Faculty Bibliography

PURPOSE: Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma. EXPERIMENTAL DESIGN: Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m2 on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m2 on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles. RESULTS: Maximum tolerated doses were 110 mg/m2 (schedule A) and 196 mg/m2 (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade >/=3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease. CONCLUSIONS: Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma. Clin Cancer Res; 1-10. (c)2015 AACR.

The International Prognostic Score (IPS-7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS-7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS-7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS-7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0.0001) and OS (P < 0.0001)]. IPS-3 outperformed the IPS-7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS-7 low risk patients were re-classified as intermediate risk and 13% of IPS-7 intermediate risk patients as low risk. For patients with advanced HL, the IPS-3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.

Over the past decade, new biologic insights have revealed the key role of the tumor microenvironment in the pathogenesis of classical Hodgkin lymphoma (cHL). The primary Hodgkin Reed-Sternberg (HRS) tumor cells normally constitute less than 1% of the tumor cellularity in cHL, and are surrounded by an abundant and heterogeneous inflammatory infiltrate. The cross talk between the HRS cells and the cells of the cHL microenvironment sustains tumor growth and survival. An improved understanding of this phenomenon has led to the development of novel antitumor strategies that alter the cHL microenvironment, changing it from protective to cytotoxic. Developing new strategies remains a high priority because-despite the curability of cHL-as many as one-third of advanced-stage patients will relapse after first-line therapy. Furthermore, only half of relapsed patients will obtain long-term disease control through autologous stem cell transplant. In this review, we will provide an overview of the role of the cHL microenvironment in disease biology, the agents currently available or under investigation targeting the cHL microenvironment, and the most promising and innovative treatment platforms being evaluated in clinical trials.

Introduction: Based on early evidence of cumulative toxicity of polatuzumab vedotin (PoV; anti-CD79b antibody-drug conjugate) at a dose of 2.4 mg/kg (Morschhauser ASH 2014; NCT01691898), a dose of 1.8 mg/kg was explored. We report updated results of the dose comparison. Safety and efficacy of PoV after 8 treatment cycles were also analysed. Methods: Patients (pts) with R/R FL received PoV at 2.4 or 1.8 mg/kg with rituximab (R) 375 mg/m², q21d until progression or unacceptable toxicity. Five pts with R/R FL from the Phase 1 study (Palanca-Wessels ASH 2013) treated with PoV 2.4 mg/kg were included in the analysis. Data at completion of PoV treatment were compared with data after 8 cycles. Results: Forty-five pts received PoV + R (25, 2.4 mg/kg; 20, 1.8 mg/kg). Median follow-up was 14 mo. in the 2.4 mg/kg group versus 8 mo. in the 1.8 mg/kg group. When limited to the first 8 treatment cycles, median follow-up was similar at 6 mo. for both groups. Baseline characteristics were balanced between the two cohorts, except for age (median 68 y 2.4 mg/kg; 62 y 1.8 mg/kg) and tumour volume (SPD 1824 mm² at 2.4 mg/kg, 2655 mm² at 1.8 mg/kg). Forty per cent (10/25, 2.4 mg/ kg) and 50% (10/20, 1.8 mg/kg) pts were refractory to their last treatment. At data cut-off for this analysis, pts received a median of 10 and 9.5 treatment cycles in the 2.4 and 1.8 mg/kg groups, respectively, with median dose intensities through cycle 8 of 88% and 99%, respectively. Safety is shown in the Table. Peripheral neuropathy (PN) was more frequent with PoV 2.4 mg/kg, and discontinuation (d/c) rates due to all causes were 56% versus 30% with the 1.8 mg/kg dose. After 8 treatment cycles, d/c rates were similar for both doses (28% vs 25%). An 84-year old pt in the 2.4 mg/kg cohort died 2 mo. after cycle 12 due to pulmonary congestion. Safety profiles of PoV + R for all treatment cycles and truncated after cycle 8 ORR was similar for both levels: 19/25 (76%) at 2.4 mg/kg and 15/20 (75%) at 1.8 mg/kg. CRs were achieved in 11/25 (44%) patients at 2.4 mg/kg and 2/20 (10%) patients at 1.8 mg/kg. Duration of response was 12 mo. for 2.4 mg/kg and not estimable for 1.8 mg/kg group. After 8 cycles, ORR remained similar (64% for 2.4 mg/kg and 60% for 1.8 mg/kg). Median PFS was 15 mo. at 2.4 mg/kg and not reached in the 1.8 mg/kg group. Conclusions: PoV + R in R/R FL showed high ORR at both doses, with higher CR at 2.4 mg/kg. D/c rates, mostly due to cumulative PN, were high. AEs and d/c rates were reduced at both doses if only the first 8 cycles are considered versus those through study completion. The safety of PoV can be improved by shorter treatment and/or lower dose. Updated PFS will be presented. (Table Presented)

Introduction: Treatment options for patients with relapsed or refractory classical Hodgkin lymphoma (cHL) have limited efficacy. Preclinical and early clinical evidence suggests that inhibition of the JAK-STAT or PI3K pathways may be efficacious in cHL, both directly and through modulation of the tumour microenvironment. Furthermore, inhibition of both pathways may be synergistic. Methods: This ongoing, open-label, dose escalation study enroled adult patients with relapsed/refractory B-cellmalignancies, including cHL. Patients received INCB040093 monotherapy (100mg once daily, 100 mg twice daily, 150 mg twice daily, or 300 mg once daily) or INCB040093 in combination with INCB039110 (INCB040093: 150 mg daily, 100 mg twice daily, or 150 mg twice daily; INCB039110: 400 mg or 600 mg once daily). Safety, efficacy, and pharmacodynamics were evaluated. Data from the patients with relapsed or refractory cHL are reported herein. Results: At the time of the current analysis, 17 patients with relapsed or refractory cHL had been enroled. At baseline, the median age was 34 years and 59% were men. Prior to study entry, patients had received a median of 5 treatment regimens, 82% had undergone haematopoietic stem cell transplantation, and all had received brentuximab vedotin therapy. The median exposure to treatment in this study was 209 days [range: 22+ (ongoing)-388]. The most common nonhaematologic adverse events (all grades) in this cHL cohort were fatigue (41%), headache (35%), and decreased appetite (35%). One nonhaematologic grade > 3 adverse event occurred in >1 patient: pneumonia (12%). Rates of allgrade neutropenia, thrombocytopenia, and anaemia were 47%, 47%, and 41%, respectively. Grade > 3 thrombocytopenia occurred in 18% of patients. No patients with cHL experienced a dose-limiting toxicity. Of 6 evaluable patients receiving INCB040093, the objective response rate (ORR) was 50%, including 1 complete response (CR). Of 9 evaluable patients receiving INCB040093 + INCB039110, ORR was 67%, including 2 CRs. A dose response in efficacy was not evident in this limited dataset of proximate dose cohorts. Based on pharmacodynamics and the safety profile of higher dose levels in the overall study population, INCB040093 100 mg twice daily and INCB040093 100 mg twice daily + INCB039110 400 mg once daily were selected for expansion. At these doses, ORR in the cHL cohort was 50% for INCB040093 and 75% (1 CR) for INCB040093 + INCB039110. Conclusions: INCB040093 alone or in combination with INCB039110 was generally well tolerated in this heavily pretreated population of patients with relapsed or refractory cHL. The efficacy seen in this limited number of evaluable patients compares well to approved therapies and investigational agents for cHL. These results warranted further investigation of INCB040093 +/- INCB039110 in patients with relapsed or refractory cHL, leading to the initiation of a phase 2 study

Introduction: Inhibiting the PI3K or JAK-STAT pathways may be therapeutic in Bcell malignancies due to their contribution to tumour growth and survival and effects on the tumour microenvironment. Furthermore, inhibition of both pathways may be synergistic due to JAK-STAT augmentation of B-cell receptor activation of the NFkappaB pathway. Methods: This ongoing dose escalation study with expansion cohorts enroled adult patients with relapsed/refractory B-cell malignancies. Patients received INCB040093 monotherapy (100 mg once daily, 100 mg twice daily, 150 mg twice daily, or 300 mg once daily) or INCB040093 in combination with INCB039110 (INCB040093: 150 mg daily, 100 mg twice daily, or 150 mg twice daily; INCB039110: 400 mg or 600 mg once daily). Safety, efficacy, and pharmacodynamics were evaluated. Results: Enrolled patients (N = 83) had follicular lymphoma (n = 19), classical Hodgkin lymphoma (cHL; n = 17), diffuse large B-cell lymphoma (DLBCL; n = 15), chronic lymphocytic leukaemia/small lymphocytic lymphoma (n = 13), or other subtypes (n = 19). At baseline, the median age was 61 years and 70% were men. The median number of prior treatment regimens was 4, and 24% of patients had undergone prior haematopoietic stem cell transplantation. The median exposure during the study was 185 days [range: 5-491+ (ongoing)] for INCB040093 alone and 99 days [range: 6-337+ (ongoing)] for INCB040093 + INCB039110. The most common adverse events were fatigue (28%), headache (19%), and pyrexia (19%). The most common grade > 3 adverse event was pneumonia (6%). The most common laboratory abnormalities were liver enzyme elevations and cytopenias. One patient had a dose-limiting toxicity on INCB040093 100 mg twice daily (gastrointestinal bleed secondary to gastric DLBCL regression). Dosing regimens of INCB040093 100 mg twice daily and INCB040093 100 mg twice daily + INCB039110 400 mg once daily were selected for expansion cohorts based on the incidence of liver enzyme elevations with INCB040093 and cytopenias with INCB040093 + INCB039110 at higher doses. At the selected doses, pAKT was decreased by =90% at trough on INCB040093, and IL-6-induced pSTAT3 was decreased an average of 65% on INCB039110. Of 75 patients evaluated for a response thus far, 28 responses have been reported. Notably, for evaluable patients with cHL (n = 15), the objective response rate was 60% (3 complete responses). Complete responses were observed in both of the patients enroled with the non-germinal centre B-cell-like subtype of DLBCL. Conclusions: Treatment with INCB040093 +/- INCB039110 was tolerable and produced responses, including complete responses, in patients with heavily pretreated relapsed/refractory B-cell malignancies. Given this activity, the study was expanded to enrol additional cohorts of patients with relapsed/refractory B-cell malignancies such as cHL and DLBCL, and a phase 2 study was initiated in patients with relapsed/refractory cHL