Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib: Development and Validation of a Four-Factor Prognostic Model.

PURPOSE: Randomized trials established the superiority of ibrutinib-based therapy over chemoimmunotherapy in chronic lymphocytic leukemia. Durability of progression-free survival (PFS) with ibrutinib can vary by patient subgroup. Clinical tools for prognostication and risk-stratification are needed. PATIENTS AND METHODS: Patients treated with ibrutinib in phase II and III trials provided the discovery data set and were subdivided into discovery and internal validation cohorts. An external validation cohort included 84 patients enrolled in our investigator-initiated phase II trial. Univariable analysis of 18 pretreatment parameters was performed using PFS and overall survival (OS) end-points. Multivariable analysis and machine-learning algorithms identified four factors for a prognostic model that was validated in internal and external cohorts. RESULTS: Factors independently associated with inferior PFS and OS were as follows: TP53 aberration, prior treatment, ß-2 microglobulin ≥ 5 mg/L, and lactate dehydrogenase > 250 U/L. Each of these four factors contributed one point to a prognostic model that stratified patients into three risk groups: three to four points, high risk; two points, intermediate risk; zero to one point, low risk. The 3-year PFS rates for all 804 patients combined were 47%, 74%, and 87% for the high-, the intermediate-, and the low-risk group, respectively (P < .0001). The 3-year OS rates were 63%, 83%, and 93%, respectively (P < .0001). The model remained significant when applied to treatment-naïve and relapsed/refractory cohorts individually. For 84 patients in the external cohort, BTK and PLCG2 mutations were tested cross-sectionally and at progression. The cumulative incidences of mutations were strongly correlated with the model. In the external cohort, Richter's transformation occurred in 17% of the high-risk group, and in no patient in the low-risk group. CONCLUSION: Patients at increased risk of ibrutinib failure can be identified at treatment initiation and considered for clinical trials.

Phase I Study of Enavatuzumab, a First-in-Class Humanized Monoclonal Antibody Targeting the TWEAK Receptor, in Patients with Advanced Solid Tumors.

This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies. Mol Cancer Ther; 17(1); 215-21. ©2017 AACR.

Consistent efficacy of daclizumab beta across patient demographic and disease activity subgroups in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Daclizumab beta is a humanized monoclonal antibody specific for the human interleukin-2 receptor alpha chain (CD25). In two pivotal studies in relapsing multiple sclerosis (MS), patients treated with daclizumab beta exhibited lower annualized relapse rates (ARR) when compared with placebo or with intramuscular (IM) interferon beta-1a. OBJECTIVES: To determine if the efficacy of daclizumab beta demonstrated in the phase 2 SELECT study and the phase 3 DECIDE study was consistent in patient subgroups. METHODS: In the SELECT study, patients received daclizumab beta 150 or 300mg administered subcutaneously every 4 weeks for 52 weeks, and were compared with patients who received placebo. In the DECIDE study, patients received daclizumab beta 150mg administered subcutaneously every 4 weeks for 96-144 weeks, and were compared with patients who received IM interferon beta-1a 30µg. Subgroups were defined by sex, age, the number of relapses in the year before the study, disease duration, baseline disability measured by EDSS, presence of Gd-enhancing lesions, T2 hyperintense lesion volume at baseline, and previous interferon beta-1a use. RESULTS: Treatment with daclizumab beta was associated with relative lower ARR, with 95% confidence intervals (CIs) below 1 in 13 of 15 subgroups (SELECT study) compared with placebo and in all 17 subgroups compared with interferon beta-1a (DECIDE study). In 2 subgroups in the SELECT study (patients who were older than 35 years of age or who had a disease duration of 10 or more years), the rate ratio point estimate for the ARR was in favor of daclizumab beta but the 95% CI overlapped with 1. The clinical benefits in ARR achieved with daclizumab beta treatment compared with placebo or interferon beta-1a across subgroups were similarly supported by reductions in lesion activity on magnetic resonance images (MRIs). CONCLUSIONS: These findings suggest that treatment with daclizumab beta is consistently effective among clinically important patient subgroups and support its potential as a viable therapeutic option across the spectrum of relapsing MS.

Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM.

In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P = .09); median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity FcγRIIIa allele had median PFS of 22.3 months vs 9.8 months in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) vs 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) vs 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd vs Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd vs Bd alone. Registered to ClinicalTrials.gov as NCT01478048.

Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study.

BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signalling lymphocytic activation molecule (SLAM) family member 7 (SLAMF7), selectively kills SLAMF7-expressing myeloma cells through direct activation and engagement of the innate immune system, and thus might have clinical benefit in the treatment of myeloma. In phase 1 of this phase 1b-2 study, 82% of patients with relapsed multiple myeloma who were given elotuzumab plus lenalidomide and dexamethasone achieved an overall response. Here we report the final phase 2 results. METHODS: We did this randomised, multicentre, open-label, dose-escalation study (1703) at 17 hospitals in the USA, Canada, France, and Germany. Patients aged at least 18 years with confirmed, relapsed multiple myeloma, Eastern Cooperative Oncology Group performance status 0-2, and one to three previous therapies but no previous lenalidomide were eligible for phase 2. We randomly assigned patients (1:1) to either 10 mg/kg or 20 mg/kg intravenous elotuzumab plus oral lenalidomide (25 mg) and dexamethasone (40 mg). We stratified patients on the basis of the number of previous therapies (one versus two or three), and status of previous treatment with immunomodulatory drugs (yes or no), and used permuted block randomisation with a block size of four. Treatment was given in 28-day cycles until disease progression or unacceptable toxic effects occurred (elotuzumab was given on days 1, 8, 15, and 22 for cycles 1 to 2 and days 1 and 15 for subsequent cycles; lenalidomide was given on days 1-21 and dexamethasone once per week). The primary endpoint was the proportion of patients who achieved an objective response according to International Myeloma Working Group criteria. Primary analyses were done in the intention-to-treat population, and safety was analysed in all patients who received at least one dose of study drugs. This study is registered with ClinicalTrials.gov, number NCT00742560. FINDINGS: Between Jan 4, 2010, and Dec 21, 2010, we recruited and randomly assigned 73 patients to elotuzumab (36 to 10 mg/kg, 37 to 20 mg/kg). At data cutoff (Jan 16, 2014), 13 patients remained on treatment (six on 10 mg/kg, seven on 20 mg/kg). 61 (84%) patients achieved an objective response (33 [92%] with 10 mg/kg, 28 [76%] with 20 mg/kg); 31 (42%) a very good partial response (17 [47%] with 10 mg/kg, 14 [38%] with 20 mg/kg); and 20 (27%) a partial response (10 [28%] with 10 mg/kg, 10 [27%] with 20 mg/kg). The most common treatment-emergent adverse events of any grade were diarrhoea (48 [66%]), muscle spasms (45 [62%]), and fatigue (41 [56%]). 57 (78%) patients had grade 3-4 events, the most common of which were lymphopenia (15 [21%]) and neutropenia (14 [19%]). Three deaths occurred, none related to the study drugs. INTERPRETATION: Elotuzumab combined with lenalidomide and dexamethasone in patients with relapsed multiple myeloma showed acceptable safety and efficacy that seems better than that previously noted with lenalidomide and dexamethasone only. Phase 3 trials are in progress. FUNDING: Bristol-Myers Squibb, AbbVie Biotherapeutics.

Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma.

PURPOSE: This phase I study evaluated elotuzumab, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). PATIENTS AND METHODS: Three cohorts were enrolled and treated with elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. The first five patients received up to six cycles of therapy; subsequent patients were treated until disease progression. RESULTS: Twenty-nine patients with advanced MM and a median of three prior MM therapies were enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. The most frequent grade 3 to 4 toxicities were neutropenia (36%) and thrombocytopenia (21%). Two patients experienced a serious infusion reaction (one grade 4 anaphylactic reaction and one grade 3 stridor) during the first treatment cycle. Objective responses were obtained in 82% (23 of 28) of treated patients. After a median of 16.4 months follow-up, the median time to progression was not reached for patients in the 20-mg/kg cohort who were treated until disease progression. CONCLUSION: The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging response rates in patients with relapsed or refractory MM.