileukemia activity. Clinical trial information: NCT02016729.

Bayesian AI to delineate molecular signatures of patient susceptibility to potential hematologic events in a phase I study of BPM31510 (ubidecarenone) in solid tumors.

e14042 Background: BPM 31510 is a ubidecarenone containing nanodispersion elicits anticancer effect by switching cancer cells energy generation from glycolysis to mitochondrial OXPHOS; i.e. reverses Warburg effect. This Phase 1 study is evaluating safety of 144-hour infusion of BPM 31510 as a single agent and in combination with 3 standard chemotherapy regimens. The molecular adaptive study design enabled longitudinal multi-omic molecular profiling to delineate personalized cause-and-effect networks relating patient biology to clinical outcomes using unbiased Bayesian statistics based bAIcis Artificial Intelligence (AI) technology Methods: Eligible pts (aged ≥ 18 y) were relapsed/refractory to standard therapy. The monotherapy arm received IV BPM31510 for 144-hour infusion in 28d cycles, and combination arms (gemcitabine, 5-FU or docetaxel) were primed with BPM 31510 for 3 wks followed by weekly dosing in a 6wk cycle. Doses were escalated in a 3+3 schema. Endpoints were safety, PK and multi-omics analysis. Clinical information was processed and integrated with multi-omic molecular data (metabolomics, lipidomics and proteomics), utilized bAIcis to learn relationships and extract actionable information from pt records, molecular features and corresponding clinical response. Results: As of 10 Dec 2016, 97 pts have been enrolled. Hematologically-related DLTs were reported at 171mg/kg in monotherapy and 137mg/kg in the BPM31510+gemcitabine arm (maximum administered dose). The bAIcis-generated set of predictors defining coagulation-related events in the clinical trial population include proteins, lipids, and metabolites, the levels of which can potentially predict undesirable events prior to and 24h after the 1st treatment with BPM 31510. Conclusions: BPM31510 is well tolerated as a monotherapy and in combination with chemotherapeutic agents. Molecular signatures of susceptibility have been identified through use of multi-omic based AI analysis. Molecular signatures predictive of coagulation-related events will be assessed in Phase 2 and 3 trials to guide the development plan for BPM 31510 as anticancer agent. Clinical trial information: NCT01957735.

Effect of antihyperglycemic drug monotherapy to prevent the progression of mild hyperglycemia in early type 2 diabetic patients: the Japan Early Diabetes Intervention Study (JEDIS).

To effectively prevent the worsening of hyperglycemia in type 2 diabetes mellitus, it is of interest to see the clinical efficacy of early introduction of pharmacotherapy in addition to lifestyle intervention which is not always easy to continue throughout life. This is a randomized unblinded comparative clinical study on suppressive effects of lifestyle intervention alone and additional monotherapies for mild hyperglycemia at an early stage of treatment-naïve type 2 diabetic patients, whose fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) are less than 140mg/dl and 7.4%, respectively. The control group (group N=arm N) received conventional lifestyle intervention assisted by routine facilities, while the pharmacological intervention group (group D composed of 4 arms) was additionally treated by monotherapy with one of four kinds of oral antihyperglycemic agents i.e., sulfonylurea (SU), α-glucosidase inhibitor, biguanide and dipeptidyl peptidase-4 inhibitor. The participants were scheduled to follow up for 3years to maintain glycemic control below primary endpoint which was defined as the first occurrence of FPG ≥140mg/dl and HbA1c ≥7.4% simultaneously even by increasing doses of oral drug in group D, if necessary. The outcomes of occurrences of primary endpoint were not different between group N and group D composed of 4 arms during 3years by Kaplan-Meyer plots (p=0.405). On the other hand, ΔFPG (Δ: incremental change from baseline) and ΔHbA1c in group D significantly decreased when compared to those of group N during 3years (p<0.05 and p<0.01 respectively). Significant reductions of ΔBMI were seen similarly in both groups throughout the study (p<0.05), but did not differ between two groups. Among these 5 arms, significant decreases of ΔHbA1c were observed in three monotherapy arms of group D compared to arm N for 3years (p<0.05 or p<0.01), except for arm SU in which ΔBMI and ΔHbA1c tended to increase at the latter half of the study. The final achievement rates of target HbA1c less than 7.4, 7.0 and 6.5% in all the participants tended to be higher in group D than in group N (p<0.047 for 7.4%, but not significant for others). In conclusion, the early introduction of pharmacological monotherapy in addition to lifestyle intervention seem to suppress mild hyperglycemia with small doses of antihyperglycemic agents for 3years, except for the use of SU drug. Although a larger scale of trial will be necessary to conclude, the early treatment with suitable monotherapy could be effective to bring and keep "safe level of glycemia".

A randomized phase II trial of docetaxel plus carboplatin versus docetaxel in patients with castration-resistant prostate cancer who have progressed after response to prior docetaxel chemotherapy: The RECARDO trial.

166 Background: Docetaxel is the standard first-line chemotherapy for patients with castration resistant prostate carcinoma (CRPC). Docetaxel re-challenge has never been tested in a prospective randomized clinical trial. As some studies supported the addition of carboplatin to docetaxel in this setting, we performed a phase II trial investigating the combination of docetaxel plus carboplatin versus docetaxel monotherapy in docetaxel pre-treated CRPC patients. Methods: Patients with CRPC with a progression-free interval (PFI) of at least 3 months after initial treatment with docetaxel were randomized between docetaxel 75mg/m2 or docetaxel 60mg/m2 plus carboplatin AUC 4, both plus prednisone in a 3-weekly schedule. Treatment was continued until progressive disease, unacceptable toxicity or completion of 10 cycles. The primary endpoint is progression-free survival (PFS) (PSA and/or RECIST). Secondary objectives are overall survival, toxicity, PSA response and quality of life. Results: As a result of insufficient recruitment, the study was discontinued early after inclusion of 75 patients, instead of the targeted 150 patients. The median PFS was comparable between both groups (docetaxel 12.7 months versus combination therapy 11.7 months p = 0.99), and no difference in OS was found (median OS 18.5 months versus 18.9 months, p = 0.88). Rates of PSA response were comparable (response/stable PSA in 42.1%/39.4% of the patients in the monotherapy arm versus 35.1%/48.6% in the combination arm, NS). The incidence of grade 3-4 infections and gastro-intestinal (GI) side effects was higher in the docetaxel plus carboplatin arm (GI side effects 0% versus 13.9% p = 0.03; infection 2.7% versus 16.7% p = 0.056). The difference in febrile neutropenia (0% versus 11.1%) is not significant. Conclusions: For patients with CRPC and an initial good response to docetaxel, re-treatment with docetaxel monotherapy is a feasible, save and effective treatment. Addition of carboplatin resulted in more toxicity. Docetaxel re-challenge is a viable therapeutic option for selected patients. Clinical trial information: NTR3070.

Abstract P5-15-04: The PROCEED trial KCSG BR11-01 phase III multicenter randomized open-label study of irinotecan plus capecitabine versus capecitabine in patients previously treated with anthracycline and taxane for HER2 negative metastatic breast cancer

Abstract Purpose We investigated whether the combination of irinotecan plus capecitabine improved progression free survival (PFS) compared with capecitabine alone in patients with HER2 negative MBC previously exposed to anthracyclines and taxanes. Patients and methods A total of 211 patients were randomly assigned to irinotecan (80mg/m2 on D1 and D8) and capecitabine (1,000mg/m2 bid on D1 to D14) or capecitabine alone (1,250mg/m2 bid on D1 to D14) every 3 weeks. The primary objective was PFS; secondary objectives included overall response rate, overall survival and safety. Results Both arms were well balanced in terms of age, hormone receptor status, visceral involvement, and number of previous treatment. There was no significant difference in PFS between the combination and capecitabine monotherapy arm (median, 6.6 vs. 5.3 months; HR=0.87; 95% CI, 0.65 to 1.16; P=0.33). In patients with triple negative breast cancer (N=87), the combination treatment significantly improved PFS (median, 4.8 vs. 2.8 months; HR=0.59 ; 95% CI, 0.37 to 0.94; P=0.03). Overall response rate was higher in the combination arm though it did not reach statistical significance (42.7% vs. 29.6%, P=0.06). Overall survival did not differ between two groups (median, 2.2 vs. 1.7 years; P=0.47). Grade 3 or 4 neutropenia occurred in 39.6% in the combination arm and 10% in the monotherapy arm. Hand-foot syndrome (≥ grade 2) was more common in the monotherapy arm (23.0% vs. 12.6%). Table 1. Patient characteristics IX(N=111)X(N=100)p-valueAge (yr, median, range)50 (29-73)49 (30-80)0.47ECOG 0.80025 (22.5%)22 (22%) 185 (76.6%)76 (76%) 21 (0.9%)2 (2%) Pre-menopause28 (25.2%)29 (29%)0.64Post-menopause83 (74.8%)71 (71%) ER/PgR 0.16positive60 (54.1%)64 (64%) negative51 (45.9%)36 (36%) Adjuvant Chemotherapy86 (77.5%)72 (72%)0.43Adjuvant Endocrine46 (41.4%)39 (39%)0.78Visceral meta 1.0yes64 (57.7%)58 (58%) no47 (42.3%)42 (42%) Previous Chemotherapy 0.40012 (10.8%)12 (12%) 160 (54.1%)46 (46%) 232 (28.8%)34 (34%) 35 (4.5%)8 (8%) 42 (1.8%)0 IX, irinotecan plus capecitabine; X, capecitabine. Conclusions Irinotecan plus capecitabine did not demonstrate superior clinical activity in heavily treated HER2 negative MBC patients. The role of adding irinotecan to capecitabine in triple negative breast cancer remains to be elucidated. Citation Format: Park IH, Im S-A, Jung KH, Sohn JH, Park YH, Park K-H, Nam B-H, Kim JH, Kim H-J, Lee S, Kim T-Y, Lee K-H, Kim S-B, Lee KS, Ro J. The PROCEED trial KCSG BR11-01 phase III multicenter randomized open-label study of irinotecan plus capecitabine versus capecitabine in patients previously treated with anthracycline and taxane for HER2 negative metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-04.

Abstract P2-09-03: Long-term comparison of anastrozole versus tamoxifen: Results from LATTE/ATAC

Abstract Background: Previous reports from the Anastrozole Tamoxifen Alone or in Combination (ATAC) trial have shown significantly prolonged disease-free survival, lower rates of recurrence and distant recurrence, and reduced contralateral breast cancer in patients treated with anastrozole compared to tamoxifen (Cuzick et al., Lancet, 2010). Here, we compare the long-term effects of anastrozole versus tamoxifen in patients randomised to either monotherapy arm in the ATAC trial. Methods: Postmenopausal women with hormone receptor positive breast cancer randomised to anastrozole or tamoxifen in the main ATAC trial were eligible for the LATTE observational study. The primary objective was to compare the long-term effects of tamoxifen and anastrozole on time to recurrence and death beyond 10 years after randomisation. Secondary objectives included time to distant recurrence, cancer-specific survival, new breast primaries, other cancers, fractures, and cardiac/cerebrovascular events. Cox proportional hazard methods were used to compute hazard ratios (95% CI) for recurrence from the time of last publication (10 years median follow-up). Results: 2452 women from 11 countries were entered into the LATTE study. 40 women withdrew consent and 759 women died or had a recurrence within 10 years, which left 1653 women for analysis (838 anastrozole vs. 815 tamoxifen). A total of 118 breast events (69 anastrozole (8.2%) vs. 49 tamoxifen (6.0%)) were reported. No significant difference between the two treatment arms were observed (HR=1.36 (0.94-1.97), P=0.098). 57 women had a distant recurrence (33 (3.9%) vs. 24 (2.9%)), 41 reported a loco-regional recurrence (23 (2.7%) vs. 18 (2.2%)), and 26 contra-lateral breast cancer were recorded (17 (2.0%) vs. 9 (1.1%)). None of the treatment comparisons were statistically significant. 305 deaths were recorded (147 (17.5%) vs. 158 (19.4%)), of which 31 were due to breast cancer. Significantly fewer gynaecological cancers were recorded with anastrozole (7 vs. 16; OR=0.42 (0.15-1.09), P=0.05), but overall the effect on other cancers was not significant (54 (6.4%) vs. 64 (7.9%). Fractures, cardiovascular, and cerebrovascular events were evenly distributed between the treatment arms. Conclusions: Although anastrozole was associated with significant fewer recurrences compared to tamoxifen in the first 10 years of follow-up, in this analysis, with limited number of patients, we could not find a significant difference between the two treatment arms. Citation Format: Cuzick J, Sestak I, Bianco A, Strobbe L, Bergh J, Hanusch C, Neven P, Dowsett M, Forbes JF, Buzdar A, Smith R, Howell A. Long-term comparison of anastrozole versus tamoxifen: Results from LATTE/ATAC [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-03.

Abstract OT2-01-08: Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in women with previously treated hormone receptor-positive (HR+), HER2- metastatic breast cancer

Abstract Background: Abemaciclib, an oral drug administered twice daily on a continuous schedule, is a specific inhibitor of both CDK4 and CDK6. In MONARCH 1, abemaciclib demonstrated evidence of single-agent activity and an acceptable safety profile in patients with heavily pretreated HR+, HER2- metastatic breast cancer (MBC) whose disease progressed on or after endocrine therapy and chemotherapy; with a confirmed objective response rate of 19.7% and a median duration of response of 8.6 months (Dickler, M. et al. American Society of Clinical Oncology (ASCO), abstr #510 (2016)). This Phase 2 study I3Y-MC-JPCG will evaluate the potential to enhance the risk/benefit profile of abemaciclib in women with previously treated HR+, HER2- MBC, either administered in combination with endocrine therapy or as monotherapy (at the maximum recommended single-agent dose with primary prophylactic antidiarrheal medication or at a lower dose of abemaciclib monotherapy). Such intervention with prophylactic loperamide may increase dose intensity and further optimize the clinical benefit for patients. Trial design: Study JPCG (NCT02747004) is a Phase 2 multicenter, randomized, open-label trial with 3 separate treatment arms in patients with HR+, HER2- MBC who have progressed on or after prior endocrine therapy and have received prior treatment with chemotherapy. Patients will be stratified based on presence of liver metastases and prior use of tamoxifen in the advanced/metastatic setting and will be randomized in a 1:1:1 ratio to receive abemaciclib 150 mg Q12H plus tamoxifen 20 mg every day (Arm A) or abemaciclib 150 mg Q12H monotherapy (Arm B); or abemaciclib 200 mg Q12H monotherapy plus primary prophylactic loperamide (Arm C). Eligibility criteria: Eligible patients include women with HR+, HER2- MBC with evidence of relapse or disease progression following endocrine therapy who have received prior treatment with at least 2 chemotherapy regimens, of which at least 1 but not more than 2 regimens have been administered in the metastatic setting. Patients are required to have measurable disease, adequate organ function, an ECOG PS of ≤1, and no prior treatment with any CDK4 and CDK6 inhibitor. Specific aims: The primary objective of JPCG is to evaluate the progression-free survival per RECIST v1.1, of abemaciclib 150 mg Q12H plus tamoxifen 20 mg QD, abemaciclib 150 mg Q12H monotherapy, and abemaciclib 200 mg Q12H plus prophylactic loperamide in women with HR+, HER2- MBC who have progressed on or after prior endocrine therapy and received prior chemotherapy. Secondary objectives are to evaluate response rates, overall survival, safety, pharmacokinetics, and quality of life. Exploratory objectives include evaluation of the associations between biomarkers relevant to abemaciclib and clinical outcomes. Statistical methods: Assuming a hazard ratio of 0.667, the study yields approximately 80% statistical power to detect superiority of Arm A over Arm C at a 1-sided alpha level of 0.10 using a log-rank test. Arms B and C will be compared using an informal non-inferiority rule. Target accrual: Approximately 225 patients. Contact information: For further information, please contact 1-877-CTLILLY (1-877-285-4559). Citation Format: Diéras V, Hamilton E, Johnston EL, Forrester T, Martín M. Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in women with previously treated hormone receptor-positive (HR+), HER2- metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-08.

Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial

Utidelone, a genetically engineered epothilone analogue, has shown promise as a potential treatment for breast cancer in phase 1 and 2 trials. The aim of this phase 3 trial was to compare the efficacy and safety of utidelone plus capecitabine versus capecitabine alone in patients with metastatic breast cancer. We did a multicentre, open-label, superiority, phase 3, randomised controlled trial in 26 hospitals in China. Eligible participants were female patients with metastatic breast cancer refractory to anthracycline and taxane chemotherapy regimens. We randomly assigned participants (2:1) using computer based randomisation and block sizes of 6 to a 21-day cycle of either utidelone (30 mg/m2 intravenously once per day on days 1-5) plus capecitabine (1000 mg/m2 orally twice per day on days 1-14), or capecitabine alone (1250 mg/m2 orally twice per day on days 1-14), until disease progression or unacceptable toxicity occurred. Patients, physicians, and assessors were not masked to treatment allocation; however, an independent radiology review committee used to additionally assess response was masked to allocation. The primary endpoint was centrally assessed (by an independent radiology review committee) progression-free survival, and analysed using the Kaplan-Meier product-limit method in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. Follow-up is ongoing. This study is registered at ClinicalTrials.gov, number NCT02253459. Between Aug 8, 2014, and Dec 14, 2015, we enrolled and randomly assigned 270 patients to treatment with utidelone plus capecitabine, and 135 to capecitabine alone. Median follow-up for progression-free survival was 6·77 months (IQR 3·81-10·32) for the utidelone plus capecitabine group and 4·55 months (2·55-9·39) for the capecitabine alone group. Median progression-free survival by central review in the utidelone plus capecitabine group was 8·44 months (95% CI 7·95-9·92) compared with 4·27 months (3·22-5·68) in the capecitabine alone group; hazard ratio 0·46, 95% CI 0·36-0·59; p<0·0001. Peripheral neuropathy was the most common grade 3 adverse event in the utidelone plus capecitabine group (58 [22%] of 267 patients vs 1 [<1%] of 130 patients in the capecitabine alone group). Palmar-plantar erythrodysaesthesia was the most prominent grade 3 adverse event in the capacitabine alone group (in 10 [8%] of 130 patients) and was the next most frequent grade 3 event in the utidelone plus capecitabine group (in 18 [7%] of 267 patients). 16 serious adverse events were reported in the combination therapy group (diarrhoea was the most common, in three [1%] patients) and 14 serious adverse events were reported in the monotherapy group (the most common were diarrhoea, increased blood bilirubin, and anaemia, in two [2%] patients for each event). 155 patients died (99 in the combination therapy arm, 56 in the monotherapy arm). All deaths were related to disease progression except for one in each group (attributed to pericardial effusion in the combination therapy group and dyspnoea in the monotherapy group) that were considered possibly or probably treatment-related. Despite disease progression with previous chemotherapies, utidelone plus capecitabine was more efficacious compared with capecitabine alone for the outcome of progression-free survival, with mild toxicity except for peripheral sensory neuropathy, which was manageable. The findings from this study support the use of utidelone plus capecitabine as an effective option for patients with metastatic breast cancer. Beijing Biostar Technologies, Beijing, China.

Combined analysis of three randomized phase III trials comparing S-1 monotherapy and S-1 combination therapy for first-line treatment of advanced gastric cancer.

49 Background: S-1 is the gold standard for first line therapy of advanced gastric cancer in Asia. There have been multiple meta-analyses published researching and comparing the efficacy and safety of S-1 monotherapy versus combination1,2. However there has been no analysis using actual trial data. Methods: Actual data from three randomized Phase III trials were combined to compare the efficacy of S-1 Monotherapy and S-1 combination therapy. The START trial, comparing S-1 and combination S-1 with docetaxel, SPIRITS, comparing S-1 and combination S-1 with cisplatin and TOP-002, comparing S-1 and S-1 combination with irinotecan, were merged and combined. For this analysis, the three S-1 arms were combined (n = 642) and the different S-1 combination therapy were combined (n = 617) creating two new treatment arms. The primary efficacy outcome of overall survival, progression free survival and subset analysis of overall survival stratified by baseline characteristics were performed. Results: A total of 1248 patients, including 210 Korean patients from the START were used in the analysis. The median overall survival days for S-1 combination and monotherapy was 382 [209, 648] and 321 [177, 597] and median progression free survival days for S-1 combination and monotherapy was 153 [81, 267] and 122 [61, 204]. Both overall survival (p = 0.0088 HR = 0.85 (0.76,0.96)) and progression free survival ( p = &lt; 0.001 HR = 0.75 (0.67,0.85)) was significantly longer in the combination therapy arm compared to the monotherapy arm. Conclusions:Although there are limitations, the analysis re-confirms that S-1 combination therapy shows to be more efficacious compared to S-1 monotherapy for advanced gastric cancer patients. It must be noted that heterogeneity of the S-1 arm was not carefully considered when combining the S-1 data for the trials. In addition, the results are limited to the Asian (Japanese and Korean) population.

Gene Mutations and Treatment Outcome in the Context of Chlorambucil (Clb) without or with the Addition of Rituximab (R) or Obinutuzumab (GA-101, G) - Results of an Extensive Analysis of the Phase III Study CLL11 of the German CLL Study Group

BACKGROUND The CLL11 trial evaluated front line treatment with Clb vs. R-Clb vs. G-Clb in 781 physically unfit patients. Genomic aberrations, IGHV and TP53 mutation status are established prognostic factors in CLL, while NOTCH1, SF3B1, ATM and othersare recurrently mutated genes of potential prognostic and/or predictive value. METHODS We performed amplicon-based targeted next generation sequencing of all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3, XPO1, POT1) or hotspots (NOTCH1 exons 33/34, SF3B1 exons 14-16/18) via Illumina TSCA™ in a representative subset of 689 (88.2%) patients of the CLL11 trial at baseline. Mean read depth was 1363x (range 636-1879) and a variant allele frequency >5% was determined as mutation. RESULTS Incidences of gene mutations were: ATM 19.6%, NOTCH1 18.6%, SF3B1 12.9%, TP53 10.7%, POT1 7.3%, XPO1 6.8%, BIRC3 5.2%, FBXW7 3.8%, and MYD88 3.3%. We found several significant associations with clinical and genetic baseline characteristics including most prominently IGHVunmut with ATMmut (p=0.013), NOTCH1mut (p Regarding response to treatment, TP53mut was associated with reduced ORR for R-Clb (p At a median observation time of 41.9 months, there were 529 (76.8%) events for PFS and 195 (28.3%) events for OS in the cohort studied. G-Clb prolonged PFS as compared to R-Clb in the overall cohort (median 27.1 vs. 15.7 months, HR 0.49, p We performed multivariable Cox regression analysis including clinical and genetic prognostic parameters that were significant in univariate analyses to evaluate their independent prognostic value for PFS and OS. For PFS we identified G-Clb vs. Clb (HR 0.21, p 10 U/l (HR 1.22, p=0.037) as independent prognostic factors. Regarding OS, 17p- (HR 2.57, p 80 years (HR 1.68, p=0.006), Binet stage C (HR 2.1, p 10 U/l (HR 1.59, p=0.004) were identified as independent adverse prognostic factors, while G-Clb vs. Clb (HR 0.61, p=0.022) and G-Clb vs. R-Clb (HR 0.69, p=0.029) correlate with a better OS. CONCLUSION The advent of targeted next generation sequencing has led to a more comprehensive molecular characterization of CLL patients and can provide the basis for genotype specific treatment concepts. G-Clb improves treatment outcome as compared to R-Clb for most subgroups defined by gene mutations and overcomes NOTCH1mut-associated Rituximab resistance. In particular, addition of G achieved more MRD negativity in NOTCH1mut, ATMmut, BIRC3mut and FBXW7mut patients. Both ATMmut and TP53mut remain strong prognostic factors. New treatment regimens with novel agents should be considered for patients with adverse independent prognostic factors for PFS and OS, most notably 17p-, 11q-, IGHVunmut and TP53mut. Disclosures Tausch:Gilead: Other: Travel support, Speakers Bureau; Amgen: Other: Travel support; Celgene: Other: Travel support. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Goede:Glaxo Smith Kline: Consultancy, Honoraria; F- Hoffmann-LaRoche: Consultancy, Honoraria, Other: Travel grants; Janssen: Consultancy, Other: Travel grants; Gilead: Consultancy; Mundipharma: Consultancy, Honoraria; Bristol Myer Squibb: Honoraria. Ritgen:Roche: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Langerak:InVivoScribe Technologies: Patents & Royalties: Royalties are provided to European Network (EuroClonality); F. Hofmann-LaRoche, Genentech: Research Funding. Fingerle-Rowson:F. Hoffmann-LaRoche: Employment. Kneba:Amgen: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants; Janssen-Cilag: Consultancy, Honoraria, Other: Travel grants; Glaxo-SmithKline: Other: Travel grants; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding. Fischer:Roche: Other: travel grants. Hallek:F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding.

Incidence, Severity, and Outcomes of AKI Associated with Dual Renin-Angiotensin System Blockade.

The benefit of dual blockade of the renin-angiotensin system is limited by adverse effects. We performed a secondary analysis of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Study to describe the effect of increased intensity of renin-angiotensin system blockade on the incidence, risk factors, and outcomes of AKI. In the VA NEPHRON-D Study, we randomized 1148 veterans receiving outpatient care with type 2 diabetes mellitus, eGFR of between 30 and 89.9 ml/min per 1.73 m2, and urinary albumin excretion of at least 300 μg/mg creatinine (or a urinary total protein of at least 0.5 mg/mg creatinine) to either combination therapy with losartan and lisinopril or monotherapy with losartan. We identified hospitalized AKI events and their outcomes during a median follow-up of 2.2 years through systematic reporting of serious adverse events. The incidence of AKI was 12.2 (95% confidence interval, 10.5 to 14.0) versus 6.7 (95% confidence interval, 5.6 to 8.2) per 100 patient-years in the combination arm versus monotherapy arms (P<0.001). Individuals with AKI were more likely to develop the primary study end point of death, ESRD, or decline in kidney function (hazard ratio, 1.78; 95% confidence interval, 1.34 to 2.26; P<0.001). Patients with AKI in the combination arm had greater recovery of kidney function (75.9% versus 66.3%; P=0.04), lower 30-day mortality (4.7% versus 15.0%; P<0.01), and lower hazard for development of the primary study end point (hazard ratio, 0.60; 95% confidence interval, 0.37 to 0.98). Dual renin-angiotensin system blockade was associated with an increased risk of AKI compared with monotherapy, but AKI in the setting of monotherapy was associated with lower rates of recovery of kidney function, higher mortality, and higher risk of progression of kidney disease.

Evaluation of cerebrospinal fluid virological escape in patients on long-term protease inhibitor monotherapy.

A strategy of protease inhibitor (PI) monotherapy with re-introduction of triple therapy in those who rebound has been shown to be a safe and effective treatment simplification approach for long-term management. We sought evidence for cerebrospinal fluid (CSF) virological escape in patients on long-term PI monotherapy. We performed lumbar puncture in asymptomatic participants with suppressed plasma HIV RNA after 96 weeks on the PI monotherapy arm (PI-mono) of the PIVOT trial. We also report CSF HIV RNA concentration in trial participants who were investigated for neurological/neurocognitive symptoms during the trial regardless of study arm allocation. All 11 asymptomatic participants on PI-mono who were tested had undetectable CSF HIV RNA at week 96. One of the three symptomatic participants on PI-mono had CSF HIV RNA of 1,895 copies/ml (undetectable in plasma) and neither of two symptomatic participants on triple therapy had CSF HIV RNA detected. CSF virological escape appears rare in asymptomatic patients on PI monotherapy and may not warrant routine CSF monitoring, but patients with symptoms merit more concern.

Higher sexual interest with androgen receptor inhibitor monotherapy than with castration plus an androgen receptor inhibitor in prostate cancer patients treated with curative radiotherapy, but otherwise small health-related quality of life differences: A randomised prospective 18-month follow-up study

PurposeTo prospectively study differences in health-related quality of life (HRQoL) in patients with localised/locally advanced prostate cancer (PC) treated with curative intended radiation therapy and randomised to androgen receptor inhibitor monotherapy treatment versus castration plus an androgen receptor inhibitor used continuously. Time to Prostate Specific Antigen (PSA) relapse, time to symptomatic metastasis and overall survival (OS) were also described for the two groups. Patients and methodsFrom 2005 to 2011, a total of 110 patients were randomised at a ratio of 1:1. HRQoL was assessed at six time points: before randomisation, before radiotherapy (RT) start and 9, 12, 15 and 18 months after randomisation, using the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) and EORTC QLQ-PR25. ResultsAt the 3-month follow-up, statistically significant differences between the two groups were found for overall quality of life (p = 0.006), fatigue (p = 0.023), sexual interest (p < 0.001) and urinary problems (p = 0.036). Small clinical differences were noted for overall quality of life, role functioning, fatigue, pain, sleeping problems and urinary problems. At that assessment point, clinical differences between the groups were substantial regarding sexual interest and moderate regarding sexual functioning (the latter indicated only by patients reporting having sexual interest at baseline). All statistical and clinical differences favoured the androgen receptor inhibitor monotherapy arm. At 18 months after randomisation, statistically significant differences were found for cognitive functioning (p = 0.040) and sexual interest (p = 0.011), both favouring the androgen receptor inhibitor monotherapy arm. ConclusionThe results suggest that neo-adjuvant androgen receptor inhibitor monotherapy might be preferred compared to castration plus an androgen receptor inhibitor before curative intended RT in men with localised/locally advanced PC, with higher levels of HRQoL, especially concerning sexual interest. HRQoL differences over time were small. The observation time and study sample were too small for evaluating time to PSA progression and OS. Further studies are needed to confirm the results. The study was registered in, identification number NCT02382094.

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

Abstract 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 &amp;lt; 5 × 109/L at the time of diagnosis and at study entry, or lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), and who have previously received ? 2 prior lines of therapy with rituximab and an alkylating agent and must be refractory to the last treatment with rituximab (refractory defined as progressing or not responding within 6 months of the last course of treatment). Patients will be randomized in 2:1 manner to receive 60 mg of copanlisib administered intravenously on days 1, 8 and 15 of a 28-day cycle or placebo administered on the same schedule until disease progression or intolerable toxicity. Patients in the placebo arm will be allowed to cross-over to receive follow-up treatment with copanlisib, after confirmed disease progression. Dose reductions due to toxicities will be allowed. Radiologic tumor assessment will be performed every 12, 16 or 24 weeks for years 1, 2, and 3, respectively. The primary endpoint will be progression-free survival (PFS). Secondary objectives include overall objective response rate (ORR), duration of response (DOR), time to progression (TTP), complete response rate (CRR), overall survival (OS), time to deterioration as well as time to improvement in disease-related symptoms. Exploratory objectives will include secondary PFS after first progression in placebo-treated patients who cross over to receive copanlisib and time to improvement and the time to deterioration in disease-related symptoms - physical (DRS-P) of at least 3 points as measured by the FLymSI-18 questionnaire. Approximately 189 patients who meet the eligibility criteria will be randomized 2:1, with approximately 126 patients in the copanlisib monotherapy arm and approximately 63 patients in placebo arm. The study is planned to detect a 132% increase in median PFS in copanlisib versus placebo (i.e. to detect a hazard ratio of 0.43), using a stratified log-rank test. This study is currently enrolling patients (NCT02369016). 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-Hodgkin's 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 CT090: Phase II trial of the NDC CRLX101 in combination with bevacizumab in patients with platinum-resistant ovarian cancer (PROC)

Abstract Background: CRLX101 is an investigational nanoparticle-drug conjugate (NDC) with a camptothecin payload. CRLX101 is a dual inhibitor of topoisomerase 1 and hypoxia inducible factors 1α and 2α (HIF1-α and HIF-2α). CRLX101 is being explored clinically in several tumor types including renal cell carcinoma (RCC) in combination with Avastin®, (Keefe, ASCO 2015, 4543) and platinum-resistant ovarian cancer (PROC) (Krasner ASCO 2014, 5581). The PROC study has a CRLX101 monotherapy arm (Group A) and a combination arm with Avastin (Group B). Group A patients (pts) received CRLX101 at 15mg/m2 every other week and Group B patients received CRLX101 15 mg/m2 with Avastin 10 mg/kg every other week until progression or unacceptable toxicity. The primary endpoint for both groups was rate of progression free survival at 6 months (PFS6) using RECIST 1.1 criteria. Secondary endpoints were objective response rate (ORR), PFS, ?50% reduction of CA125 over baseline, and safety. Adverse events (AEs) were assessed by CTCAE v4.0. Pre- and post-treatment tumor biopsies were collected from a cohort of patients in Group A to evaluate relevant PD endpoints, suggesting that CRLX101 is active in PROC. Results: A total of 18 PROC patients were evaluated in Group B. Demographics: Median age of the patient was 59years (range: 46-68). Median number of previous regimens was 2 (range: 1-3), ECOG PS 0 (13 pts) or 1 (5 pts). The PFS6 was demonstrated in 56% pts (10 out of 18). The PR and stable disease (SD) rates were 17% (3 out of 18 pts) and 78% (14 out of 18 pts), respectively. Median progression-free survival is 6.2 months to date. A ? 50% decline in CA125 was demonstrated in 44% pts (8 out of 18). AEs most commonly observed with the combination were nausea (10 pts, 56%), anemia (10 pts, 56%); proteinuria (8 pts, 44%) and fatigue (6 pts, 33%). The majority of AEs were Grade 1. There were only two drug-related AEs Grade ? 3: one patient developed uncomplicated and reversible elevated ALT (grade 3) and another patient had a short-lived decrease in ANC (grade 4). A retrospective analysis for both cohorts, Group A vs. Group B, demonstrated that the combination showed increased antitumor activity: PFS6: 27 vs 56%, mPFS 4.2 vs 6.2 months and CA125: 23 vs 44%. Conclusions: CRLX101 15 mg/m2 in combination with Avastin 10 mg/kg given every other week demonstrated antitumor activity and was generally well-tolerated in advanced PROC pts. An additional 25 pts will be enrolled in Group B. This combination is currently being explored in an ongoing randomized controlled Phase 2 trial in 3rd and 4th line RCC, and is also being tested in combination with weekly paclitaxel in an ongoing Phase 1b trial in PROC. Clinical trial information: NCT01652079 Citation Format: Carolyn Krasner, Michael Birrer, Christian Peters, Lata Jayaraman, Scott Eliasof, Andres Tellez, William Downing, Adrian Senderowicz. Phase II trial of the NDC CRLX101 in combination with bevacizumab in patients with platinum-resistant ovarian cancer (PROC). [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 CT090.

HCV1b genome evolution under selective pressure of the cyclophilin inhibitor alisporivir during the DEB-025-HCV-203 phase II clinical trial

Major advances have revolutionized the HCV antiviral treatment field, with interferon-free combinations of direct-acting antivirals (DAAs) resulting into success rates of >90% for all HCV genotypes. Nevertheless, viral eradication at a global level stills remains challenging, stimulating the continued search for new affordable pan-genotypic drugs. To overcome selection of drug resistant variants, targeting host proteins can be an attractive mechanism of action. Alisporivir (Debio 025) is a potent pan-genotypic host-targeting antiviral agent, acting on cyclophilin A, which is necessary for HCV replication. The efficacy and safety of three different oral doses of alisporivir in combination with pegylated interferon-α2a given over a period of four weeks, was investigated in a randomized, double-blind and placebo-controlled phase IIa clinical trial, in 90 treatment-naïve subjects infected with chronic hepatitis C, wherefrom 58 HCV1b samples were selected for genetic sequencing purposes. Sequencing results were used to study the HCV genome for amino acid changes potentially related with selective pressure and resistance to alisporivir. By comparing baseline and on-treatment sequences, a large variation in proportion of amino acid changes was detected in all treatment arms. The NS5A variant D320E, which was previously identified during in vitro resistance selection and resulted in 3.6-fold reduced alisporivir susceptibility, emerged in two subjects in the alisporivir monotherapy arm. However, emergence of D320E appeared to be associated only with concurrent viral load rebound in one subject with 0.8log10IU/ml increase in HCV RNA. In general, for all datasets, low numbers of positions under positive selective pressure were observed, with no significant differences between naïve and treated sequences. Additionally, incomplete sequence information for some of the 22 patients and the low number of individuals per treatment arm, is limiting the power to assess the association of alisporivir or interferon treatment with the observed amino acid changes.