Bruce J. Dezube

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study

This trial was conducted to determine the dose‐limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8‐activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60‐min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21‐days. Dose escalation proceeded using a standard ‘3 + 3’ design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m2, respectively. On schedule A, hepatotoxicity was dose limiting. Multi‐organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target‐specific activity of pevonedistat. In conclusion, administration of the first‐in‐class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma

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; 22(1); 34–43. ©2015 AACR.

Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors.

Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies. Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0. Results: Schedule A MTD was 50 mg/m2; based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m2, respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. Conclusions: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m2 and 67 mg/m2. DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors. Clinical trials are ongoing. Clin Cancer Res; 22(4); 847–57. ©2015 AACR.

A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma

SummaryPurpose The therapeutic index of proteasome inhibitors may be improved through selective inhibition of a sub-component of the ubiquitin-proteasome system, such as the NEDD8-conjugation pathway. This multicenter, phase I, dose-escalation study assessed safety and the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of pevonedistat, an investigational NEDD8-activating enzyme (NAE) inhibitor, in patients with metastatic melanoma. Methods Patients received intravenous pevonedistat on Days 1, 4, 8, 11 (schedule A) or 1, 8, 15 (schedule B) of 21-day cycles. Results 26 patients received pevonedistat 50–278xa0mg/m2 on schedule A; 11 patients received pevonedistat 157xa0mg/m2 on schedule B. The schedule A MTD was 209xa0mg/m2: dose-limiting toxicities (DLTs) included grade 3 hypophosphatemia and grade 3 increased blood creatinine (associated with grade 3 hyperbilirubinemia). Two schedule A patients experienced acute organ failure toxicities, one of whom experienced grade 5 acute renal failure. Dose escalation did not occur in schedule B: DLTs included grade 3 myocarditis, grade 2 acute renal failure, and grade 2 hyperbilirubinemia in a single patient. Pevonedistat pharmacokinetics were approximately dose-proportional across the dose range studied, with a biphasic disposition profile characterized by a short elimination half-life (~10xa0h). Pharmacodynamic studies showed increases in NAE-regulated transcripts post-treatment; all post-dose biopsy samples were positive for pevonedistat-NEDD8 adduct. One schedule A patient achieved a partial response; 15 patients had stable disease (4 lasting ≥6.5xa0months). Conclusions Pevonedistat was generally well tolerated at the MTD. Anticipated pharmacodynamic effects of NAE inhibition were observed with single-agent pevonedistat in peripheral blood and tumor tissue.

Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML

Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.

Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes

Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes

An Evaluation of Treatment Patterns and Outcomes in Elderly Patients Newly Diagnosed With Acute Myeloid Leukemia: A Retrospective Analysis of Electronic Medical Records From US Community Oncology Practices

BACKGROUNDnMany elderly patients with acute myeloid leukemia (AML) are considered ineligible for standard intensive induction therapy due to performance status and comorbidities. We analyzed treatment patterns and outcomes among elderly patients newly diagnosed with AML in the US community oncology setting.nnnMETHODSnA retrospective observational study was conducted using patient-level data from a network of US community oncology practices provided by Altos Solutions. Patients agedxa0≥ 60 years, diagnosed with AML between November 2005 and February 2014, withxa0≥ 1 recorded visit andxa0≥ 6 months between diagnosis and data cutoff, were included. Only patients who received active treatment or best supportive care (BSC) per National Comprehensive Cancer Network (NCCN) AML Guidelines were analyzed.nnnRESULTSnOf 1139 patients meeting the inclusion criteria, 922 (median age 76 years) received NCCN-recommended treatments: standard induction (nxa0= 5), low-intensity therapy (nxa0= 425), BSC with hydroxyurea (HU) (nxa0= 36), or BSC without HU (nxa0= 455). For the low-intensity therapy cohort, median time from diagnosis to treatment initiation was 17 days; median duration of therapy was 5.1 months. Median overall survival (OS) from diagnosis in the low-intensity, BSC with HU, and BSC without HU groups was 12.3, 7.0, and 49.4 months, respectively. Median time to next therapy/death was 10.1 months in patients receiving low-intensity therapy. A higher proportion of patients receiving low-intensity therapy required transfusion or other supportive care versus those receiving BSC.nnnCONCLUSIONSnAs expected, OS in patients receiving low-intensity therapy or BSC with HU is poor for elderly patients with AML. Remarkably, intensive induction strategies are rarely used for older patients in community oncology practice.

Personalized medicine for acute myelogenous leukemia—At the entrance gate

With the advent of molecularly targeted therapies in the oncology clinic, previously fatal blood cancers have now become chronic diseases. Imatinib, a small molecule tyrosine kinase inhibitor that targets the BCR-ABL fusion protein, dramatically extends survival for patients with chronic myelogenous leukemia and has opened the flood gates for modern ‘‘personalized cancer medicine’’. Rituximab, a monoclonal antibody with affinity for the CD20 antigen of B-lymphocytes, in an analogous fashion has revolutionized treatment for patients with B-cell lymphomas. Does this paradigm, a rather commonplace approach for the treatment of hematologic malignancies, apply also to acute myelogenous leukemia (AML)? This is an exciting time to be involved in AML research, and an explosion of new basic science discoveries has formed a springboard for some brand new personalized treatment concepts that this commentary will serve to outline. Targeted Therapy

Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors

SummaryPurpose This phase Ib study (NCT01862328) evaluated the maximum tolerated dose (MTD), safety, and efficacy of pevonedistat in combination with standard-of-care chemotherapies in patients with solid tumors. Methods Patients received pevonedistat with docetaxel (arm 1, nxa0=u200922), carboplatin plus paclitaxel (arm 2, nxa0=u200926), or gemcitabine (arm 3, nxa0=u200910) in 21-days (arms 1 and 2) or 28-days (arm 3) cycles. A lead-in cohort (arm 2a, nxa0=u20096) determined the arm 2 carboplatin dose. Dose escalation proceeded via continual modified reassessment. Results Pevonedistat MTD was 25xa0mg/m2 (arm 1) or 20xa0mg/m2 (arm 2); arm 3 was discontinued due to poor tolerability. Fifteen (23%) patients experienced dose-limiting toxicities during cycle 1 (grade ≥3 liver enzyme elevations, febrile neutropenia, and thrombocytopenia), managed with dose holds or reductions. Drug-related adverse events (AEs) occurred in 95% of patients. Most common AEs included fatigue (56%) and nausea (50%). One drug-related death occurred in arm 3 (febrile neutropenia). Pevonedistat exposure increased when co-administered with carboplatin plus paclitaxel; no obvious changes were observed when co-administered with docetaxel or gemcitabine. Among 54 response-evaluable patients, two had complete responses (arm 2) and 10 had partial responses (three in arm 1, one in arm 2a, six in arm 2); overall response rates were 16% (arm 1) and 35% (arm 2). High ERCC1 expression correlated with clinical benefit in arm 2. Conclusion Pevonedistat with docetaxel or with carboplatin plus paclitaxel was tolerable without cumulative toxicity. Sustained clinical responses were observed in pretreated patients receiving pevonedistat with carboplatin and paclitaxel. ClinicalTrials.gov identifier: NCT01862328.

Abstract B148: Population pharmacokinetics (PK) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) administered alone or in combination with azacitidine in patients (pts) with solid or hematologic malignancies

Introduction: Pevonedistat is a first-in-class small molecule inhibitor of NAE that is currently in phase 1b clinical development across multiple solid tumors and in acute myeloid leukemia (AML). Here we report a population modeling analysis to describe pevonedistat IV PK in cancer pts and identify potential predictors of interpatient variability in pevonedistat exposures when given alone or combined with azacitidine. Methods: Plasma concentration-time data were analyzed using nonlinear mixed effects modeling (NONMEM 7.2). Two- and 3-compartment linear disposition with zero-order input models were tested. Subsequently, effects of selected demographic (age, sex, race, and body size) and physiologic (hepatic transaminases, bilirubin, blood parameters, and creatinine clearance [CRCL]) covariates were evaluated. First Order Conditional Estimation method with log transform-both-sides was used. Model goodness-of-fit and performance (visual predictive check and nonparametric bootstrapping) were also assessed. Results: A total of 250 pts (64% male; 80% white) from 5 completed or ongoing phase 1/1b dose-escalation clinical studies contributed 2882 observations. Of these, 42% were 65 yrs or older and 18% were 75 yrs or older. Half of pts had normal renal function, while 34% and 17% had mild (CRCL 60-89 mL/min) to moderate (CRCL 30-59 mL/min) renal impairment, respectively. Data were described by a 2-compartment PK model parameterized in terms of systemic clearance (CL), intercompartmental clearance (Q), and central (Vc) and peripheral (Vp) volumes of distribution with associated between-subject variability (BSV). Terms describing correlations between BSV for CL, Q, and Vp were included. Body size was described as an allometric function with the effect of body surface area (BSA, range 1.38-3.00 m2) on all parameters. Age (range 19-90 yrs) on CL was included as a power function normalized by the reference age of 65 yrs. Categorical covariates (sex and race) were modeled to estimate the proportional change in the typical value of the PK parameter. Consistent with observations of dose-proportional increases in pevonedistat exposures within each study, CL was constant across doses. Pevonedistat PK was unaffected after daily dosing with azacitidine in pts with AML. Final population mean parameter estimates (95% bootstrap confidence interval [CI]) were CL = 29.0 L/h (25.8, 32.7); Vc = 93.5 L (79.1, 110); Vp = 107 L (99.3, 115); and Q = 20.1 L/h (18.3, 22.2). Proportional residual variability was 28%. Upon exploration of patient-specific covariate effects, body size influenced CL (interindividual variability [IIV] ∼25% CV) and volume of distribution (IIV∼22% CV). Pevonedistat CL tended to gradually decrease with age (∼25% over the 30-90 yrs age range). There was no apparent effect of renal function status (CRCL >30 mL/min) on pevonedistat PK. Conclusions: The clinical PK profile of pevonedistat is comparable in pts with solid tumors, lymphomas, or AML. No changes were observed in the presence of azacitidine when compared to historical single-agent data. Elderly pts may have reduced pevonedistat CL; additional monitoring of these pts is recommended. Citation Format: Helene M. Faessel, Diane R. Mould, Bruce J. Dezube, Sergio Santillana, Karthik Venkatakrishnan. Population pharmacokinetics (PK) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) administered alone or in combination with azacitidine in patients (pts) with solid or hematologic malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B148.