Fowler, Nathan

Abstract Abstract 2799 Background: Aurora A kinase (AAK) is important in a diverse set of mitotic processes and is amplified or overexpressed in a number of heme-lymphatic malignancies. MLN8237 is an investigational, orally administered, selective AAK inhibitor in clinical development for the treatment of hematologic and solid tumors. This multicenter study (NCT00697346) is the first phase 1 program to assess safety and pharmacology of MLN8237 in patients with advanced hematologic malignancies. Methods: Eligible patients were aged ≥18 yr, had response-evaluable, relapsed or refractory hematologic malignancies, and had ECOG performance status 0–2; there was no restriction on the number of prior therapies, but prior allogeneic transplant was excluded. Patients received escalating doses of MLN8237 as powder-in-capsule formulation in a 3+3 design. Endpoints included safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and response. Results: Twenty-eight patients were included; median age was 62 yr (range 41–74), 50% were male, 86% were white, and 43% had prior transplant. Diagnoses were non-Hodgkin's lymphoma (68%), including diffuse large B-cell (DLBCL), mantle cell, follicular, and small lymphocytic lymphoma; multiple myeloma (29%); and chronic lymphocytic leukemia (4%). Seventy-nine percent of patients had received ≥3 prior therapies. Patients initially received a 21-day treatment schedule of MLN8237 25 or 35 mg (BID loading dose on Day 1, then QD on Days 2–21) followed by a 7-day rest period (28-day cycles). Based on results with the first two cohorts, subsequent cohorts received a 14-day treatment schedule of MLN8237 35, 45, 65, or 90 mg (BID loading dose on Day 1, then QD on Days 2–14) followed by a 14-day rest period (28-day cycles). Median number of cycles administered was 2 (range 1–14+). After escalation to 90 mg (maximum administered dose), two DLTs per cohort led to de-escalation to 65 mg and then 45 mg, which was the MTD on the 14-day schedule. The most common treatment-related adverse events (AEs) were neutropenia (46%), thrombocytopenia (36%), and asthenic conditions (32%); grade ≥3 treatment-related AEs were reported in 14 (50%) patients, and 13 (46%) had a serious AE. DLTs included grade 3–4 myelosuppression associated with infection or delay in treatment, which were generally manageable by reduction in dose or schedule. AEs were generally reversible and manageable, although 5 (18%) patients discontinued due to AEs. Three patients died, from causes (renal failure; airway obstruction; progressive large cell lymphoma) not considered related to MLN8237. Following multiple doses, an overall median Tmax of 2 hr, a mean t1/2 of 23 hr, and a peak/trough ratio of 5 were observed. The geometric mean of steady-state AUC increased from 19,534 to 30,811 nM*hr when the daily dose was increased from 25 to 65 mg. With the 14-day schedule, antitumor activity was observed in a patient with relapsed DLBCL treated with 65 mg and reduced to 45 mg, who enrolled after disease progression following ifosfamide-carboplatin-etoposide (ICE) salvage therapy. A durable PR coupled with resolution of B symptoms sustained for >1 yr was observed in a patient with post-transplant grade 3B follicular lymphoma treated with 35 mg, escalated per protocol to 45 mg and then 65 mg. Stable disease (SD; 5 months) was observed in a patient with myeloma treated at 90 mg. Conclusions: MLN8237 toxicities were consistent with AAK inhibition in proliferating tissue (chiefly bone marrow), and were generally manageable. The MTD was 45 mg on the 14-day schedule in these patients with advanced hematologic malignancies. Antitumor activity was observed, and repeat cycles were tolerable over 6–12 months in some patients who achieved PR or SD. The results support further investigation of MLN8237 in heme-lymphatic malignancies, and ongoing clinical development includes alternative schedules and formulations. Disclosures: Padmanabhan: Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of advanced hematologic malignancies. Shea:Millennium Pharmaceuticals, Inc: Consultancy, Research Funding. Vose:Millennium Pharmaceuticals, Inc.: Research Funding. Goy:Millennium Pharmaceuticals, Inc., Celgene, GSK, Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Fingert:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Fowler:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Research Funding; Cephalon: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria.

Background:Lenalidomide plus rituximab (R2) has established efficacy and a tolerable safety profile in patients with previously untreated and relapsed/refractory (R/R) indolent NHL. This includes patients with marginal zone lymphoma (MZL) who are generally treated in a similar manner to follicular lymphoma (FL).Aims:Primary results for the AUGMENT study in R/R FL grade 1–3a and MZL showed significantly improved progression‐free survival (PFS) for R2 over R/placebo in the overall population and in the subgroup analyses, with the exception of the MZL subgroup. Given the small sample size for MZL patients, post hoc analyses of baseline characteristics and univariate/multivariate analyses of PFS were conducted to examine possible explanations for these results.Methods:The phase III AUGMENT study randomized patients 1:1 to R2 (lenalidomide PO 20 mg/day (d), d1–21/28 X12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2–5) or rituximab‐placebo (R/placebo; same dosing schedule). PFS by 2007 IWG (without PET) was the primary endpoint. Post hoc Cox regression models were used for univariate analysis of one risk factor and multivariate analyses including treatment arm and significant risk factors (P < 0.05) from the univariate analyses.Results:A total of 63/358 (18%) MZL patients were part of the overall study population, including n = 14/16 MALT, n = 9/6 splenic, and n = 8/10 nodal MZL subtypes for respective R2 and R/placebo arms. Numerical differences between treatment arms for baseline demographics and disease characteristics for MZL patients favoring the R/placebo arm were: fewer R2 patients had an ECOG score of 0 (55% R2 vs 72% R/placebo), and more R2 (vs R/placebo) patients were older (≥65 y: 68% vs 59%; ≥70 y: 42% vs 38%), were refractory to the last prior regimen (13% vs 3%), had Ann Arbor stage IV disease at enrollment (65% vs 41%), high‐risk MALT‐IPI score (50% vs 19%), elevated LDH (29% vs 19%), B symptoms (13% vs 3%), and high tumor burden per GELF criteria (65% vs 56%). The most common grade 3/4 AEs for MZL patients receiving R2 vs R/placebo, respectively, were neutropenia (47% vs 16%), pneumonia (3% vs 13%), and leukopenia (10% vs 0). A total of 5 deaths occurred in the R2 arm (most associated with progression of disease; 2 deaths occurred early at 3 and 13 days after randomization [one prior to receiving R2 and one 2 days after treatment initiation]) and 2 in the R/placebo arm. Despite worse prognostic features, best response was improved with R2 (vs R/placebo) with ORR = 65% vs 44% (P = 0.13) and CR = 29% vs 13% (P = 0.13), although neither were statistically significant. Improved response rates did not translate into a survival advantage for R2. Median PFS for MZL patients was 20.2 mo R2 vs 25.2 mo R/placebo (HR = 1.00; 95% CI, 0.47–2.13; P = 1.0). Univariate analyses showed that several baseline factors were prognostic for MZL patients (P < 0.05): Ann Arbor stage IV, elevated LDH, and unfit for chemotherapy (Table). Multivariate analyses adjusting for the imbalance in these 3 significant prognostic factors showed an adjusted PFS HR of 0.51 (95% CI, 0.20–1.28) favoring the R2 arm, similar to the PFS HR in the overall population (HR = 0.46; 95% CI, 0.34–0.63). The univariate and multivariate analyses suggested that the imbalance in baseline prognostic factors impacted PFS results for MZL patients.Summary/Conclusion:Overall, these findings suggest that the PFS results in MZL patients were negatively impacted by the imbalance in baseline prognostic factors and more aggressive disease in the R2 over the R/placebo arm.image

PURPOSEPatients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab.METHODSA phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.RESULTSA total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.CONCLUSIONLenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.

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

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, > 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2WLS) and bivariate copula (R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.