All Grades Research Articles

A single-arm biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer (PRCC).

436 Background: Savolitinib (HMPL504/Volitinib, AZD6094) is a potent, selective MET inhibitor (IC50 of 4nM). MET and its ligand, HGF, are known to play an important role in the molecular events underlying oncogenesis in PRCC, a disease without a clear standard of care and marked by alterations of chromosome 7 (containing both MET and HGF genes) in a majority of patients as well as gene amplification or MET kinase domain mutations (Albiges et al. 2014, Linehan et al., 2015). Methods: This study evaluates savolitinib in PRCC patients dosed at 600mg daily until disease progression. ORR is the primary endpoint. PFS & DoR are secondary endpoints. PRO & HRQoL questionnaires are exploratory endpoints. Eligibility includes naive and previously treated metastatic PRCC, ECOG PS 0 or 1. Archival tumor was used to centrally confirm PRCC pathology post hoc and to determine MET status using Next Generation Sequencing (Foundation Medicine Inc, USA). Results: As of 27 June 2016, 109 pts were dosed. Best response was PR n=8, SD n=43, PD n=48 and 10 patients were not evaluable for response. 44 pts are MET-driven (MET/HGF gene copy number gain or kinase domain mutations), 46 pts were MET-negative, 19 pts are status unknown. MET-driven pts included Papillary Type I & II histologies. All 8 responders were in the MET-driven group, 18% RR in this subset. Median PFS in the MET-driven group was 6.2 months (95% CI: 4.1–7.0) vs. 1.4 months (95% CI: 1.4–2.7) in the MET-negative group (p = 0.002). Overall 10/109 pts had AEs leading to discontinuation. 23/109 pts had ≥ Grade 3 toxicity related to savolitinib. The most common AEs (all grades) includes: nausea (39%), fatigue (27%), edema (18%), and abnormal LFTs (17%). One death from hepatic encephalopathy was considered related to savolitinib. PRO & HRQoL data was not statistically analysed, descriptive data support main efficacy findings. Conclusions: In the largest biomarker-profiled trial dedicated to PRCC, savolitinib was generally well tolerated with anti-tumor activity in MET-driven patients. These findings warrant further clinical investigation of savolitinib in MET-driven PRCC. Clinical trial information: NCT02127710.

A phase 1b/2 study of INCB039110 + nab-paclitaxel (N) and gemcitabine (G) in patients (pts) with advanced solid tumors and pancreatic cancer (PC).

362 Background: JAK-STAT activity has been associated with malignant cell proliferation and production of proinflammatory cytokines involved in cancer progression. INCB039110 is a potent and selective inhibitor of JAK1. Methods: This was a 2-part phase 1b/2 open-label study evaluating INCB039110 (300 or 400 mg QD) in combination with N and G in pts with advanced or metastatic solid tumors (Part 1 [P1], dose optimization phase) and pts with advanced or metastatic PC who had not received prior chemotherapy (Part 2 [P2] and 2A [P2A]). Pts in P2 received the MTD established in P1: INCB039110 (300 mg QD) + N (125 mg/m2 day [d] 1, 8, 15) + G (1000 mg/m2 d 1, 8, 15), 28-d cycle. For exploratory purposes, pts in P2A underwent a 7-d induction phase with INCB039110 (200 mg QD) before receiving INCB039110 (200 mg QD) + N (125 mg/m2 d 1, 8, 15) + G (1000 mg/m2d 1, 8, 15). The primary objective was to evaluate safety/tolerability. Results: 55 pts were enrolled (27 P1, 20 P2, and 8 P2A). Most patients had advanced PC (n = 46). Median age was 65 (P1), 67 (P2), and 66 years (P2A). Prior therapy: 67% in P1, 30% in P2, and 0% in P2A. The most common reasons for treatment discontinuation were adverse events (AEs; 41% P1, 20% P2, 38% P2A), disease progression (37% P1, 45% P2, 0% P2A), and study termination by the sponsor (0% P1, 0% P2, 38% P2A). Median treatment durations were 84 d (P1), 121 d (P2), and 47 d (P2A). The most common non-hematologic AEs (all grades) were fatigue (59% P1, 75% P2, 88% P2A), nausea (41% P1, 50% P2, 38% P2A), pyrexia (37% P1, 40% P2, 13% P2A), and peripheral edema (30% P1, 50% P2, 25% P2A), with few grade 3 or 4 non-hematologic AEs. The most common grade 3 or 4 hematologic AEs (laboratory values) were neutropenia (33% P1, 60% P2, 13% P2A), lymphopenia (30% P1, 30% P2, 13% P2A), and leukopenia (30% P1, 45% P2, 0% P2A). The most common serious AEs occurring in ≥ 3 pts were pneumonia (n = 4 P1, n = 2 P2, n = 0 P2A) and anemia (n = 3 P1, n = 2 P2, n = 2 P2A). Among evaluable patients, ORR (all PRs) and DCR were 27% (13/48) and 75% (36/48), respectively. Responses were seen across INCB039110 doses. Conclusions: INCB039110 + N/G showed an acceptable safety profile in pts with advanced PC, with the combination demonstrating clinical activity. Clinical trial information: NCT01858883.

Phase 2 Study of Venetoclax Plus Rituximab or Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with Relapsed/Refractory Follicular Lymphoma: Interim Data

Phase 2 Study of Venetoclax Plus Rituximab or Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with Relapsed/Refractory Follicular Lymphoma: Interim Data

Results of a Phase Ib Study of Venetoclax Plus R- or G-CHOP in Patients with B-Cell Non-Hodgkin Lymphoma

Results of a Phase Ib Study of Venetoclax Plus R- or G-CHOP in Patients with B-Cell Non-Hodgkin Lymphoma

A phase 1 study of CRLX301, a novel nanoparticle-drug conjugate (NDC) containing docetaxel (DOC), in patients with refractory solid tumors.

2526Background: CRLX301 is an investigational NDC with DOC covalently conjugated to a cyclodextrin-polyethylene glycol co-polymer designed to enhance delivery to tumor tissue. Preclinical studies of CRLX301 showed enhanced drug accumulation in tumor and greater tumor growth suppression in murine models compared to DOC. Methods: Patients (pt) with advanced solid tumors were treated with escalating doses of CRLX301 IV once every 21 days (Q3W). The first two cohorts were single pt cohorts and then adjusted to 3+3 design. Primary objective: MTD and/or RP2D. Secondary objectives: safety, anti-tumor activity and PK. Results: 20 pts were enrolled. All were evaluable for DLT. Prior lines of chemotherapy: median 3 (range 0 to 6); 8 pts had prior taxane therapy. Tumor types: cholangiocarcinoma (5), head and neck (3), lung (2) and others (10). All drug-related AEs were toxicities typically associated with DOC. The most common drug-related AEs (all grades) were fatigue (70%), infusion reaction (40%), nausea (35%), di...

Venetoclax (ABT-199/GDC-0199) Monotherapy Induces Deep Remissions, Including Complete Remission and Undetectable MRD, in Ultra-High Risk Relapsed/Refractory Chronic Lymphocytic Leukemia with 17p Deletion: Results of the Pivotal International Phase 2 Study

Venetoclax (ABT-199/GDC-0199) Monotherapy Induces Deep Remissions, Including Complete Remission and Undetectable MRD, in Ultra-High Risk Relapsed/Refractory Chronic Lymphocytic Leukemia with 17p Deletion: Results of the Pivotal International Phase 2 Study

O10.3 - Rociletinib: an oral, irreversible, highly selective small molecule inhibitor of mutant EGFR including T790M

ABSTRACT Background: Rociletinib (CO-1686) is a potent, oral, irreversible inhibitor of mutant EGFR, including the T790M resistance mutation. T790M accounts for 60% of acquired resistance to first and second generation EGFR inhibitors1. We review interim phase 2 data from an ongoing phase 1/2 study (TIGERX; EudraCT 2011-005215-86) in patients with advanced, previously treated, mutant EGFR non small cell lung cancer2. Materials and Methods: Eligible patients have advanced EGFR mutant T790M + /- non small cell lung cancer (NSCLC), previous treatment with at least one EGFR inhibitor, ECOG PS 0-1, and adequate organ function. Stable brain metastases are allowed. Patients all received prior EGFR TKI, with separate phase 2 cohorts receiving EGFR TKI as the only prior treatment and others who had additional prior systemic therapies. Results: We present efficacy data from T790M positive and negative pts enrolled at therapeutic doses (500mg BID and 625mg BID). Demographic characteristics reflect a Western population with advanced mutant EGFR NSCLC: median age 59 yrs, 70% female, 80% ECOG 1, 55% >1 previous TKI line, median prior therapies 3. The only related ≥ Grade 3 AE occurring in ≥ 5% patients was hyperglycemia (14%) and no pt discontinued for this event. Related AEs (all grades) in ≥ 15% patients were: hyperglycemia (32%), diarrhea (25%), nausea (25%), reduced appetite (20%). In the T790M+ group, the RECIST overall response rate (ORR) is currently 67%, median PFS 10.4 months. In the T790M negative group, the overall response rate is 42%, median PFS 7.5 months. We also present non clinical data that elucidates the mechanism of action of hyperglycemia together with an overview of the current and future development strategy. Conclusion: Rociletinib is associated with durable clinical benefit in patients with advanced EGFR mutant NSCLC. The activity in the T790M negative group may result from assay insensitivity, tumor heterogeneity or from concomitant inhibition by rociletinib of other tyrosine kinases involved in tumor growth.

An Open-Label Phase II Study of Buparlisib (BKM120) in Patients with Relapsed and Refractory Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma or Follicular Lymphoma

Abstract Background: Non-Hodgkin's lymphoma (NHL), which includes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL), is associated with a high unmet need in the relapsed and refractory setting. The PI3K/AKT/mTOR pathway has been shown to play a key role in the pathogenesis of NHL. Overexpression of PIK3CD (encoding the PI3Kd isoform) is common in B-cell malignancies and is therefore widely viewed as a therapeutic target in NHL. PIK3CA and PIK3CB are also expressed in B-cell malignancies, with PIK3CA overexpression seen particularly at relapse, thereby justifying exploration of pan-PI3K inhibitors in the relapsed or refractory setting. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor which has demonstrated activity in patients with solid tumors as well as in in vitro and in vivo models of hematologic malignancies. Methods: The primary objective of this Phase II study (NCT01693614) was to evaluate the efficacy of buparlisib in three parallel cohorts of adult patients with relapsed or refractory DLBCL, FL, or MCL. Secondary objectives were to evaluate safety and tolerability, progression-free survival, duration of response, and overall survival. Inclusion criteria were: patients with relapsed or refractory disease who have received at least one prior line of therapy; at least one measurable nodal lesion (≥2 cm); ECOG performance status ≤2; and adequate bone marrow and organ function. Patients with DLBCL must have received, or be ineligible for, autologous or allogeneic stem cell transplant. All patients received single-agent buparlisib 100 mg orally QD continuously until progression, intolerance, or patient withdrawal. Tumor response was evaluated by investigators per standard criteria (Cheson, 2007). Results: At data cut-off (June 19, 2014), 64 patients had been enrolled; 26 DLBCL, 24 FL, and 14 MCL. Here, results are presented for the DLBCL cohort only. Updated results from the DLBCL cohort including biomarker analyses and results for the FL cohort will be presented at the meeting. The MCL cohort is currently enrolling. For the DLBCL cohort, median age (range) was 63.5 (28–81) years and 69% were male. The median (range) number of prior therapy regimens was 3 (1–12). Specific prior therapies included: rituximab (n=25, 96%) and bendamustine/carmustine (n=8, 31%); all patients had received prior anthracycline and an alkylating agent (e.g. cyclophosphamide), and 6 (23%) patients had undergone prior stem cell transplantation. The most common (≥15%) AEs (all grades) regardless of causality were hyperglycemia and nausea (39% each), depression (31%), anxiety and fatigue (23% each), vomiting and diarrhea (19% each), and abdominal pain (15%). Alanine transaminase or aspartate transaminase elevations were rare (4% each, with no Grade 3/4 AEs). The most common (>5%) Grade 3/4 AEs regardless of causality were hyperglycemia (23%), and nausea, depression, anxiety, urinary tract infection, and neutropenia (8% each). Six (23%) patients discontinued therapy due to AEs (potentially treatment-related). Seven on-treatment deaths were reported: 6 were disease-related and 1 was suspected to be treatment-related (unexplained death following a gastrointestinal [GI] bleed in a patient with massive GI lymphoma involvement). Overall response rate was 12% (95% CI = 2.4, 30.2) with 3 responses: 1 complete response (4%) and 2 partial responses (8%). Five patients had stable disease (19%). Eight patients (31%) experienced some decrease in tumor burden (Figure 1). At data cut-off, 2 patients demonstrated durable responses, as they were still on study treatment after 9.2 and 7.4 months, respectively. Figure 1 Figure 1. Conclusions: Early results from this Phase II study of the pan-PI3K inhibitor, buparlisib, demonstrate encouraging clinical activity, and a favorable safety profile in heavily pretreated patients with relapsed or refractory DLBCL. These data suggest that targeting all 4 PI3K isoforms in DLBCL is a viable strategy and worthy of further exploration in patients with NHL. Future combination studies with buparlisib will take a mechanism-based approach. Disclosures Younes: Novartis, Curis, J&J: Research Funding; Bayer, BMS, Celgene, Incyte, Janssen R&D: Honoraria; Sanofi, Seattle Genetics, Takeda Millenium: Honoraria. Mukherjee:Novartis Healthcare Pvt. Ltd. India: Employment. Williams:Novartis: Employment. Herbst:Novartis: Employment. Tavorath:Novartis: Employment. Kim:Novartis, Celgene, Takeda: Research Funding.

Phase 2 Study of Bendamustine in Combination with Dexamethasone (Ben/Dex) in Patients with Previously-Treated Systemic Light Chain (AL) Amyloidosis

Background: Melphalan is an alkylator and in combination with dexamethasone an active and standard regimen in AL amyloidosis. However these patients relapse and other drugs are needed. Bendamustine is a bifunctional alkylating agent with established efficacy in CLL, NHL, and MM but its safety and efficacy in AL amyloidosis is not known. In an effort to investigate the activity of Ben/Dex and improve the outcome of patients with relapsed AL we conduct a multi-center, Phase 2 study of Ben/Dex in AL (NCT01222260) and report data of an interim analysis.Methods: All patients had relapsed AL after a median of 2 prior therapies (range 1-4). Patients with very advanced cardiac involvement (NYHA Class IIIB/IV) were excluded. Patients with NYHA Class IIIA, NT-proBNP ≥ 1800 ng/L or BNP ≥ 400 ng/L, abnormal cTnT or cTnI could be included after evaluation by cardiology to determine the risk associated with the treatment. Patients with a CrCl ≥ 15 mL/min were considered for the trial if they were not in active renal failure. This Phase IIa clinical trial uses a two-stage optimal Simon design enrolling 13 patients in the first stage. Since at least three patients experienced hematologic PR or better, the trial proceeded to the second stage treating an additional 16 patients. If 9 or more patients out of the total of 29 patients evaluable for response experience a hematologic PR or better, the treatment will be considered worthy of further development. The primary objective is to determine the partial hematologic response rate (PR) of patients who received at least 2 cycles of therapy. Secondary objectives included overall hematologic response (OHR) rate, organ response rate (OrRR) (Palladini et al., JCO 2012), time to failure (TTF), toxicities (adverse events at least possibly related to treatment), overall survival (OS) and the assessment of expression of genes associated with ER stress. Patients were assigned to bendamustine according to CrCl: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle, CrCl 59 – 15 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle. The option to dose escalate was available to qualifying subjects including escalating to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) and 100 mg/m2 (if CrCl 59 – 15 mL/min at the time of inclusion into the study). Dexamethasone was started at 20-40mg weekly according to the performance status of the patient.Results: As of 7/15/14, 15 patients have received treatment. Median age was 66.5 (range 43-76). Patients received a median of 2 prior regimens (range 1-4). Six patients received prior autologous stem cell transplant. Median number of cycles is 3.5 (range is 1-9), with 5 patients still receiving treatment. Of note, only 1 patient discontinued treatment due to disease progression. Only 3 patients discontinued treatment due to AE. Most common drug-related AEs (all grades) included fatigue (67%), nausea (53%), anemia, constipation and dyspnea (47% each), limb edema and increased creatinine (40% each). Grade ≥3 AE occurring in >25% of patients were only fatigue and chronic kidney disease (27% each). Of note, no cardiac events were observed, including any increase in NT-proBNP. No deaths have occurred in association with the treatment. Of 11 patients eligible for response evaluation, 5 (45%) have responded hematologically, including (≥PR 36%, CR 9%). Median time to PR was 2 cycles and the CR occurred in a patient after 5 cycles suggesting that this heavily pretreated patient population needs longer treatment to achieve response. With a median follow-up of 8.7 months (range 1.4 to 18.6 months) the median OS has not been reached yet (Figure 1). The median PFS is 11.2 months with a range of 0.4-15.7 months (Figure 2)Conclusions: Bendamustine in combination with dexamethasone is feasible and effective in heavily pretreated AL amyloidosis with impaired organ function (NYHA IIIB and creatinine clearance of 30-15 mL/min were allowed). Cardiac events were not observed. Preliminary hematologic response rates are promising in this heavily pretreated patient population, and organ assessments are ongoing. Further study of this approach is warranted. [Display omitted] [Display omitted] DisclosuresLentzsch:Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding. Off Label Use: Bendamustine treatment in amyloidosis .

642P - Trastuzumab in Combination with Different First-Line Chemotherapies for Treatment of Her2-Positive Metastatic Gastric Cancer: Updated Findings from the German Non-Interventional Study Hermes

ABSTRACT Aim: The international phase III study ToGA has shown that trastuzumab (TRA) (Herceptin®) is effective in prolonging survival in HER2-positive metastatic gastric or gastro-oesophageal junction cancer (MGC). However, few data are available for TRA as part of routine clinical practice. Methods: This non-interventional observational study (NCT01220934) aims to evaluate the efficacy, safety and feasibility of TRA in previously untreated pts with HER2-positive MGC. Results: Between Apr 2010 and Apr 2014, we collected data from 360 pts. All pts were evaluable for safety. Baseline pt characteristics were as follows: median age 66 y (range 29–90); gender (male 74%; female 26%); ECOG PS (0: 28%; 1: 47%; 2: 12%; 3: 2%); distant mets (90%): liver (53%), lymph node (35%); peritoneal carcinomatosis (21%); lung (14%). Only 28% of pts received TRA in combination with cisplatin and 5-FU or capecitabine (see table). Most pts (51%) did not receive cisplatin-based therapy. 54 pts (15%) received TRA for more than 12 months. TRA containing regimen n (%) + 5-FU + cisplatin 75 (21) + 5-FU + cisplatin + leucovorin 54 (15) + 5-FU + oxaliplatin (+ leucovorin) 50 (14) + 5-FU + oxaliplatin + docetaxel 36 (10) + capecitabine + cisplatin 25 (7) + capecitabine 20 (6) other combinations * 87 (23) TRA monotherapy 13 (4) cisplatin-free regimen 184 (51) * including cisplatin. Preliminary median PFS was 7.6 m (number of events: n = 282), thus comparable to the ToGA data. Most common AEs (all grades) were diarrhoea (9%), nausea (7%), and fatigue (6%). Most common grade 3/4 AEs were general physical health deterioration (2%), vomiting (1%), and diarrhoea (1%). Health-related quality of life as assessed by EORTC QLQ-C30 and QLQ-STO22 remained stable during observation time. An updated analysis of approx. 400 pts will be presented at the meeting. Conclusions: TRA combined with diverse chemotherapies, including less toxic cisplatin-free schedules, is safe and effective in the routine treatment of MGC. Overall, the results are in line with those from the ToGA trial. TRA is the standard of care for pts with HER2-positive MGC. Disclosure: S. Al-Batran: Receipt of grants / research support from Roche;K. Zielke: employee of Roche;T. Wohlfarth: employee, stock ownership (Roche); P.C. Thuss-Patience: receipt of honoraria from Roche;M. Moehler: 1) receipt of honoraria from Roche for speeches, presentations or appearances 2); consultancy and advisory role compensated by Roche. All other authors have declared no conflicts of interest.

728P - Final Analysis of Overall Survival Per Subgroups of Hcc Patients in the Prospective, Non-Interventional Insight Study Treated with Sorafenib

ABSTRACT Aim: INSIGHT is a prospective, non-interventional study, conducted in Germany and Austria in pts with hepatocellular carcinoma HCC. The objectives of this study are the evaluation of safety and efficacy under practice conditions in both hospitals and private practices. Enrollment into INSIGHT is not restricted to a particular tumor stage. Methods: This final analysis evaluated overall survival and safety data incluling relevant subgroups. All patients with HCC were observed for the duration of their sorafenib therapy. In addition to baseline data the performance status, tumor status (clinical and/or radiological), and overall survival time are documented. Documentation of adverse events comprises relationship with drug, seriousness, grade (CTCAE version 3.0), and outcome. Results: 791 pts have been enrolled; 788 of which are evaluable for safety and 782 for efficacy analyses. The table summarises major baseline characteristics together with median overall survival (mOS) data for relevant subpopulations. Patients recruited n, Male n (%) 782, 668 (85) ECOG PS, n (%), 0, 1, 2 243 (31); 404 (52); 192 (16) BCLC-Stage n (%), A, B, C, D 101 (13); 194 (25); 392 (50); 14 (2) Child Pugh Stage, n (%), A( 9), Missing 443 (57); 182 (23); 26 (3); 131 (17) MOS total population (Events n = 278) 14.8 months mPFS total population (Events n = 633) 4.1 months MOS according to BCLC A, B, C, D 29.1; 19.5; 13.6; 3.1 months MOS according to Child Pugh A, B, C 17.5; 8.1; 5.6 months MOS Child Pugh B: 7, 8, 9 points 8.1; 9.4; 2.4 months mOS Duration of therapy > 24 weeks (n = 352); >40 weeks (n = 209) 25.1; 31.8 months MOS according to age 16.8; 14.5 months (p = 0.5625) MOS according to etiology: Hep C, Hep B, NASH, alcohol 23.3; 10.8; 11.8; 14.3 months AEs (all grades), n (%); Drug-related AEs (all grades), n (%) 688 (87.3); 511 (64.9) SAEs (all grades), n (%); Drug-related SAEs (all grades), n (%) 394 (50); 77 (9.8) Conclusions: Results of mOS in pts with HCC treated under daily practice conditions in hospitals and private practices confirms the general efficacy of Sorafenib and gives further insight into survival of pts with CHILD B, BCLC stage A/B, age ≥65, etiology of HCC and a relevant subgroup of patients treated longer than 40 weeks. Further demographic data, efficacy and safety results will be presented. Disclosure: T.M. Ganten: - Advisor Bayer Healthcare - holding Bayer stocks - fees for Advisor and corporate; sponsored research funding from Bayer Healthcare - other fees from Novartis; R. Stauber: - Fees for Advisory Boards for Abbvie, BMS, Gilead, MSD - corporate sponsored research funding from MSD; R. Buder: - corporate sponsored research funding from Bayer Healthcare; P.R. Galle: - Advisor and Consultant for Bayer, Lilly, Jennerex and BMS; I. Bernard: - Bayer Employee. All other authors have declared no conflicts of interest.

First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M).

8010^ Background: Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 60% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition. CO-1686 is an oral, covalent TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Methods: This is a completed dose finding study in patients with EGFR mutated advanced NSCLC. Patients were previously treated with EGFR TKI and had a tumor biopsy in screening for central EGFR genotyping. CO-1686 was administered twice daily. Endpoints included safety, pharmacokinetics (PK), and efficacy. Results: As of 17thJanuary 2014, 88 patients were treated: 57 with CO-1686 free base (up to 900 mg BID); 31 with CO-1686 HBr (500 to1000 mg BID). 10 transitioned from free base to HBr. 63% were T790M+, median age 61 years, 77% female, 76% white, and 72% ECOG 1. Median number of previous therapies was 3 (1- 7); 40% had >1 prior line of EGFR TKI. PK of the CO-1686 HBr formulation was dose proportional with three times greater exposure than the equivalent free base dose. The dose limiting toxicity (DLT) rate at all doses was <33%. Related AEs (all grades) in ≥ 20% patients were: nausea (25%), fatigue (21%), impaired glucose tolerance/hyperglycemia (21%). Hyperglycemia was well managed with oral hypoglycemics and/or dose reduction. A recommended phase 2 dose of 750 mg BID has been selected. Nine T790M+ patients treated with 900 mg BID (free base) were evaluable for response; 6 (67%) achieved PRs, 2 (22%) achieved SD, one of whom subsequently achieved a PR after transition to CO-1686 HBr. Eight of nine progressed on EGFR TKI immediately before CO-1686. PRs have occurred among patients treated with CO-1686 HBr, however the majority of patients have not reached the first restaging. Efficacy data for at least 41 patients on CO-1686 HBr will be presented at the meeting. Conclusions: CO-1686 has demonstrated promising efficacy against T790M+ EGFR mutant NSCLC. CO-1686 HBr delivered higher exposures than free base and was equally well tolerated. Dose-related WT-driven diarrhea and rash has not been seen. The phase 2/3 program will open in 2014. Clinical trial information: NCT01526928.

A phase 1b study of the anticancer stem cell agent demcizumab (DEM) and gemcitabine (GEM) with or without paclitaxel protein bound particles (nab-paclitaxel) in patients with pancreatic cancer.

279 Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway. DEM is a humanized IgG2anti-DLL4 antibody that inhibits tumor growth and decreases cancer stem cell (CSC) frequency in minimally passaged human xenograft models. In addition, DEM has been shown to have an antiangiogenic effect and showed synergistic activity when combined with GEM and nab-paclitaxel in human pancreatic tumor-derived xenograft models. Methods: Pts with 1st line stage pancreatic cancer received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks) and GEM 1000 mg/m27 of 8 wks, then 3 of every 4 wks. The primary objective was to determine the MTD of DEM. Other objectives were safety, efficacy, immunogenicity, PK and biomarkers of Notch signaling and CSCs. Results: Twenty four pts were enrolled; 8 received 2.5 mg/kg every 2 wks, 8 received 2.5 mg/kg every 4 wks &amp; 8 received 5 mg/kg every 4 wks of DEM. Three (12.5%) and 21 (87.5%) pts had stage III and IV disease, respectively. Related AEs (all grades) in &gt; 15% of pts were: fatigue (29%), hypertension (29%), vomiting (29%), nausea (25%), thrombocytopenia (21%) and decreased appetite (21%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. One pt who received 5 mg/kg developed reversible pulmonary hypertension and heart failure on study day 143. As a result, the duration of DEM will be limited to 70 days in subsequent cohorts. Four of 16 (25%) pts had a RECIST partial response and 7 had stable disease. The median PFS for the 5 mg/kg cohort was 5.9 months. The PK and immunogenicity data will also be presented. Conclusions: DEM plus GEM were generally well tolerated with fatigue, hypertension, and vomiting being the most common drug related AEs. Encouraging early clinical activity was observed. The duration of DEM is being limited to 70 days and nab-paclitaxel is also being given in subsequent cohorts. The first cohort of pts receiving GEM, nab-paclitaxel, and DEM has been enrolled and &gt; 100 days of follow-up on these pts will be presented. Clinical trial information: NCT01189929.

Abstract P2-16-01: A randomized, phase II, multicenter, double-blind, placebo-controlled trial evaluating onartuzumab with or without bevacizumab in combination with weekly paclitaxel in locally recurrent or metastatic triple-negative breast cancer (TNBC)

Abstract Background: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway has been observed in many malignancies. In patients with TNBC, overexpression of MET has been shown to be associated with poor prognosis. Onartuzumab (MetMAb) is a recombinant, humanized, monovalent, monoclonal antibody directed against MET, which selectively blocks ligand binding and subsequent HGF activation. A recent phase 2 trial demonstrated improved progression-free survival (PFS) and overall survival (OS) when onartuzumab was added to erlotinib for patients with MET 2+/3+ non-small-cell lung cancer (NSCLC). Methods: Patients with locally recurrent or metastatic TNBC who had received 0 or 1 prior therapies for metastatic disease were enrolled, provided tumor sample, and randomized (1:1:1) to receive paclitaxel (P) + bevacizumab (B) + onartuzumab (O); P+O; or P+B. Dosing regimens were given IV q4w: P 90 mg/m2 d1, 8 &amp; 15; B 10 mg/kg d1 &amp; 15; O 10 mg/kg d1 &amp; 15. Treatment continued until disease progression or unacceptable toxicity or death; crossover was not permitted. Stratification was by number of metastatic sites (&amp;lt;3, ≥3), number of prior MBC regimens (1 vs 2), and disease-free interval for first-line patients (≤6 months, &amp;gt;6 months). The primary endpoint was PFS; secondary endpoints included OS, objective response rate (ORR), and safety. MET immunohistochemistry (IHC) was performed centrally for exploratory analyses. Results: 185 patients were enrolled from 30 US and 37 EU sites: median age was 53 years (range 30-79); 77% and 23% were treated in the first- and second-line settings, respectively. Baseline characteristics were balanced. Efficacy data for the ITT population are shown in Table 1. The distribution of MET expression using the NSCLC diagnostic algorithm is shown in Table 2. The MET 2+/3+ group was too small for efficacy analyses. Frequently observed AEs (all grades) included peripheral edema (58% vs 59% vs 18%), fatigue (47% vs 41% vs 48%) and diarrhea (53% vs 22% vs 50%), in the P+B+O vs P+O vs P+B arms, respectively. No new safety signals were observed. Table 1Table 1ITT populationP+B+O n = 63P+O n = 60P+B (control) n = 62Median PFS, months7.35.47.2HR vs control (95% CI)1.08 (0.69 - 1.70)1.74 (1.13 - 2.78)-Median OS, months14.713.417.4HR vs control (95% CI)1.35 (0.74 - 2.44)1.88 (1.00 - 3.54)-ORR,% (95% CI)42 (29 - 57)28 (16 - 41)55 (41 - 68) Conclusions: In the ITT population, the addition of O to either P+B or to P alone did not improve PFS and other clinical outcomes compared with P+B alone. Further exploratory subgroup analyses are ongoing. Table 2Table 2MET IHC score01+2+3+Not availablen (%)81 (44)75 (41)21 (11)1 (0.5)7 (4) Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-01.

A Phase III Study Of Enzastaurin In Patients With High-Risk Diffuse Large B Cell Lymphoma Following Response To Primary Treatment: The Prelude Trial

BackgroundDespite improvements in outcome following the addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (R-CHOP), patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and International Prognostic Index (IPI) scores of 3-5 at diagnosis have a poor outcome. Enzastaurin is a potent inhibitor of PKCβ, a component of the B-cell receptor signaling complex, with preclinical activity and clinical activity in a phase II trial in patients with relapsed DLBCL, providing the rationale for this study in the primary therapy setting. MethodsPRELUDE was a multi-national, randomized, double-blinded, placebo-controlled study. Patients were required to have a histologic diagnosis of DLBCL, pre-treatment IPI score ≥3, and a complete response (CR) or CRu by International Working Group Criteria, or a negative FDG-PET scan after 6–8 cycles of R-CHOP. Patients were randomly assigned in a 2:1 ratio to receive either enzastaurin 500 mg daily or an identical placebo as maintenance therapy, for a planned treatment duration of 3 years. The primary endpoint was DFS, defined as lack of disease progression or death. Assuming a 2-year DFS rate in the control group of 70%, the primary analysis had 80% power to detect a HR of 0.67, eg, a 2-year DFS rate of 79% in the enzastaurin group. Secondary endpoints included overall survival (OS) and event-free survival (EFS). Data were analyzed 3 years after the last enrolled patient initiated treatment. ResultsFrom May 2006–April 2010, 758 patients were enrolled (enzastaurin, n=504; placebo, n=254). Median age at enrollment was 64 years (range 21-89); at diagnosis, 65% of patients had stage IV disease, 48% had B symptoms, and 25% had a mass >10 cm; baseline disease and patient characteristics were well balanced between treatment arms. Fifty-seven percent had a negative PET scan following completion of R-CHOP. Median follow-up time for all patients was 48 months (range 0.03–80). At the time of analysis, 209 events had occurred. The DFS HR for enzastaurin vs. placebo was 0.92 (95% CI: 0.69, 1.22; 2-sided log-rank p=0.54). DFS at 24 and 48 months were 79% and 70% for the enzastaurin arm, and 75% and 71% for placebo, respectively. OS at 24 and 48 months was 87% and 81% for enzastaurin, and 89% and 82% for placebo; HR for enzastaurin vs. placebo was 1.04 (95% CI: 0.74, 1.47; 2-sided log-rank p=0.81). Percent of ITT population patients on therapy at 12, 24, and 36 months was 70.6%, 60.6%, and 20.1% for enzastaurin; 72.3%, 60.6%, and 22.1% for placebo. Biomarker subgroup analysis was performed and will be available at time of presentation. Treatment emergent AEs (all grades) that were possibly study drug-related and significantly different between enzastaurin and placebo included chromaturia (18.5% vs. 0.4%), QTc prolongation (10.8% vs. 3.6%), and diarrhea (10.3% vs. 2.8%). There were no significant differences in number of patients with at least 1 grade 3 or higher AE between treatment arms. No significant differences were observed in the frequency of deaths while on therapy. ConclusionEnzastaurin did not improve DFS, EFS, or OS in patients with high-risk DLBCL and CR following R-CHOP treatment. Disclosures:Crump:Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria. Off Label Use: rituximab for maintenance therapy post autolgous transplant for lymphoma. Leppä:Eli Lilly: Research Funding. Ogura:Eli Lilly: Research Funding. Rifkin:Millenium, Celgene, ONYX: Membership on an entity's Board of Directors or advisory committees. Mackensen:Eli Lilly: Consultancy. Offner:Eli Lilly: Membership on an entity's Board of Directors or advisory committees. Smith:Genentech, Celgene, Spectrum, Seattle Genetics, Gilead, Amgen/Micronet: Consultancy. Tobinai:Eli Lilly: Research Funding. Hahka-Kemppinen:Eli Lilly: Employment. Thornton:Eli Lilly: Employment. Shi:Eli Lilly: Employment. Lin:Eli Lilly: Employment. Kahl:Genentech: Consultancy. Savage:Eli Lilly: Consultancy.

Phase I dose finding study of AZD8931, an inhibitor of EGFR, HER2, and HER3 signaling, alone or in combination with paclitaxel in Japanese patients.

e13501 Background: AZD8931 is an equipotent, reversible inhibitor of signaling by EGFR, HER2 and HER3. Methods: This open-label, multiple-dose cohort study (NCT01003158) was conducted in Japan to evaluate the safety, tolerability and PK of ascending doses of AZD8931 alone (starting dose 40 mg bd) in patients (pts) with advanced solid malignancies and AZD8931 in combination with paclitaxel (P; 90 mg/m2on days 1, 8 and 15 of a 28-day cycle) in pts with advanced breast cancer. Results: Between Jan 2010 and Apr 2012,17 pts were treated; 11 with AZD8931 monotherapy (40/60/80 mg bd [n=3/4/4]) and 6 with AZD8931 40 mg bd plus P. Median (range) duration of exposure to AZD8931 was 42.5 (22–238) and 79.5 (53–244) days for monotherapy and combination therapy, respectively. No DLTs were observed (in the DLT evaluation period) and therefore the MTD was not confirmed for AZD8931 alone or with P. The most frequent AEs (all grades) with AZD8931 monotherapy were diarrhea, paronychia, rash pustule and dry skin (each n=8) and with combination therapy were diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n=4). Throughout the study grade ≥3 AEs were reported for 1, 2 and 4 pts in the 40 mg, 60 mg and combination groups, respectively. One serious AE was reported each in the 40 mg (grade 3 intervertebral disc protrusion) and combination (grade 2 infectious pneumonia) groups; neither was considered related to study treatment. One pt in the combination therapy part discontinued due to an AE of grade 1 pneumonia. AZD8931 was rapidly absorbed (median tmax 1–2 hours), well distributed, had moderate clearance (31–39 L/h) and a t½ of 12 hours. There was no suggestion of a PK interaction between AZD8931 and P. One pt on AZD8931 80 mg bd (primary stomach cancer) and another receiving AZD8931 plus P (advanced breast cancer) had an unconfirmed and confirmed PR, respectively (duration of responses 42 and 172 days, respectively) demonstrating preliminary efficacy. Conclusions: Although a MTD was not confirmed for AZD8931, based on overall incidence of AEs of rash and diarrhea in the 80 mg group, doses up to 60 mg bd as monotherapy and 40 mg bd combined with P are the recommended doses for evaluation in Japanese pts. Clinical trial information: NCT01003158.

Phase I study of olaparib in combination with carboplatin and/or paclitaxel in patients with advanced solid tumors.

2579 Background: This three-center phase I study evaluated the PARP1/2 inhibitor olaparib (O) in combination with carboplatin (C), paclitaxel (Pa) or both (CPa) in patients (pts) with advanced solid tumors refractory to standard therapies (NCT00516724). Methods: This ongoing study consists of multiple parts (P) in which escalating doses of O capsule and tablet formulations were studied. Capsule formulation data are presented; continuous O with C (P1; 21 day cycle), CPa (P2a; 21 day cycle) and weekly Pa (P2b; 28 day cycle) or intermittent O with CPa (P3; 21 day cycle). Primary and secondary objectives were safety/tolerability and antitumor activity (RECIST), respectively. Results: This analysis (non validated data) included 87 enrolled pts (P1 [n=25] P2a [n=20] P2b [n=12] and P3 [n=30]). Most common tumor types were breast (26%), melanoma (10%) and ovarian (7%). 12 pts had known gBRCA1/2 mutations. A tolerable continuous dosing schedule of O with CPa was not determined. Most common AEs (all grades) were myelosuppression (71%) notably neutropenia (54%) and thrombocytopenia (26%), and fatigue (77%). Excessive treatment cycle delays due to hematologic toxicity occurred with continuous O combined with standard doses of C or CPa. Two doses were identified as tolerable: continuous O 100 mg bd with weekly Pa 80 mg/m2 and intermittent O 200 mg bd (d1–10) with CPa AUC4/175 mg/m2 q 3 weeks. 14/87 pts (16%) had an objective response (complete response [CR] 5%; partial response [PR] 11%); 28% had stable disease for ≥4 months. Activity appeared greater in pts with BRCA1/2 mutations (CR 17%; PR 33%). Conclusions: Continuous O in combination with CPa exacerbated hematologic toxicities leading to schedule delays. Tolerability improved with intermittent O. Antitumor activity was highest in pts with a BRCA1/2 mutation. This study identified two tolerable O capsule treatment schedules for further development. Clinical trial information: NCT00516724. [Table: see text]

A Phase II Study of the Histone Deacetylase Inhibitor, Vorinostat, in Combination with Trastuzumab in Patients with Advanced Metastatic and/or Local Chest Wall Recurrent HER-2 Amplified Breast Cancer Resistant to Transtuzumab-Containing Therapy: (E1104) a Trial of the Eastern Cooperative Oncology Group.

Abstract BackgroundVorinostat, also known as suberoylanilide hydroxamic acid or SAHA, is a potent, small molecule, pan-inhibitor of histone deacetylase (HDAC) with excellent oral bioavailability, and is commercially approved for cutaneous T cell lymphoma. Pan HDAC inhibitors induce acetylation of histone tails, relaxing condensed chromatin for transcriptional regulation of specific genes and can also target non histone nuclear proteins. In pre-clinical studies of HER-2 overexpressing breast cancer cells, vorinostat(V) synergistically augmented the effects of trastuzumab(T) by downregulating Her-2, pAKT, pERK 1/2, reduced apoptosis by decreasing Bcl-2, Bcl-XL, XIAP and survivin levels, while inducing pro-apoptotic Bim and Bak. Therefore, we hypothesized that adding vorinostat to trastuzumab would reverse trastuzumab resistance in patients with HER-2 positive metastatic breast cancer.MethodsAn open label dose de-escalation schema for the initial portion of the trial was planned. V 200 mg bid continuous daily dosing with 6 mg/kg T every 21 days was administered. Eligible patients: HER-2 positive by IHC (3+) or FISH, subsequently centrally confirmed; measurable metastatic or chest wall disease; any number of prior therapies including endocrine, chemotherapy, prior treatment with T and/or lapatinib were allowed; evidence of progressive disease on prior T was required. The Phase II primary objective was response rate by RECIST criteria.ResultsMedian age - 54 (range 40-69); PS was 0 or 1; 6 patients - ER+; median number of prior therapies - 3 (range 2-6). Six patients were treated at the starting dose of 200 mg bid daily V combined with 6 mg/kg T every 21 days. There were no dose limiting adverse events at this dosing level, eliminating the need to de-escalate and this was determined to be the optimal Phase II dose. A total of 16 patients were enrolled. The most common AEs (all grades) were 62%-diarrhea, 37%-nausea, fatigue; 31%-anemia, anorexia, vomiting, elevated creatinine, hyperglycemia, hypokalemia; 25%-thrombocytopenia. Grade 3,4 toxicities were dyspnea(n=2) and thrombocytopenia(n=2). Of the 16 total enrolled, 10 were centrally confirmed to have HER-2 positive disease by the ECOG Pathology Coordinating Office, 5 were HER-2 negative and 1 had insufficient tissue. None of 11 patients with centrally confirmed HER-2 positive disease (or unknown) had an objective response. One of 5 patients with centrally confirmed HER-2 negative disease had an objective response.ConclusionsIn this heavily pre-treated population who had either relapsed or progressed during trastuzumab containing therapy (either alone or in combination with chemotherapy), we failed to confirm our hypothesis that adding the histone deacetylase inhibitor, vorinostat, could reverse trastuzumab resistance. Correlative studies including hyperacetylation status of PBMC, CTC enumeration and peripheral as well as tumor methylation are ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5084.

Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC)

5032 Background: AV-951 is a potent inhibitor of VEGFR-1, 2 &amp; 3 kinases (IC50 0.21, 0.16 and 0.24 nM respectively), and inhibits cKit and PDGFR at 10-times higher concentrations (IC50 1.63 and 1.72 nM respectively). In a phase II RDT of AV-951 (1.5 mg/day; 3 wks on, 1 wk off) in RCC, preliminary ORR at wk 16 was 28% (ASCO GU. 2008; abstract #283). Methods: Pts with locally advanced or metastatic RCC (any histology) and no prior VEGF-targeted therapy received AV-951 for 16 wks, after which further treatment was assigned based on response. Pts with ≥ 25% tumor shrinkage continued treatment with AV-951, while pts with &lt; 25% change from baseline were randomly assigned to receive AV-951 or placebo for 12 wks (double-blinded). The primary end points were (1) objective response rate (ORR) at 16 wks, (2) percentage of randomly assigned pts remaining progression free at 12 wks following randomization, (3) safety profile. Results: 272 pts were enrolled: 70% male, 93% white, median age 56 yrs. 53% pts were treatement naïve, 72% had undergone nephrectomy and 83% had RCC with clear cell component. With a median duration of treatment of 5 mo (range 0–12 mo), the investigator assessed ORR (CR+PR) is 27.2% (30% in clear cell RCC), SD 60.5% and Disease Control Rate (CR/PR + SD) 88%. 118 (43%) pts were randomized to AV-951 or placebo. The most common treatment-related AEs (all grades) were hypertension (HTN, 42%) and dysphonia (16%). Guidelines for management of HTN were provided to investigators, and 52% pts received anti-hypertensives. Minimal (all grades) diarrhea (9%), fatigue (8%), stomatitis (3%) and hand-foot syndrome (2%) were observed. Laboratory abnormalities (all grades) were notable for minimal neutropenia (8%) and elevations of AST (21%) and ALT (21%). AEs led to dose reduction in 4% and treatment discontinuation in 5.5% of pts. Conclusions: Interim results of this phase II study demonstrate that AV-951 is active in RCC. The AE profile of AV-951 is consistent with that of a selective VEGFR inhibitor, with minimal off-target toxicities. Updated results of ORR (including independent radiology assessment), safety, percentage of randomly assigned pts remaining progression free at 12 wks, and overall PFS will be presented. [Table: see text]

Efficacy of lapatinib in patients with high tumor EGFR expression: Results of a phase III trial in advanced renal cell carcinoma (RCC)

4502 Background: Lapatinib is an orally-active, reversible inhibitor of EGFR/ErbB2 tyrosine kinases. In Phase I/II trials, lapatinib has demonstrated activity in patients (pts) with advanced breast cancer. We report the first results of a randomized open-label Phase III trial ( EGF20001 ) of lapatinib vs. hormone therapy (HT) in pts with advanced RCC that express EGFR and/or ErbB2 by immunohistochemistry (IHC). The main endpoints were time to progression (TTP) and overall survival (OS). Methods: Pts with advanced RCC of any histology who had failed first-line cytokine therapy were stratified by Karnofsky performance score (KPS) and number of metastatic sites. Pts were randomized to receive oral lapatinib 1250 mg OD or HT. The primary efficacy endpoint was TTP, with 90% power to detect a 50% increase (i.e. 4 vs. 6 months) at a two-sided 5% significance level. All pt scans were interpreted by independent radiologic review. Results: At the time of the TTP analysis, 417 pts were randomized and 298 TTP events were reported. Demographic and baseline characteristics were similar between both arms; pooled results were: median age: 61 yrs; Stage IV disease: 97%, KPS 90–100: 59%, metastatic sites &gt;2: 49%, prior nephrectomy: 94%, prior interferon therapy: 64%. No unexpected toxicities were observed, and drug-related AE (all grades) for lapatinib vs. HT included rash (44%:3%), diarrhoea (40%:3%). When results from all pts were analysed, median TTP was 15.3 weeks for lapatinib vs. 15.4 weeks for HT (hazard ratio (HR) = 0.94; p = 0.60), and median OS was 46.9 weeks for lapatinib vs. 43.1 weeks for HT (HR=0.88; p=0.29). In the major subgroup of 241 pts with EGFR overexpressed disease (3+ by IHC), median TTP was 15.1 weeks for lapatinib vs. 10.9 weeks for HT (HR = 0.76; p = 0.06), and median OS was 46.0 weeks for lapatinib vs. 37.9 weeks for HT (HR = 0.69; p = 0.02). These results were confirmed by Cox Regression analysis, and additional biomarker evaluation, including FISH, is underway. Conclusions: The EGFR/ErbB2 dual targeted inhibitor, lapatinib, appears to prolong overall survival compared to hormone therapy in advanced RCC pts with overexpressed EGFR who failed prior therapy. [Table: see text]