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PURPOSE Overexpression of c-Met protein and epidermal growth factor receptor ( EGFR) mutations can co-occur in non–small-cell lung cancer (NSCLC), providing strong rationale for dual targeting. Telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate targeting c-Met, has shown a tolerable safety profile and antitumor activity as monotherapy. Herein, we report the results of a phase Ib study (ClinicalTrials.gov identifier: NCT02099058 ) evaluating Teliso-V plus erlotinib, an EGFR tyrosine kinase inhibitor (TKI), in patients with c-Met–positive (+) NSCLC. PATIENTS AND METHODS This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age ≥ 18 years) with c-Met+ NSCLC. Later enrollment required presence of an EGFR-activating mutation ( EGFR-M +) and progression on a prior EGFR TKI. End points included safety, pharmacokinetics, objective response rate (ORR), and progression-free survival (PFS). The efficacy-evaluable population consisted of c-Met+ patients (confirmed histology [H]-score ≥ 150) who had at least one postbaseline scan; c-Met+ patients with H-scores ≥ 225 were classified as c-Met high. RESULTS As of January 2020, 42 patients were enrolled (N = 36 efficacy-evaluable). Neuropathies were the most common any-grade adverse events reported, with 24 of 42 patients (57%) experiencing at least one event. The pharmacokinetic profile of Teliso-V plus erlotinib was similar to Teliso-V monotherapy. Median PFS for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8 to not reached). ORR for EGFR-M + patients (n = 28) was 32.1%. Of EGFR-M + patients, those who were c-Met high (n = 15) had an ORR of 52.6%. Median PFS was 6.8 months for non-T790M+ and for those whose T790M status was unknown, versus 3.7 months for T790M+. CONCLUSION Teliso-V plus erlotinib showed encouraging antitumor activity and acceptable toxicity in EGFR TKI-pretreated patients with EGFR-M+, c-Met+ NSCLC.

Supplementary Table S1. Overall activity and predictors of treatment failure (PD or less than partial response by IWG criteria). Supplementary Figure S1. BCL-2 family protein index at screening. Supplementary Figure S2. Mean (+ SD) venetoclax plasma concentration-time profile at week 6 day 1 (800 mg). Supplementary Figure S3. Study design.

Purpose:This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC).Patients and Methods:Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4–6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control.Results:Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50–0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36–0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09–1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic.Conclusions:Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.

Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5–15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25–7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017)).

Objectives Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/metastatic NSCLC. Materials and Methods Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and paclitaxel 200 mg/m2 (C/PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and pemetrexed 500 mg/m2 (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed. Results Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80–240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80–240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%. Conclusion Veliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug–drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity.

Purpose: This study investigated the efficacy and safety of oral PARP inhibitor veliparib, plus carboplatin and etoposide in patients with treatment-naïve, extensive-stage small cell lung cancer (ED-SCLC). Patients and Methods: Patients were randomized 1:1:1 to veliparib [240 mg twice daily (BID) for 14 days] plus chemotherapy followed by veliparib maintenance (400 mg BID; veliparib throughout), veliparib plus chemotherapy followed by placebo (veliparib combination only), or placebo plus chemotherapy followed by placebo (control). Patients received 4–6 cycles of combination therapy, then maintenance until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) with veliparib throughout versus control. Results: Overall (N = 181), PFS was improved with veliparib throughout versus control [hazard ratio (HR), 0.67; 80% confidence interval (CI), 0.50–0.88; P = 0.059]; median PFS was 5.8 and 5.6 months, respectively. There was a trend toward improved PFS with veliparib throughout versus control in SLFN11-positive patients (HR, 0.6; 80% CI, 0.36–0.97). Median overall survival (OS) was 10.1 versus 12.4 months in the veliparib throughout and control arms, respectively (HR, 1.43; 80% CI, 1.09–1.88). Grade 3/4 adverse events were experienced by 82%, 88%, and 68% of patients in the veliparib throughout, veliparib combination-only and control arms, most commonly hematologic. Conclusions: Veliparib plus platinum chemotherapy followed by veliparib maintenance demonstrated improved PFS as first-line treatment for ED-SCLC with an acceptable safety profile, but there was no corresponding benefit in OS. Further investigation is warranted to define the role of biomarkers in this setting.

We applaud many of the sentiments put forward by Cohen et al in their critique of language and logic in pain medicine. 8 Pleas to avoid conflation between nociception and pain are not new - “The mislabelling of nociceptors as pain fibres was not an elegant simplification but a most unfortunate trivialisation of pain”29 ; “.. we don't actually have ‘pain receptors’, or ‘pain nerves’ or ‘pain pathways’ or ‘pain centres.’”4 We are among those who see such conflation as contrasting with contemporary understandings of ‘how pain works’ and undermining evidence-based treatment approaches.

BACKGROUND: This open-label Phase III trial (NCT02264990) evaluated the PARP inhibitor, veliparib, combined with carboplatin/paclitaxel versus chemotherapy alone for first-line treatment of patients with advanced non-squamous non-small cell lung cancers (NSCLC). A 52-gene expression classifier (LP52) previously shown to identify patients more likely to respond to veliparib was evaluated as a planned correlative analysis.; MATERIALS AND METHODS: Adult current or former smokers with advanced non-squamous NSCLC were randomized 1:1 to veliparib (120 mg daily for 7 days/cycle) with carboplatin and paclitaxel or to investigators' choice of platinum doublet chemotherapy (up to 6, 21-day cycles), with optional pemetrexed maintenance. Prospective analysis of the LP52 signature was conducted using a clinical Qiagen/HTG assay. The primary endpoint was overall survival (OS) in LP52+ patients.; RESULTS: Overall, 595 patients received veliparib+carboplatin/paclitaxel (n=298) or chemotherapy alone (n=297); 13% (n=40) in each arm were LP52+. The primary endpoint was not met; median OS was 11.2 months with veliparib+carboplatin/paclitaxel versus 9.2 months with chemotherapy alone in the LP52+ subgroup (hazard ratio [HR] 0.644, 95% confidence interval [CI]: 0.396-1.048; P=.113). In the overall population, median OS was 12.1 months in both arms (HR 0.986, 95% CI: 0.827-1.176; P=.846). No new safety signals were observed.; CONCLUSION: In patients with non-squamous NSCLC, there was no significant improvement in OS with veliparib+carboplatin/paclitaxel versus chemotherapy alone, although a trend toward improved OS in the LP52+ population suggests this subgroup may benefit from veliparib. Statistical power was limited due to the small sample size. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

PURPOSE Squamous non–small-cell lung cancer (sqNSCLC) is genetically complex with evidence of DNA damage. This phase III study investigated the efficacy and safety of poly (ADP-ribose) polymerase inhibitor veliparib in combination with conventional chemotherapy for advanced sqNSCLC ( NCT02106546 ). PATIENTS AND METHODS Patients age ≥ 18 years with untreated, advanced sqNSCLC were randomly assigned 1:1 to carboplatin and paclitaxel with veliparib 120 mg twice daily (twice a day) or placebo twice a day for up to six cycles. The primary end point was overall survival (OS) in the veliparib arm versus the control arm in current smokers, based on phase II findings. Archival tumor samples were provided for biomarker analysis using a 52-gene expression histology classifier (LP52). RESULTS Overall, 970 patients were randomly assigned to carboplatin and paclitaxel plus either veliparib (n = 486) or placebo (n = 484); 57% were current smokers. There was no significant OS benefit with veliparib in current smokers, with median OS 11.9 versus 11.1 months (hazard ratio [HR], 0.905; 95% CI, 0.744 to 1.101; P = .266). In the overall population, OS favored veliparib; median OS was 12.2 versus 11.2 months (HR, 0.853; 95% CI, 0.747 to 0.974), with no difference in progression-free survival (median 5.6 months per arm). In patients with biomarker-evaluable tumor samples (n = 360), OS favored veliparib in the LP52-positive population (median 14.0 v 9.6 months; HR, 0.66; 95% CI, 0.49 to 0.89), but favored placebo in the LP52-negative population (median 11.0 v 14.4 months; HR, 1.33; 95% CI, 0.95 to 1.86). No new safety signals were observed in the experimental arm. CONCLUSION In current smokers with advanced sqNSCLC, there was no therapeutic benefit of adding veliparib to first-line chemotherapy. The LP52 signature may identify a subgroup of patients likely to derive benefit from veliparib with chemotherapy.

Introduction: The Faculty of Pain Medicine recently published the first UK-focused Core Standards for Pain Management Services (CSPMS). We present an audit checklist tool developed to map compliance to the CSPMS, which offers a practical method of auditing any pain management service against the standards. Methods: The checklist tool was developed and its utility was field-tested in the Scottish National Residential Pain Management Programme (SNRPMP), a newly established service offering residential service to people in Scotland. Results: The checklist tool developed provides an easy and practical approach to evaluating any pain service against the national standards. Its application to evaluate the SNRPMP indicates that the service meets the majority of CSPMS standards and highlights aspects of the service requiring improvement. Conclusion: The layout of the developed checklist tool offers an alternative format for the structuring of the national standards in possible future revisions. The audit checklist tool enables evaluation of services with a numerical score, enabling monitoring of their compliance with national standards as well as comparisons between pain services.

9013 Background: Osi (third-generation tyrosine kinase inhibitor) is a standard frontline treatment (Tx) for advanced/metastatic EGFR-mutated NSCLC. However, tumors invariably progress after an initial response, with c-Met protein overexpression (OE) often associated with acquired resistance. Second- and third-line Tx options are limited to chemotherapy-based regimens with limited efficacy and significant toxicities. Teliso-V (ABBV-399), an anti–c-Met antibody-drug conjugate, delivers a cytotoxic payload (monomethyl auristatin E) into c-Met OE tumor cells. In a phase 1/1b study (NCT02099058) in patients (pts) with c-Met OE NSCLC, Teliso-V alone or in combination with erlotinib demonstrated an acceptable safety profile and antitumor activity. Interim safety and efficacy data from the Teliso-V + Osi cohort (arm E) of this trial are presented. Methods: Pts (≥18 yr) with metastatic EGFR-mutated, c-Met OE (by central immunohistochemistry) NSCLC who had progressed on a prior Osi regimen were eligible. Pts received Teliso-V (IV Q2W) + Osi (oral; 80 mg QD). Teliso-V was evaluated at 1.6 mg/kg and, after review of safety data, escalated to 1.9 mg/kg (safety evaluation). An expansion cohort was opened at 1.9 mg/kg for pts who had received ≤2 prior lines of systemic therapy. Pharmacokinetics (PK) were assessed throughout the study. Pts received study Tx until disease progression, unacceptable toxicity, or for up to 24 months. Results: As of 20 Dec 2021, 25 pts received Teliso-V (1.6 mg/kg, n = 7; 1.9 mg/kg, n = 18) + Osi. Median age was 60.0 yr; 14 (58%) pts were on prior Tx with Osi for > 12 mo. No dose-limiting toxicities (grade [Gr] ≥3 non-hematologic or Gr 4 hematologic Tx-related adverse events [AEs]) were reported during the safety lead-in or evaluation phases. All-Gr AEs considered possibly related to Teliso-V occurred in 22/25 (88%) pts: the most common (≥20%) were peripheral sensory neuropathy (36%), nausea, and peripheral edema (20% each); Gr ≥3 AEs (> 5%) were anemia (12%) and peripheral motor neuropathy (8%). No Gr 5 events related to Tx were reported. PK of Teliso-V + Osi was similar to single-agent Teliso-V. Efficacy data (19/25 pts) are in the table. The overall objective response rate (ORR) was 58% (67% at 1.9 mg/kg). Conclusions: Teliso-V + Osi is well tolerated with an ORR of 58% (67% at 1.9 mg/kg) in pts with c-Met OE NSCLC who progressed on prior Osi. Clinical trial information: NCT02099058. [Table: see text]

9016 Background: Teliso-V is an antibody-drug conjugate composed of a c-Met antibody (ABT-700) and a microtubule inhibitor (monomethyl auristatin E). The phase 2 M14-239 trial (LUMINOSITY, NCT03539536) aims to identify the c-Met OE NSCLC populations best suited to Teliso-V (Stage 1) and expand selected groups for further evaluation of efficacy (Stage 2). In Stage 1, pts were enrolled into cohorts defined by histopathology (non-squamous [NSQ] or squamous [SQ]) and EGFR mutation status (mutant or wild type [WT]); NSQ cohorts were further divided in groups on the basis of c-Met expression (high or intermediate). Updated data from the fourth interim analysis (IA4) are presented. Methods: Pts had locally advanced/metastatic NSCLC, ≤2 prior lines of systemic therapy, ≤1 line of chemotherapy, and tumors that were c-Met OE by central immunohistochemistry (IHC; Ventana; Tucson, AZ). c-Met OE was defined for the NSQ cohort as ≥25% 3+ by IHC (high, ≥50% 3+; intermediate, 25 to

Venetoclax is a first-in-class orally available, B-cell lymphoma (BCL)-2 inhibitor indicated for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. We used a novel approach for evaluating venetoclax pharmacokinetics using only sparse sampling in 155 patients enrolled in a phase 2, multicenter, open-label study in CLL patients with the 17p deletion. Patients received venetoclax doses within 30 min after the completion of breakfast or the first meal of the day, with no specific recommendations for the fat content in the meal. Blood samples for venetoclax assay were collected during the ramp-up period and on day 1 of weeks 8, 12, 16, 24, and every 12 weeks thereafter. The mean postdose (8 h) plasma venetoclax concentrations increased with increasing weekly venetoclax dose during the ramp-up period to reach 1.89 µg/ml on week 5 day 1 at the 400 mg dose. The mean predose concentration at the 400 mg dose ranged between 0.69 and 0.99 µg/ml across visits between weeks 8 and 120. Repeated-measures analysis detected no statistical significance (P≥0.05) for the mean predose concentrations at any of the times tested from weeks 8 to 24. The study shows that the pharmacokinetic profile of venetoclax in CLL patients with the 17p deletion is comparable to the overall CLL as well as non-Hodgkin's lymphoma patient populations. Furthermore, no specific recommendation in terms of fat content in the meal is needed for the intake of venetoclax in patients with CLL.

Background/Aims: Venetoclax (Ven), a selective oral BCL-2 inhibitor, has shown synergy with hypomethylating agents (HMAs) such as Azacitidine (Aza), in treatment of higher-risk myelodysplastic syndrome (HR)-MDS. We evaluate prognostic impact of cytogenetic categories of revised International Prognostic Scoring System (IPSS-R) among HR-MDS patients treated with Ven+Aza. Methods: This study enrolled patients age ≥ 18 yrs, untreated for MDS, with IPSS score of ≥1.5, bone marrow blasts Results: As of 8/21/2019, 57 patients (75% male, median age 71yrs) received Ven+Aza combination. According to IPSS-R classification, at baseline, 9 (16%) patients were at intermediate risk, 13 (24%) at high risk, and 33 (60%) at very high risk. Cytogenetic risk based on IPSS-R: 2 (4%) were very good, 18 (32%) good, 8 (15%) intermediate, 13 (23%) poor, and 15 (26%) very poor. Ten genes were mutated in >10% of patients, including poor prognosis conferring TP53, RUNX1, TET2, ASXL1, SRSF2, STAG2, and IDH1/2. Median follow-up time was 8.9 months. Complete remission (CR)+marrow CR (mCR) rates by IPSS-R cytogenetic risk were: very good 100% (2/2), good 94% (17/18), intermediate 63% (5/8), poor 62% (8/13), and very poor 73% (11/15). Median with 95% confidence interval (CI) in progression-free survival (PFS) was 6.7 (0.7–not estimable), 9.3 (3.2–not estimable), and 9.5 months (2.7–9.5) in the intermediate, poor, and very-poor risk groups, respectively, and not reached in the good and very-good risk groups. Median overall survival (OS) in patients with very poor risk was 16.2 months (2.0–16.2). The estimated 12-month OS were 53%, 88%, and 100% in the poor, intermediate, and good risk groups, respectively. Conclusion: This preliminary analysis shows promising efficacy of Ven+Aza combination treatment across all IPSS-R cytogenetic risk categories and suggests prognostic relevance of the IPSS-R cytogenetic scoring system. Abstract was previously published at EHA25.

Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.

Venetoclax is a selective, first-in-class, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: (1) a bioequivalence study to compare the bioavailability of the film-coated tablet with that of an earlier uncoated tablet and (2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open-label, single-dose, crossover studies. In the bioequivalence study, 15 subjects received a single dose of venetoclax 50 mg under nonfasting conditions, in each of 2 periods; one period used the uncoated tablet, and the other used the film-coated tablet. In the food effect study, 24 subjects received a single dose of venetoclax film-coated 100-mg tablet under fasting conditions, after a low-fat breakfast or after a high-fat breakfast in different periods. The venetoclax film-coated tablet was bioequivalent to the uncoated tablet, which indicates that the film coating does not affect bioavailability. The median Tmax of venetoclax was delayed by about 2 hours when administered with food. Compared with fasting conditions, Cmax and AUC increased by approximately 3.4-fold following a low-fat breakfast. High-fat meals increased Cmax and AUC by approximately 50% relative to low-fat meals. The mean terminal half-life was comparable between the high-fat meal and fasting conditions (19.1 versus 16.1 hours). Based on these results and the venetoclax exposure-response profile, venetoclax should be administered with food and without specific recommendations for fat content to ensure adequate and consistent bioavailability.

The poly(ADP‐ribose) polymerase‐1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended‐release (ER) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib‐ER up to 800 mg once daily or 600 mg twice daily. Dose‐limiting toxicities (DLTs), recommended phase II dose (RP2D), and maximum tolerated dose (MTD) were assessed in cycle 1 and safety/tolerability during continuous administration (28‐day cycles). Seventy‐one patients (n = 53 ovarian, n = 17 breast, n = 1 prostate carcinoma) received veliparib; 50 had deleterious breast cancer susceptibility (BRCA) gene mutations. Single‐dose veliparib‐ER 200 mg (fasting) led to 58% lower peak concentration and similar area under the concentration‐time curve compared with veliparib immediate‐release (IR). Three patients experienced DLTs (grade 2: asthenia; grade 3: nausea/vomiting, seizure). RP2D and MTD for veliparib‐ER were 400 mg BID. The most frequent adverse events (AEs) were nausea (78.9%) and vomiting (50.7%). The most common grade 3/4 treatment‐related AEs were as follows: thrombocytopenia (7.0%), nausea, and anemia (4.2% each). Overall, 12 (27.3%) patients with ovarian and 10 (62.5%) patients with breast carcinoma had a partial response. Veliparib‐ER, versus veliparib‐IR, exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and BRCA‐mutated breast cancers.

Summary Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined. Results Ninety-three patients were treated with ABT-767; 80 had a primary diagnosis of ovarian cancer. ABT-767 demonstrated dose-proportional PK up to 500 mg BID and half-life of ~2 h. Food had no effect on ABT-767 bioavailability. Most common grade 3/4 treatment-related adverse events were nausea, fatigue, decreased appetite, and anemia. Anemia showed dose-dependent increase. RP2D was 400 mg BID. Objective response rate by RECIST 1.1 was 21% (17/80) in all evaluable patients and 20% (14/71) in evaluable patients with ovarian cancer. Response rate by RECIST 1.1 and/or CA-125 was 30% (24/80) in patients with ovarian cancer. Mutations in BRCA1 or BRCA2, homologous recombination deficiency (HRD), and platinum sensitivity were associated with tumor response. Median progression-free survival was longer for HRD positive (6.7 months) versus HRD negative patients (1.8 months) with ovarian cancer. Conclusions ABT-767 had an acceptable safety profile up to the established RP2D of 400 mg BID and dose-proportional PK. Patients with BRCA1 or BRCA2 mutation, HRD positivity, and platinum sensitivity were more sensitive to ABT-767.

Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood-brain barrier. This was a phase 1 dose-escalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10-300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were non-small cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, ≥15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only Grade 3/4 AEs deemed possibly related to veliparib observed in ≥2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9-13.5) and for the breast cancer subgroup was 7.7 mo (2.8-15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3-3.8) and 4.9 mo (4.2-5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing.

Summary Background Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study. Methods Previously untreated patients aged 65 years and over with acute myeloid leukaemia who were ineligible for standard induction therapy were enrolled into this non-randomised, open-label, phase 1b study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0–2 and either intermediate-risk or poor-risk cytogenetics. Patients were enrolled into one of three groups for the dose-escalation phase of this study: group A (venetoclax and intravenous decitabine 20 mg/m 2 [days 1–5 of each 28-day cycle]), group B (venetoclax and subcutaneous or intravenous azacitidine 75 mg/m 2 [days 1–7 of each 28-day cycle]), and group C (a venetoclax and decitabine substudy with the oral CYP3A inhibitor posaconazole, 300 mg twice on cycle 1, day 21, and 300 mg once daily from cycle 1, days 22–28, to assess its effect on venetoclax pharmacokinetics). Dose escalation followed a standard 3 + 3 design with at least three evaluable patients enrolled per cohort; daily target doses of venetoclax for groups A and B were 400 mg (cohort 1), 800 mg (cohorts 2 and 3), and 1200 mg (cohort 4), and 400 mg for group C. The primary endpoints were the safety and pharmacokinetics of venetoclax plus decitabine or azacitidine, and to determine the maximum tolerated dose and recommended phase 2 dose. Secondary endpoints included the preliminary anti-leukaemic activity of venetoclax with decitabine or azacitidine through the analysis of overall response, duration of response, and overall survival. We analysed safety, pharmacokinetics, and anti-leukaemic activity in all patients who received one or more venetoclax doses. The expansion phase of the study is ongoing but is closed to accrual. This trial is registered with ClinicalTrials.gov, number NCT02203773. Findings 57 patients were enrolled in the study. 23 patients in group A and 22 patients in group B were enrolled between Nov 19, 2014, and Dec 15, 2015, and 12 patients in group C were enrolled between June 14, 2015, and Jan 16, 2016. As of data cutoff on June 15, 2016, the most common grade 3–4 treatment-emergent adverse events were thrombocytopenia (27 [47%] of 57 patients; nine in group A, 13 in group B, and five in group C), febrile neutropenia (24 [42%] of 57; 11 in group A, ten in group B, and three in group C), and neutropenia (23 [40%] of 57; 12 in group A, eight in group B, and three in group C). The most common serious treatment-emergent adverse event in groups A and B was febrile neutropenia (seven [30%] of 23 patients vs seven [32%] of 22), whereas in group C it was lung infection (four [33%] of 12 patients). 49 (86%) of 57 patients had treatment-related adverse events; the most common in groups A and B included nausea (12 [52%] patients vs seven [32%] patients), fatigue (six [26%] patients vs seven [32%]), and decreased neutrophil count (six [26%] patients vs six [27%]), whereas in group C the most common were nausea (seven [58%] of 12 patients), leucopenia (six [50%]), vomiting (five [42%]), and decreased platelet count (five [42%]). The maximum tolerated dose was not reached. The recommended phase 2 dose was 400 mg once a day or 800 mg with an interrupted dosing schedule (safety expansion). In total, four (7%) of 57 patients had died within 30 days of the first venetoclax dose caused by sepsis (group B), bacteraemia (group A), lung infection (group C), and respiratory failure (group A). Tumour lysis syndrome was not observed. Decitabine and azacitidine did not substantially affect venetoclax exposures. Overall, 35 (61%; 95% CI 47·6–74·0) of 57 patients achieved complete remission or complete remission with incomplete marrow recovery. In groups A and B, 27 (60%; 95% CI 44·3–74·3) of 45 patients had complete remission or complete remission with incomplete marrow recovery. Interpretation Venetoclax plus hypomethylating agent therapy seems to be a novel, well-tolerated regimen with promising activity in this underserved patient population. Evaluation of expansion cohorts is ongoing at 400 mg and 800 mg doses using both hypomethylating agent combinations. Funding AbbVie and Genentech.

International audience; Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase 1 study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Dexamethasone could be added on progression during treatment. Sixty-six patients were enrolled (30, dose-escalation cohorts; 36, safety expansion). Patients received a median of 5 prior therapies (range, 1-15); 61% were bortezomib and lenalidomide double refractory, and 46% had t(11;14). Venetoclax was generally well tolerated. Most common adverse events included mild gastrointestinal symptoms (nausea [47%], diarrhea [36%], vomiting [21%]). Cytopenias were the most common grade 3/4 events, with thrombocytopenia (32%), neutropenia (27%), anemia (23%), and leukopenia (23%) reported. The overall response rate (ORR) was 21% (14/66), and 15% achieved very good partial response or better (≥VGPR). Most responses (12/14 [86%]) were reported in patients with t(11;14). In this group, ORR was 40%, with 27% of patients achieving ≥VGPR. Biomarker analysis confirmed that response to venetoclax correlated with higher BCL2:BCL2L1 and BCL2:MCL1 mRNA expression ratios. Venetoclax monotherapy at a daily dose up to 1200 mg has an acceptable safety profile and evidence of single-agent antimyeloma activity in patients with relapsed/refractory MM, predominantly in patients with t(11;14) abnormality and those with a favorable BCL2 family profile. Registered at www.clinicaltrials.gov: #NCT01794520.

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

BackgroundSupported self-management is a recommended intervention for chronic pain. Effective self-management should enable an individual to reduce the impact of pain on their everyday life. Clinical guidelines suggest primary care services have a role to play in supporting self-management of chronic pain.AimTo examine the opinions of primary care healthcare professionals (HCPs) and people with chronic pain and their carers, in order to identify possible barriers to the facilitation and adoption of self-management.Design and settingA qualitative study using focus groups in locations throughout Scotland.MethodEighteen focus groups were held with patients and HCPs. Fifty-four patients, nine carers, and 38 HCPs attended the groups.ResultsFour categories of barriers were found. 1) Patient–HCP consultation: some patients felt a discussion about self-management came too late or not at all. Communication and building positive relations were sometimes challenging. 2) Patient experience: the emotional impact of pain was difficult and patients often felt unsupported by HCPs. 3) Limited treatment options: some participants felt there was a tendency for overmedicalisation. 4) Organisational constraints: short appointment times, long waiting lists, and a compartmentalised NHS created challenges.ConclusionThis study illustrates some of the barriers faced by HCPs and patients in the facilitation and adoption of self-management of chronic pain. If self-management is to be an important approach to chronic pain, primary care services need to be designed to address the barriers identified.

Introduction Hypomethylating agents (HMAs), azacitidine (Aza) or decitabine, are standard treatment (Tx) for patients (pts) with higher-risk myelodysplastic syndrome (HR-MDS) not candidates for immediate allogeneic hematopoietic stem cell transplantation (HSCT). However, complete remission was only reported for 17% receiving Aza, and only half the pts are alive after 2 yrs (Fenaux et. al., 2009). Venetoclax (Ven), a selective, potent, orally bioavailable BCL-2 inhibitor, has been shown to synergize with HMAs in preclinical studies in HR-MDS (Jilg et. al., 2016) and clinical studies in AML (DiNardo et. al., 2016), suggesting that the combination of Ven+Aza may be a promising approach for HR-MDS Tx. This ongoing, open-label, Phase 1b, dose-escalation study is evaluating the safety and preliminary efficacy of Ven+Aza for Tx-naive HR-MDS. Methods The study (NCT02942290) initially included a 3-arm randomized cohort. Data from this cohort included 10 pts treated with Ven (400 mg or 800 mg for 28 days) + Aza and 2 pts treated with Aza alone. Following two deaths (Ven 400 mg=1/5 and Ven 800 mg=1/5), the study was amended to a dose-escalation and safety expansion design to determine the recommended Phase 2 dose (RP2D) of Ven+Aza. Key inclusion criteria were age ≥18 yrs, no prior therapy for MDS, IPSS score of ≥1.5, bone marrow blasts Results As of April 9, 2019, 59 pts have been treated and dose-escalation is complete. These included 12 pts in the initial randomized cohort. The dose-escalation cohort included 25 pts (Ven 100 mg=8, Ven 200 mg=9, Ven 400 mg=8) and the safety expansion included 22 pts. Results are presented for all 59 pts [75% male, median age 71 yrs (range 26-85)]. At baseline, 15 (25%) pts had an overall IPSS score of 1.5, 29 (49%) had a score of 2, 8 (14%) had a score of 2.5, 6 (10%) had a score of 3.0, and 1 (2%) pt had a score of 3.5. Eleven (19%) pts had intermediate and 24 (41%) pts had poor baseline cytogenetic risk. In treated pts, the most common treatment-emergent adverse events (TEAE's) were anemia, neutropenia, and thrombocytopenia (Table). Common gastrointestinal symptoms were constipation, nausea, diarrhea, and vomiting. Infection was predominantly febrile neutropenia. Predominant Grade 3 or 4 AEs included neutropenia (61%), thrombocytopenia (39%), leukopenia (31%), and anemia (20%). Major SAEs were febrile neutropenia (31%). There were 10 deaths of which 4 were due to infections (pneumonia-2, neutropenic sepsis-1 and septic shock- 1). Other causes of death were multiorgan failure (n=1), respiratory failure (n=1), progressive disease (n=3), and unexplained death (n=1). Twenty pts discontinued the study including 10 who underwent transplantation. Among 57 pts evaluable for response, the ORR with (CR) was documented in 18, mCR in 22 , and stable disease (SD) in 11. Disease progression was observed in 2 pts. Median TTR for ORR was 1.0 mos (range 0.7-3.5 mos). At this data cut, the median time to FU was 4.3 mos (range 3.3-6.5 months). Median DOR, PFS and OS were not reached. With this short follow up, the 12-mo estimates for DOR for ORR was 74% (95% CI: 34%, 92%) and PFS was 59% (95% CI: 31%, 79%). The 18-mo estimate for OS was 74% (95% CI: 50%, 87%). Among 56 pts eligible for hematological improvement (HI), 28 (50%) patients achieved HI as either HI-erythroid, HI-platelet, or HI-neutrophil. Conclusion The combination therapy of Ven+Aza demonstrated a tolerable safety profile and promising efficacy in pts with HR-MDS. The maximum tolerated dose of Ven without dose-limiting toxicities was determined to be 400 mg in this HR-MDS population. Disclosures Wei: Pfizer: Honoraria; Astellas: former employee, Honoraria; Novartis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee, Patents & Royalties: receives a fraction of its royalty stream related to venetoclax; Macrogenics: Honoraria; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Borate:Pfizer: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy. Fong:Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy. Baer:Al Therapeutics: Research Funding; Kite: Research Funding; Takeda: Research Funding; Astellas: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Incyte: Research Funding. Nolte:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Peterlin:AbbVie Inc: Consultancy; Astellas: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy. Jurcic:Incyte: Consultancy; AbbVie Inc: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Astellas: Research Funding; Syros Pharmaceuticals: Research Funding; Actinium Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Forma Therapeutics: Research Funding; Kura Oncology: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Odenike:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Oncotherapy: Research Funding; Astra Zeneca: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Janssen Oncology: Research Funding; NS Pharma: Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dunbar:AbbVie Inc: Employment, Other: Stock/stock options. Zhou:AbbVie Inc: Employment, Other: Stock/stock options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Tanwani:AbbVie Inc: Employment, Other: Stock/stock options. Wolff:AbbVie Inc: Employment, Other: Stock/stock options. Jacoby:Celgene: Speakers Bureau; Novo Nordisk: Consultancy; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment in myelodysplastic syndromes, which is not an approved indication.

Introduction Over-expression of the anti-apoptotic protein BCL-2 in MDS has been implicated in progression and drug resistance in MDS. Venetoclax (Ven), a selective, potent, orally bioavailable BCL-2 inhibitor, was recently approved in combination with HMAs or low dose cytarabine for the frontline management of older unfit pts with AML. In this study, we sought to evaluate the safety and efficacy of Ven in pts with R/R MDS. Methods This is an ongoing phase 1b, open-label, multicenter study in R/R MDS (NCT02966782). Key eligibility criteria include age ≥18 years, failure of HMA after receiving at least 4 cycles of Aza or 4 cycles of decitabine within the previous 5 years, marrow blasts The primary objectives were to evaluate the safety profiles and the recommended Phase 2 dose (RP2D) of Ven monotherapy and Ven+Aza. Key secondary objectives included a preliminary assessment of overall response rate (ORR, defined as complete remission [CR]+marrow complete remission [mCR]+partial response [PR]) , time to first response (TTR), progression-free survival (PFS), and overall survival (OS). We used the modified International Working Group 2006 criteria for response assessment (Cheson et. al., Blood, 2006). Results As of April 9, 2019, 46 pts [87% male, median age 76 years (range 44-91)] were enrolled. C1 (Ven monotherapy) included 22 pts, C2 (combination therapy) included 24 pts. At baseline, 37 (80%) pts received at least one prior therapy, 2 (15%) pts received 2, and 1 (2%) patient received >3 therapies prior to enrollment in the study. Baseline bone marrow blasts were: ≤5% was observed in 16 (35%) pts, >5% and ≤10% in 23 (50%), and >10% in 7 (15%) pts respectively. Cytogenetics risk was evaluated in 27/46 pts and were as follows: Good 12 (44%), Intermediate 9 (33%), and Poor 6 (22%). Overall, 9 pts discontinued study therapy (8 deaths, 1 withdrew consent). The most frequent treatment-emergent adverse events (TEAEs) included neutropenia, thrombocytopenia, nausea, and diarrhea (Table ). Infectious TEAEs included febrile neutropenia and pneumonia. Predominant Grade 3 and 4 TEAEs were hematological and included neutropenia (41%), thrombocytopenia (30%), leukopenia (24%), and anemia (15%). Serious TEAEs occurring in ≥2 pts were febrile neutropenia (n=8), pneumonia (n=6), thrombocytopenia (n=2), and epistaxis (n=2). Death on study occurred in 8 (17%) pts, of whom 6 died of progressive disease. Other causes of death were septic shock (n=1) and pneumonia (n=1). Forty of 46 pts were response evaluable. Median follow-up time was 4.7 mos (range: 3.7-6.3 mos). In C1, ORR was 7% (1/16). Stable disease was observed in 75% (12/16) pts. Median TTR was 1.6 mos (range: 1.6-1.6 mos). Median PFS was 3.4 mos (95% CI: 1.9-5.2 mos) and 6-mos estimate for OS was 57% (95% CI: 22%, 81%). In C2, ORR was 50% (12/24 pts). Of those, 13% (3/24) had CR and 38% (9/24) had mCR. Stable disease was observed in 31% (10/24) pts. Median PFS, and OS were not reached. The 6-mos estimate for PFS was 76% (95% CI: 50%, 89%) and estimated OS at 9-mos was 83% (95% CI: 55%, 95%). Finally, 4 pts came off study to receive allogeneic stem cell transplantation. Conclusion Ven monotherapy and combination Ven+Aza were well tolerated in pts with R/R MDS and most AEs were manageable. Although the study is still ongoing, the 6-mos OS estimate of 57% in monotherapy pts compares favorably to historical controls. In addition, the ORR observed with combination therapy, and the observed 9-mos OS rate of 83% also compare favorably with historical data. Updated data on safety and efficacy, including data on RP2D, will be presented at the meeting. Disclosures Zeidan: Ariad: Honoraria; Agios: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding. Pollyea:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Brunner:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Roncolato:St. George Hospital: Employment. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Odenike:Astra Zeneca: Research Funding; Astex Pharmaceuticals: Research Funding; Agios: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI/Baxalta: Research Funding; NS Pharma: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Research Funding; Oncotherapy: Research Funding. Bajel:Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria. Watson:Amgen: Other: Travel grant; Roche: Other: Travel grant. Götze:AbbVie: Membership on an entity's Board of Directors or advisory committees. Nolte:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Tan:AbbVie Inc: Other: Investigator in AbbVie funded trial. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Dunbar:AbbVie Inc: Employment, Other: Stock/stock options. Zhou:AbbVie Inc: Employment, Other: Stock/stock options. Gressick:AbbVie Inc: Employment, Other: Stock/stock options. Ainsworth:AbbVie Inc: Employment, Other: Stock/stock options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Salem:AbbVie: Employment, Other: Stock/stock options. Hayslip:AbbVie Inc: Employment, Other: Stock/stock options. Swords:AbbVie Inc: Employment, Other: Stock/stock options. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment in myelodysplastic syndromes, which is not an approved indication.

3013 Background: ABBV-621 is a potent tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist fusion protein that induces apoptotic cell death, particularly in DR4/5 expressing tumor models. Methods: Patients (pts) with previously treated solid tumors and ECOG 0–2 were administered ABBV-621 (2.5–15 mg/kg IV) on day (D) 1 (dose level [DL] 1) or D1D8 (DL2 and beyond) of each 21-day cycle. Dose escalation (DE) was guided by a Bayesian continual reassessment method. In addition to PK studies, blood-based PD markers of apoptosis (M30, M65) and drug binding were assessed. Results: As of 14 December 2018, 57 pts were enrolled in the DE portion, of which 30% had pancreatic, 23% colorectal cancer, and 47% other tumor types; 13 were KRAS mutant. Median age was 61 yrs. 60% were male; pts had a median of 4 prior regimens (range 1–10). Pts per DL: 2.5 (5 on D1, 16 on D1D8), 3.75 (12), 5 (6), 6.5 (6), 8.5 (4), 11 (4), and 15 mg/kg (4). Median duration of ABBV-621 exposure was 2 cycles (range 1–11). Seven pts had dose-limiting toxicities: respiratory failure (5 mg/kg; Grade 5, the only treatment-related death), blood bilirubin increased (3.75, 6.5 mg/kg), nausea (3.75 mg/kg), fatigue (3.75 mg/kg), increased ALT (2.5, 3.75, 6.5, 15 mg/kg), and increased AST (6.5 mg/kg). Summary of AEs is shown in Table. Clinical trial information: NCT03082209. A partial response (duration 20 weeks) was observed in a pt with pancreatic cancer (2.5 mg/kg D1D8). 27 pts had stable disease (6 pts for > 12 weeks). ABBV-621 PK was linear (mean ± SD clearance was 1.79 mL/h/kg ± 0.44) with a terminal half-life of 36.7 ± 5.55 h (n = 49). ABBV-621 bound to decoy receptors on neutrophils for up to 168 h; the duration of binding was dose-dependent. M30 and M65 increased at 8, 24, and 48 h following ABBV-621, but effect was independent of dose. Conclusions: ABBV-621 shows evidence of antitumor activity and effect on blood-based markers of apoptosis, with acceptable toxicity (MTD not reached). NCT03082209.[Table: see text]

Purpose The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction. Methods Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m 2 of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20. On days 21 through 28, patients received 300 mg of posaconazole plus reduced doses of venetoclax (50 or 100 mg) to account for expected increases in venetoclax plasma concentrations. Blood samples were collected before dosing and up to 24 hours after the venetoclax dose on days 20 and 28. Findings Compared with a venetoclax dose of 400 mg when administered alone (day 20), coadministration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax C max and AUC 0–24 by 53% and 76%, respectively, whereas coadministration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax C max and AUC 0–24 by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase venetoclax C max and AUC 0–24 by 7.1- and 8.8-fold, respectively. Both the 50- and 100-mg venetoclax doses administered with posaconazole were well tolerated. Implications The results are consistent with inhibition of CYP3A-mediated metabolism of venetoclax. Posaconazole can be used for antifungal prophylaxis in patients with acute myeloid leukemia receiving venetoclax after reducing the venetoclax dose by at least 75%. ClinicalTrials.gov identifier: NCT02203773.

Venetoclax (ABT-199), a B-cell lymphoma-2 (Bcl-2) protein inhibitor, is currently in clinical development for the treatment of hematologic malignancies. We characterized the absorption, metabolism, and excretion of venetoclax in humans. After a single oral dose of [14C]venetoclax to healthy volunteers, the recovery of total radioactive dose was 100%, with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (

Venetoclax (ABT-199/GDC-0199) is a selective first-in-class B cell lymphoma-2 inhibitor being developed for the treatment of hematological malignancies. The aim of this study was to determine the potential of venetoclax to prolong the corrected QT (QTc) interval and to evaluate the relationship between systemic venetoclax concentration and QTc interval.The study population included 176 male and female patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 105) or non-Hodgkin's lymphoma (n = 71) enrolled in a phase 1 safety, pharmacokinetic, and efficacy study. Electrocardiograms were collected in triplicate at time-matched points (2, 4, 6, and 8 h) prior to the first venetoclax administration and after repeated venetoclax administration to achieve steady state conditions. Venetoclax doses ranged from 100 to 1200 mg daily. Plasma venetoclax samples were collected after steady state electrocardiogram measurements.The mean and upper bound of the 2-sided 90 % confidence interval (CI) QTc change from baseline were5 and10 ms, respectively, at all time points and doses (400, 400, and400 mg). Three subjects had single QTc values500 ms and/or ΔQTc 60 ms. The effect of venetoclax concentration on both ΔQTc and QTc was not statistically significant (P 0.05). At the mean maximum concentrations achieved with therapeutic (400 mg) and supra-therapeutic (1200 mg) venetoclax doses, the estimated drug effects on QTc were 0.137 (90 % CI [-1.01 to 1.28]) and 0.263 (90 % CI [-1.92 to 2.45]) ms, respectively.Venetoclax does not prolong QTc interval even at supra-therapeutic doses, and there is no relationship between venetoclax concentrations and QTc interval.

We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features. Significance: Venetoclax monotherapy demonstrated clinical activity in patients with AML (relapsed/refractory or unfit for intensive chemotherapy) with a tolerable safety profile in this phase II study. Predictive markers of response consistent with BCL2 dependence were identified. Clinical and preclinical findings provide a compelling rationale to evaluate venetoclax combined with other agents in AML. Cancer Discov; 6(10); 1106–17. ©2016 AACR. See related commentary by Pullarkat and Newman, p. 1082. This article is highlighted in the In This Issue feature, p. 1069

BACKGROUND: New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. METHODS: We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. RESULTS: The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. CONCLUSIONS: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.)

3061Background: Veliparib (V), a PARP inhibitor, combined with platinum (Pt) doublet CT has shown promise in a Phase 2 study of NSCLC. Nivolumab (N), a PD-1 inhibitor, has demonstrated single-agent...

Background: Older patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy are unlikely to achieve remission with available therapy and have unacceptably short survival. Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC). Presented are long-term outcomes, including 1-year overall survival (OS) and biomarker analyses. Methods: This phase 1b/2, open-label study (NCT02287233) evaluates the safety and preliminary efficacy of orally administered VEN combined with LDAC in patients ≥65 years with previously untreated AML (except for hydroxyurea). Patients were ineligible for intensive chemotherapy because of comorbidity or other factors and had an ECOG performance score of 0-2, with adequate hepatic and renal function. Exclusion criteria were acute promyelocytic leukemia, active CNS involvement with AML, concominant use of moderate or strong CYP3A inhibitors, or prior treament with cytarabine for a preexisting myeloid disorder. Prior treatment for myelodysplastic syndrome (MDS) was allowed. In cycle 1, VEN was started at 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28. In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28. LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle. Preliminary efficacy was assessed as the overall response rate (ORR, which included complete remission [CR], CR with incomplete blood count recovery [CRi], and partial remission [PR]). Adverse events (AEs) and laboratory values were monitored. Exploratory analysis of biomarkers (eg, cytogenetics, molecular markers) was performed to identify potential predictors of clinical outcomes. Results: Data cutoff was May 30, 2017. All 71 patients were enrolled ≥1 year prior (46 [65%] male; median age, 74 years [range, 66-87 years]): 10 received VEN 800 mg and 61 received VEN 600 mg, the recommended phase 2 dose. Thirty-three patients (47%) had a history of antecedent hematologic disorder (AHD), most commonly MDS. Among 61 patients given VEN 600 mg, median time on VEN treatment was 6 months (range, Conclusions: The safety profile of VEN 600 mg/day plus LDAC was acceptable for elderly patients with treatment-naive AML who were ineligible for intensive chemotherapy. After ≥1 year of follow-up, the observed median OS was 11.4 months. This cohort included 44% (27/61) of patients with AHDs. Corelations of specified AML mutations with response and duration should be confirmed in later trials. Due to the observced CR/CRi rate of 62%, extended duration of response, and encouraging OS in a cohort of patients with particularly poor-risk features, the 600-mg dose of VEN combined with LDAC is being tested in an ongoing phase 3 study. Figure Figure. Disclosures Wei: AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria; AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees. Strickland: Boehringer-Ingelheim: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy; Tolero: Consultancy; Astellas: Consultancy; CTI BioPharma: Consultancy; Baxalta: Consultancy. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Hou: Teva Oncology, Seattle Genetics: Speakers Bureau. Fiedler: Amgen, Pfizer: Research Funding; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen: Patents & Royalties; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Consultancy. Walter: ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Chyla: Abbvie: Employment, Equity Ownership. Popovic: AbbVie: Employment, Equity Ownership. Fakouhi: AbbVie: Employment, Equity Ownership. Shah: AbbVie: Employment, Equity Ownership. Dunbar: AbbVie: Employment, Equity Ownership. Xu: AbbVie: Employment, Equity Ownership. Mabry: AbbVie: Employment, Equity Ownership. Hayslip: AbbVie: Employment, Equity Ownership.

Background Chronic pain can contribute to disability, depression, anxiety, sleep disturbances, poor quality of life and increased health care costs, with close to 20 % of the adult population in Europe reporting chronic pain. To empower the person to self-manage, it is advocated that education and training about the nature of pain and its effects and how to live with pain is provided. The objective of this review is to determine the level of evidence for education to facilitate knowledge about chronic pain, delivered as a stand-alone intervention for adults, to reduce pain and disability. Methods We identified randomised controlled trials of educational intervention for chronic pain by searching CENTRAL, MEDLINE, EMBASE and ongoing trials registries (inception to December 2013). Main inclusion criteria were (1) pain >3 months; (2) study design that allowed isolation of effects of education and (3) measures of pain or disability. Two reviewers independently screened and appraised each study. Results Nine studies were analysed. Pooled data from five studies, where the comparator group was usual care, showed no improvement in pain or disability. In the other four studies, comparing different types of education, there was no evidence for an improvement in pain; although, there was evidence (from one study) of a decrease in disability with a particular form of education—pain neurophysiology education (PNE). Post-hoc analysis of psychosocial outcomes reported in the studies showed evidence of a reduction in catastrophising and an increase of knowledge about pain following PNE. Conclusions The evidence base is limited by the small numbers of studies, their relatively small sample sizes, and the diversity in types of education studied. From that limited evidence, the only support for this type of education is for PNE, though it is insufficiently strong to recommend conclusively that PNE should be delivered as a stand-alone intervention. It therefore remains sensible to recommend that education be delivered in conjunction with other pain management approaches as we cannot confidently conclude that education alone is effective in reducing pain intensity or related disability in chronic pain in adults. Electronic supplementary material The online version of this article (doi:10.1186/s13643-015-0120-5) contains supplementary material, which is available to authorized users.

Background: Multiple studies have demonstrated the modest efficacy of low-dose cytarabine (LDAC) in older patients (≥65 years) with Acute Myeloid Leukemia(AML) who are unlikely to benefit from an anthracycline and cytarabine intensive induction [CR/CRi rates of 10 - 26%; (CRi = complete remission with incomplete marrow recovery)]. Venetoclax, a selective BCL-2 inhibitor has demonstrated single-agent activity in patients with relapsed and refractory AML [Konopleva et al., ASH 2014]. When administered with LDAC, the recommended phase 2 dose (RP2D) of venetoclax was 600 mg daily [Lin et al., ASCO 2016 (abstract 7007)]. Here we present the safety and efficacy data at RP2D of venetoclax from the dose escalation and expansion phases of the study (NCT02287233). Methods: Patients enrolled as of 15DEC2015 are included in this analysis with a data cut-off date of 31MAR2016. Patients were eligible if considered unfit for intensive chemotherapy, had an ECOG performance status of 0-2 and adequate renal and liver function. Patients treated with cytarabine for a pre-existing myeloid disorder, or those with acute promyelocytic leukemia or active CNS involvement with AML were excluded from the study. Venetoclax 600 mg was administered orally once daily on days 2 - 28 of Cycle 1 and days 1 - 28 of subsequent cycles. A 5-day dose ramp-up schedule was followed to reach the 600 mg dose. LDAC 20 mg/m2 was administered s.c. daily on days 1-10 in 28-day cycles. To mitigate the potential risk of tumor lysis syndrome (TLS), all patients were hospitalized and received prophylaxis commencing 48 hours prior to venetoclax during Cycle 1. Adverse events (AEs) were graded by NCI CTCAE Version 4.0. Results: Twenty patients were enrolled in the study (escalation, n=8; expansion, n=12). The median age was 74 years (range: 66 - 87). 8/20 (40%) patients had an antecedent hematologic disorder. Median time on venetoclax was 147.5 days (range: 8 - 455). Grade 3/4 AEs (≥10% patients) excluding cytopenias were febrile neutropenia (35%), hypertension (20%), hypophosphatemia (20%), decreased appetite, increased blood bilirubin, hyponatremia, hypoxia, hypotension, pneumonia, sepsis, syncope, urinary tract infection, and vomiting (10% each). No events of TLS occurred. Venetoclax exposures on Cycle 1 Day 10 (with LDAC) vs. Cycle 1 Day 18 (venetoclax alone) were comparable. The mean ± SD of maximum observed concentration (Cmax, µg/mL/mg) were 2.04 ± 1.45 vs. 2.92 ± 2.15, respectively. The mean ± SD of area under the curve (AUC24, µg*hr/mL) were 33.3 ± 27.5 vs. 46.1 ± 36.8, respectively. Similarly, co-administration of venetoclax did not markedly affect LDAC exposures. The mean ± SD of Cmax (ng/mL) of LDAC on Cycle 1 Day 1 (LDAC alone) vs. Cycle 1 Day 10 (with venetoclax) were 158.89 ± 79.08 vs 166.49 ± 32.06, respectively. Similarly, the mean ± SD of AUCinf (ng*hr/mL) were 170.64 ± 102.86 vs 246.51 ± 93.41, respectively. 15/20 (75%) patients achieved an objective response (CR+CRi+PR). Of them, 14/20 (70%) patients had a CR+CRi; all 14 patients belonged to a subset of 18 patients with no prior myeloproliferative neoplasm (MPN). 16/19 (84%) patients with available data had their bone marrow blast percentage reduced to below 5%. The 12-month overall survival (OS) estimate for all patients was 74.7% (95% CI=49.4 - 88.6) and that for the responders (n=15) was 86.7% (95% CI=56.4 - 96.5). The overall response rates and 12-month OS estimates for patients with or without prior hypomethylating agent (HMA) and with or without MPN are summarized in Table 1. A Kaplan-Meier curve showing OS for responders vs. non-responders is shown in Figure 1. The median time to best response was 30 days (range: 23 - 169). Only 2/14 patients who achieved CR/CRi have died [disease progression (n=1), acute hepatic failure (n=1)]. Conclusions: Venetoclax (600 mg RP2D) plus LDAC demonstrated an acceptable safety and pharmacokenitic profile in patients aged ≥65 years with treatment-naive AML who are not eligible for an intensive anthracycline-containing induction chemotherapy. Clinical remission was achieved in the majority of patients. The median OS has not been reached. A substantially better survival in responders as compared to non-responders suggests that the improvement is likely due to treatment with venetoclax plus LDAC. Updated responses and survival estimates for all patients, including those in dose expansion phase that were enrolled after the preliminary data cut, will be presented. Disclosures Wei: Novartis: Honoraria, Research Funding. Strickland:Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sanofi: Research Funding; Sunesis Pharmaceuticals: Consultancy, Research Funding; Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Fiedler:Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Kolltan: Research Funding; Novartis: Consultancy; Teva: Other: Travel; Ariad/Incyte: Consultancy; Gilead: Other: Travel; Pfizer: Research Funding; GSO: Other: Travel. Martinelli:MSD: Consultancy; Celgene: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; BMS: Speakers Bureau; Novartis: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Fakouhi:AbbVie Inc.: Employment, Other: may own stock. Darden:AbbVie Inc.: Employment, Other: may own stock. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Agarwal:AbbVie Inc.: Employment, Other: may own stock. Salem:AbbVie Inc.: Employment, Other: Stocks or options. Mabry:AbbVie Inc.: Employment, Other: May own stock. Hayslip:AbbVie Inc.: Employment, Other: May own stock.

Background: Venetoclax (VEN) is a potent, selective, orally available small-molecule BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those with t(11;14), which mostly have a favorable high BCL-2, low BCL-XL, and low MCL-1 profile. Methods: In this Phase 1, open-label study, patients (pts) with relapsed/refractory (R/R) MM received VEN monotherapy. Objectives of the study were to assess safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose, and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of VEN. After a 2-week lead in period with weekly dose escalation, VEN was given daily at final doses of 300, 600, 900, or 1200mg in dose escalation cohorts and 1200mg in the safety expansion. Pts who progressed during VEN monotherapy could receive VEN plus dexamethasone and continue in the study. Results: As of 01July2016, 66 pts were enrolled in the study (30 in dose escalation cohorts and 36 in safety expansion). Median age was 63 years and 39 (62%) pts were ISS stage II/III. The median number of prior therapies was 5 (range: 1-15), and 62 (94%) pts had received bortezomib (46 [70%] refractory), 62 (94%) received lenalidomide (51 [77%] refractory), and 50 (76%) had prior autologous stem cell transplant. Thirty (46%) pts had t(11;14) MM. Median time on VEN monotherapy for all pts was 2.5 months (.2-23); 17 (26%) elected to receive VEN and dexamethasone combination after disease progression for a median of 1.4 months (.1-11). Fifty-one (77%) pts discontinued the study for the following primary reasons: 39 related to disease progression, 5 due to AEs/toxicity, 2 withdrew consent, 1 was lost to follow up, and 4 for other reasons not specified. Common adverse events (AEs) in ≥20% of pts were nausea (48%), diarrhea (36%), neutropenia (32%), thrombocytopenia (32%), fatigue (27%), anemia (23%), back pain (21%), and vomiting (21%). Grade 3/4 AEs in ≥10% of pts were thrombocytopenia (26%), neutropenia (20%), lymphopenia (15%), anemia (14%), and decreased white blood cells (12%). Serious AEs in ≥2 pts were pneumonia (n=5), sepsis (3), pain, pyrexia, cough, and hypotension (2 each). Two pts experienced dose-limiting toxicities at 600mg of abdominal pain and nausea. Eight deaths were reported: 6 due to disease progression, 1 due to lung disorder, and 1 due to brain hemorrhage following injury; neither were considered by the investigator as related to VEN. Steady state VEN exposures were approximately dose proportional at all doses but 900mg. As of 20July2016, ORR for all pts on VEN monotherapy was 21% (14/66) and 10 (15%) achieved very good partial response (VGPR) or better (2 stringent complete response [sCR], 2 CR, 6 VGPR) (Figure); median DoR and TTP was 9.7 and 2.6 months, respectively. Most objective responses (12/14 [86%]) were reported in the subset of pts with t(11;14) MM. In this group, ORR was 40% (12/30) and 27% (8/30) achieved a response of ≥VGPR; median DoR for pts with t(11;14) was 9.7 months (95% CI: 6.3, -). Pts who achieved at least minimal response in the t(11;14) group (14/30) had a median of 4 prior therapies and were mostly refractory to bortezomib, lenalidomide, or double refractory (71% [10/14] each). For two pts with response in the non-t(11;14)/undetermined group, 1 had a translocation of chromosome 14 with an unidentified partner, and the other had no cytogenetics data available. DoR was 9.5 and 7.2 months in these pts and both are still ongoing. Median TTP for pts with or without/undetermined t(11;14) was 6.6 and 1.9 months, respectively. The median best percent change in primary M protein for pts with t(11;14) (n=23) was -53% vs +11% in the non-t(11;14)/undetermined group (n=23). Additional biomarker subgroup analyses (n=32) showed that efficacy was primarily observed in pts with myeloma cells expressing a favorable BCL-2 family expression profile (high BCL-2, low BCL-XL, low MCL-1) by immunohistochemistry, which was significantly enriched in the t(11;14) population. Indeed, although high BCL-2 expression was observed in a majority of bone marrow core biopsy samples (88%), the t(11;14) subgroup was enriched (81% vs 25%) for tumors expressing high BCL-2, low BCL-XL, and low MCL-1. Conclusions: VEN monotherapy has an acceptable safety profile and clear anti-myeloma activity in pts with R/R MM, primarily with t(11;14) having a high BCL-2, low BCL-XL and low MCL-1 expression levels. Figure Figure. Disclosures Kumar: Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy. Kaufman:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Incyte: Consultancy. Mikhael:Abbvie: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Facon:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol: Consultancy; Millenium/Takeda: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Benboubker:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Alzate:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Xu:AbbVie: Employment. Agarwal:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Touzeau:AbbVie: Research Funding.

The objective of this investigation is to consider the role of family food interaction in healthful dietary activity. A theoretical model is proposed in which three sets of determinate variables are specified as leading to interaction in the family on food issues which, in turn, is predicted to have a positive effect on four indicators of dietary quality. 150 married couples from a midwestern US state were randomly selected and interviewed. The findings provide clear evidence of the importance of family food interaction for the quality of marital partners' diet. Also differences found between husbands and wives indicate that wives contribute more to husbands' dietary quality than the reverse, suggesting again the dominant status of wives in family food selection and preparation.

Although there is a great deal of research linking social support with favourable psychological well-being outcomes a number of contradictory findings have been published showing support to be associated with increased psychological distress. These contrary findings arise when social support is measured as the receipt of supportive behavior rather than perceptions of support availability and quality. This paper examines three hypotheses that have been advanced to explain why the receipt of support is associated with distress. The first of these hypotheses (the support mobilisation hypothesis) argues that the relationship is a spurious one, and that it is a product of distressing circumstances which increase both support receipt and psychological distress. The other two hypotheses (the inequity hypothesis and the esteem threat hypothesis) both argue that receiving support actually causes distress. We tested these hypotheses in two samples. One sample was a group of individuals who reported having ...

This paper begins with a critical review of studies which have examined the effects of caring on health. Most are shown to suffer from defects in sampling and design, so that the evidence for detrimental effects is suggestive rather than conclusive. The substantive part of the paper then utilizes data on a cohort of 55-year-olds to compare the health of carers with the health of non-carers and to examine changes in caring and health over a 3-year period. The comparison yields no systematic evidence of the deleterious effects of caring on health; indeed, if there is a tendency in the accumulated data, it is in the opposite direction i.e. that carers report better health and functioning than non-carers. It is suggested that part of the explanation relates to selection and self-selection and the longitudinal data reveals high volatility in caring status, even over a short time period. The paper goes on to examine sub-groups of carers considered to be at greater risk. There is no evidence that their health is compromised but the authors acknowledge weaknesses in the data and argue for a specially designed study. The paper concludes with a discussion of the findings and their implications for research, policy and practice.

8032Background: The anti-apoptotic protein BCL-2 has been implicated in the survival of multiple myeloma (MM) cells. Venetoclax (VEN) is an oral, highly selective BCL-2 inhibitor, which induces cel...

7527Background: Venetoclax (VEN) is an orally bioavailable BCL2 selective inhibitor. Patients (pts) with relapsed or refractory CLL or small lymphocytic lymphoma were treated in a phase 1 trial (M1...

2579Background: Veliparib is a potent oral PARP1/2 inhibitor. Monotherapy trials with immediate release formulation veliparib (IR-v) showed antitumor activity in BRCA+ cancers. An extended release formulation (ER-v) may lower the peak-to-trough concentration ratio while maintaining exposure and improving tolerability, providing a rationale to conduct a phase 1 study (NCT01853306) of ER-v in pts with advanced tumors. Methods: Eligible pts had metastatic BRCA+ cancer, BRCA± high-grade serous ovarian/primary peritoneal/fallopian tube cancer (OC), (part 1/2), or BRCA+ breast cancer (BC), or OC (part 3). Part 1 – PK assessment: pts received ER-v (3 different ER-vs tested) or IR-v 200 mg in fed/fasted state on days 1/3/5 (3-group, single-sequence crossover). Part 2 – 3+3 dose escalation: pts received ER-v daily (QD or BID) starting at 200 mg. Part 3 – safety expansion: ER-v was administered continuously at the RP2D. Primary objectives were to determine the bioavailability and food effect of ER-v vs IR-v, the MT...

7007Background: Treatment options for older patients (pts) with acute myelogenous leukemia (AML) unfit for intensive chemotherapy are limited. Expected complete remission rates for low-dose cytarabine (LDAC) are about 10% in this population. Targeting the pro-survival molecule BCL-2 has demonstrated clinical efficacy as a therapeutic strategy in various hematologic malignancies. Venetoclax (VEN), a selective BCL-2 inhibitor, shows synergy with cytarabine in several AML cell lines and primary samples. Methods: This is a non-randomized, open-label phase 1/2 dose-escalation/expansion study of VEN + LDAC, in treatment-naive AML pts ≥ 65 years not eligible for intensive chemotherapy. Pts receive oral VEN once daily (QD) on days 1‒28 and subcutaneous LDAC 20 mg/m2 QD on days 1‒10 of each 28-day cycle. VEN dose escalation follows a 3 + 3 design; dose-limiting toxicities (DLTs: grade 4 toxicity, platelet count < 25,000/μL, or absolute neutrophil count < 500/μL within 14 days of last VEN dose) areassessed during c...

Background: The anti-apoptotic protein BCL-2 has been implicated in mediating the survival of multiple myeloma (MM) cells. Venetoclax is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. Venetoclax induces cell death in MM cell lines in vitro and primary MM samples ex vivo. Certain genetic subtypes of MM cells are particularly sensitive to venetoclax, including t(11;14) cells, which express a high ratio of BCL2 to MCL1 (venetoclax resistance factor). The current Phase 1 study evaluates safety, efficacy, and pharmacokinetics (PK) in patients (pts) with relapsed/refractory MM. Methods: Primary objectives are to evaluate safety, PK, and recommended phase two dose; other objectives include assessing preliminary efficacy and the impact of chromosomal abnormalities. In dose-escalation (DE) cohorts, venetoclax was given orally daily at 300, 600, 900, or 1200 mg after a 2-week dose ramp-up (3+3 design). Patients in the safety expansion (SE) cohort received 1200 mg daily after ramp-up. All patients were monitored for tumor lysis syndrome (TLS). Results: As of June 17, 2015, 37 patients were enrolled in the study: 30 from DE cohorts and 7 from the SE. Median (range) age was 66 years; 19 (51%) were female. Fourteen were ISS stage I, 13 stage II, 8 stage III, 2 unknown. The median (range) number of prior lines of therapy was 6 (1-19). Thirty-two had prior bortezomib (20 refractory), 35 lenalidomide (18 refractory), and 26 had prior stem cell transplant. Fourteen patients had t(11;14), 4 had t(4;14), 5 had del 17p, and 17 had del 13q. Adverse events (AEs) in ≥20% of patients were nausea (49%), diarrhea (38%), vomiting (30%), anemia (27%), fatigue (24%). Grade 3/4 AEs (≥10%): thrombocytopenia (22%), anemia (19%), neutropenia (11 %). Serious AEs (≥2 patients): pyrexia (n=3), cough, malignant neoplasm progression, and sepsis (2 each); 2 (upper abdominal pain and anemia) were possibly related to venetoclax. Thirty (81%) patients have discontinued venetoclax: 24 due to PD, 3 for AEs (worsening shortness of breath, hypokalemia, and nausea), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). Four deaths occurred (2 due to PD, 1 due to brain hemorrhage, 1 due to pneumopathy). Two of the 6 patients in the 600 mg cohort experienced DLTs of upper abdominal pain and nausea with abdominal pain. No patients met the criteria for laboratory or clinical TLS. Based on preliminary PK (n=21), the mean Cmax and AUC24 were ~dose-proportional at all studied doses (300, 600, 1200 mg) except 900 mg, and dose-normalized venetoclax exposure in MM was similar to that in CLL and NHL pts. Thirty-two of the 37 patients were evaluable for preliminary efficacy (Table). Two patients, both t(11;14), achieved a complete response (1 at 600 mg and 1 at 900 mg). Responses were first achieved at 1.8 and 1.1 months and were maintained for 9.7 and 9.0 months, respectively (900 mg pt remains in CR). Among the 16 patients receiving 1200 mg in the DE or SE cohort, 6 of whom had t(11;14), 5 achieved SD, 6 experienced PD, and 5 are not yet evaluable. Conclusions: Venetoclax monotherapy had a tolerable safety profile in heavily-pretreated relapsed/refractory MM, and no new safety signals were observed compared to other venetoclax studies. The study continues to enroll in the SE cohort at 1200 mg. Responses (including CR) and longer time on venetoclax were observed in t(11;14) patients. These early results suggest that venetoclax has single agent activity, most prominently in t(11;14) patients. Figure 1. Figure 1. Disclosures Kumar: Celgene: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. Kaufman:Janssen: Consultancy; Spectrum: Consultancy; Merck: Research Funding; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Novartis: Research Funding; Onyx: Research Funding. Mikhael:Sanofi: Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Onyx: Research Funding. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Celgene: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard. Alzate:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Agarwal:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Touzeau:AbbVie: Research Funding.

Introduction: BCL-2 is an anti-apoptotic protein that is commonly overexpressed in hematologic malignancies, including Non-Hodgkin Lymphoma (NHL). Venetoclax is a selective, potent, orally bioavailable BCL-2 inhibitor. Patients (pts) with relapsed/refractory (R/R) NHL were enrolled in a phase 1, open-label, dose-escalation, multicenter study to determine the safety, pharmacokinetics, and efficacy of venetoclax monotherapy. We present updated data on the safety profile and efficacy as of June 10, 2015. Methods: Venetoclax was administered once-daily until progressive disease or unacceptable toxicity. To mitigate the risk of tumor lysis syndrome (TLS), a 3-week period with a stepwise, intrapatient dose ramp-up was used, starting at 200 mg and reaching a maximum dose level of 1,200 mg in the dose escalation cohorts. In a safety expansion cohort, stepwise escalation from 400 mg to 800 mg to 1200 mg was evaluated. Adverse events (AEs) were graded according to NCI-CTCAE version 4.0. Responses were assessed using 2007 Cheson IWG response criteria including CT scans beginning at week 6. Results: Accrual is complete with 106 pts enrolled. NHL subtypes included in the dose escalation cohorts (200-1200 mg/day) were diffuse large B-cell lymphoma (DLBCL, n=20), follicular lymphoma (FL, n=14), mantle cell lymphoma (n=28), Waldenström macroglobulinemia (n=4), marginal zone lymphoma (n=3), and multiple myeloma (n=1). NHL subtypes enrolled in the safety expansion cohort (1200 mg/day) were DLBCL (n=21) and FL (n=15). The current analysis focuses on pts with DLBCL and FL from the dose escalation and safety expansion cohorts. Data on other subtypes will be presented at the meeting. In total, 57/70 pts with DLBCL and FL have discontinued (n=49 due to PD, n=3 due to AE, n=2 withdrew consent, n=2 proceeded to transplant and n=1 due to non-compliance). Treatment emergent-AEs of any grade in ≥20% of the 70 pts with DLBCL or FL were diarrhea and fatigue (each 44%), nausea (33%) and vomiting (23%). Treatment-emergent grade 3/4 AEs in ≥5 pts, were anemia (14%), fatigue (9%) and thrombocytopenia (7%). Serious adverse events in ≥2 pts were hyponatremia (4%), and dehydration, diarrhea, and febrile neutropenia (each 3%). Two events of laboratory TLS were previously reported. There were no new events of laboratory TLS and no pts had clinical TLS. Among 41 pts with DLBCL, 7 were DLBCL-Richter's transformation (RT) and 2 had primary mediastinal large B-cell lymphoma (PMBCL). The median age was 68 (range: 25-86). The median number of prior therapies was 3 (range: 1-8). Five (12%) had rituximab-refractory disease. The median time on venetoclax for pts with DLBCL was 5 months (range: 0.4-9). The overall response rate (ORR) was 15% [3 (9%) CR and 2 (6%) PR] for pts with DLBCL (n=34). The median duration of response for DLBCL was 3.3 months (range: 2-4) with no responses ongoing and the median duration of SD was 2.3 months (range: 1-15). One pt with SD remains on study at 9 months of venetoclax. Two responders (1 with DLBCL who achieved CR and 1 with PMBCL who achieved PR) proceeded to allogeneic hematopoietic stem cell transplant. The ORR was 43% (3 PR) for pts with DLBCL-RT (n=7). One pt with PR remains on study at 18 months of venetoclax. Among 29 pts with FL, the median age was 64 (range: 46-75). The median number of prior therapies was 3 (range: 1-10). Eight (28%) had rituximab-refractory disease. The median time on venetoclax was 7 months (range: 1-19). The ORR was 34% [3 (10%) CR and 7 (24%) PR] for pts with FL (n=29). All 3 patients with CR were enrolled in the dose escalation cohorts. The median duration of response was 10 months (range: 1-30) and the median duration of SD was 4.2 months (range: 2-18). Eleven patients remain on study. Response rates are summarized in the table. Conclusions: Venetoclax monotherapy demonstrated a tolerable safety profile in pts with R/R NHL. Several pts with DLBCL had an initial response to venetoclax, but this response was not sustained. In FL, venetoclax monotherapy achieved an ORR of 34% indicating clinical benefit, as evidenced by long durations on therapy. These results suggest that the optimal role of venetoclax for treatment of DLBCL and FL will be in combination therapies. Venetoclax is currently being evaluated in combination with bendamustine and rituximab and in combination with R or obinutuzumab plus CHOP in phase 2 studies of pts with FL. Table 1. Table 1. Disclosures Gerecitano: Genentech: Consultancy, Other: Advisory Board; AbbVie: Consultancy, Other: Advisory Board. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Roberts:Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax: Employment; AbbVie and Genentech: Research Funding. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Consultant and speaker bureau for Genentech: Consultancy; AbbVie and Genentech: Research Funding. Kahl:Genentech: Consultancy; AbbVie: Research Funding; Teva: Consultancy. Pagel:Actinium Pharmacetuicals, Inc.: Equity Ownership. Puvvada:AbbVie and Genentech: Research Funding. Kipps:AbbVie: Consultancy, Research Funding. Anderson:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Gressick:AbbVie: Employment, Equity Ownership. Wagner:AbbVie: Employment, Equity Ownership. Kim:AbbVie: Employment, Equity Ownership. Heitner Enschende:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy.

Introduction: Bcl-2 is an antiapoptotic protein commonly overexpressed in hematologic malignancies, including non-Hodgkin's lymphoma (NHL). Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor that has demonstrated single-agent activity in patients with relapsed or refractory (R/R) NHL. Data in NHL xenograft models indicate that VEN enhances the efficacy of bendamustine (B) and rituximab (R). Methods: This ongoing phase 1, open-label, dose-escalation study with a safety expansion portion evaluates VEN in combination with BR in patients with R/R NHL (NCT01594229). Patients (≥18 years) with ECOG PS ≤1 are treated with oral VEN (50-800 mg) for 3, 7, or 28 consecutive days of each 28-day cycle. Patients with refractory diffuse large B-cell lymphoma (DLBCL) who progressed during or within 2 months of completion of their last planned course of chemotherapy were excluded. Dose escalation follows a 3+3 design. The BR regimen is administrated for 6 cycles: B (90 mg/m2; 2 days/cycle) and R (375 mg/m2; 1 day/cycle). Patients who complete VEN + BR treatment can continue VEN monotherapy for up to 2 years following the date of the last subject enrolled, in the absence of disease progression or toxicity. Primary objectives are to assess safety, pharmacokinetics (PK) profile, and to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose of VEN in combination with BR. Secondary objectives include preliminary efficacy evaluations. Dose-limiting toxicities (DLTs) are assessed during cycle 1. Disease responses were evaluated on day 1 of cycles 3, 5, 7, 11, 14, 17, 23, and every 6 cycles thereafter. Results: As of June 17, 2015, 47 patients (64% male; median age 63 years) have been enrolled in 10 escalation cohorts. Twenty-seven patients (57%) had been diagnosed with follicular lymphoma, 15 (32%) with DLBCL, and 5 (11%) with marginal zone lymphoma. Patients had a median of 3 (range: 1-8) prior therapies. All patients had prior R or R-combination, of whom 44 (94%) had R-based chemotherapy. Eleven patients (23%) had prior B or BR therapy. Median time on study is 128 days (range: 3-1066). As of June 2015, 25 patients (53%) are active and 22 (47%) discontinued (13 progressive disease, 4 adverse events [AEs; Table 1], 3 consent withdrawal, 1 noncompliance, and 1 completion of BR regimen per protocol). For the 17 patients who completed 6 cycles of combination therapy, 14 have continued to monotherapy and 11 active patients have not reached 6 cycles. Most common AEs (≥25%) in the combination therapy portion of the study (≤6 cycles) were nausea (51%), thrombocytopenia (45%), neutropenia (40%), constipation (36%), anemia (34%), diarrhea (30%), fatigue (30%), hyperglycemia (30%), lymphocyte count decrease (28%), and hypokalemia (28%). Most common grade 3/4 AEs (≥10%) during combination therapy were neutropenia (32%), lymphocyte count decrease (26%), thrombocytopenia (21%), anemia (15%), and leukopenia (13%). The most frequent serious AE was febrile neutropenia (9%). Three deaths occurred; none were drug-related AEs. Four patients experienced a DLT during cycle 1 (Table 1). Following 2 DLTs (febrile neutropenia and thrombocytopenia) in Cohort 5 (200 mg; 28/28d), a protocol amendment was filed in order to strongly encourage granulocyte colony-stimulating factor prophylaxis during VEN administration, particularly in heavily pretreated patients, and to refine the DLT definition in the context of known BR toxicities. Escalation continues with only 2 observed DLTs: Stevens-Johnson syndrome (400 mg 28/28d; primary reasonable possibility due to allopurinol; patient discontinued) and thrombocytopenia (600 mg 28/28d). Coadministration of BR did not significantly impact the PK of VEN. A total of 38 patients were evaluable for disease response. Overall, 29 patients had an objective response: 10 complete responses, 19 partial responses, and 4 patients had stable disease. Objective responses were observed across dose cohorts. Responses by NHL histology subgroups are shown in Table 1. Enrolling in Cohort 11 (1200 mg 28/28d) is currently ongoing. Conclusions: Combination therapy with VEN and BR demonstrated a tolerable safety profile. Responses were observed across dose cohorts in this heavily pretreated population. The MTD has not been reached and dose escalation is ongoing. Disclosures Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Kozloff:Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Nastoupil:AbbVie: Research Funding; Celgene: Honoraria; TG Therapeutics: Research Funding; Janssen: Research Funding; Genentech: Honoraria. Cordero:AbbVie: Employment, Equity Ownership. D'Amico:AbbVie: Employment, Equity Ownership. Diehl:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Wong:AbbVie: Employment, Equity Ownership. Heitner Enschede:AbbVie: Employment, Equity Ownership. Chien:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Flowers:Millennium/Takeda: Research Funding; Gilead Sciences: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Millennium/Takeda: Research Funding; Onyx Pharmaceuticals: Research Funding; OptumRx: Consultancy; Janssen: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Gilead Sciences: Research Funding; Janssen: Research Funding; Onyx Pharmaceuticals: Research Funding; Spectrum: Research Funding; Spectrum: Research Funding; Acerta: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Acerta: Research Funding; Infinity Pharmaceuticals: Research Funding; OptumRx: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Research Funding; Infinity Pharmaceuticals: Research Funding; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding.