ALBERT

Description: Background Pevonedistat is the first small-molecule inhibitor of neural precursor cell expressed, developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE). Inhibiting NAE blocks ubiquitination of select proteins upstream of the proteasome. Treatment with pevonedistat disrupts cell cycle progression and cell survival, leading to cell death in cancers, including myeloid malignancies. In a phase 1b study in patients aged ≥60 yrs with untreated AML, pevonedistat in combination with azacitidine (AZA) was tolerable and showed clinical activity (Swords et al. Blood 2018). In a randomized phase 2 study of pevonedistat + AZA vs AZA alone in patients with higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia and low-blast AML, pevonedistat + AZA improved event-free survival (EFS) and overall survival (OS), had a similar safety profile to AZA alone, did not increase myelosuppression, and maintained AZA dose intensity (Adès et al. ASCO 2020). Venetoclax (VEN) is a small-molecule inhibitor of B-cell lymphoma 2 that is approved in the United States in combination with low-dose cytarabine or hypomethylating agents for the treatment of patients with AML. VEN + AZA has been shown to improve OS vs AZA alone, and the combination is emerging as a standard of care for older patients with newly diagnosed AML who are unfit for standard intensive chemotherapy. Despite recent advances, outcomes for these patients remain poor; novel therapies that increase duration of response (DOR) or reduce relapse rates are needed. Pevonedistat in combination with VEN has shown synergistic cytotoxic effects in AML cell lines and primary clinical AML samples (Knorr et al. Cell Death Differ 2015). This is likely mediated through pevonedistat-induced neutralization of prosurvival proteins including myeloid leukemia cell differentiation protein (MCL-1). Upregulation of MCL-1 is thought to be a primary mode of resistance to VEN. Therefore, treatment with pevonedistat + VEN may help to prevent or overcome resistance to VEN and prolong DOR. The reported clinical benefit of both pevonedistat + AZA and VEN + AZA in AML, and preclinical evidence of synergy between pevonedistat and VEN, suggest that combination treatment with all 3 therapies may result in improved outcomes compared with VEN + AZA in patients with newly diagnosed AML who are unfit for intensive chemotherapy. A phase 1/2 study of the triplet combination of pevonedistat, VEN, and AZA in secondary AML established the recommended phase 2 dose and demonstrated a high response rate in this relatively refractory population (Short et al. EHA 2020). Methods NCT04266795 is a randomized, open-label, controlled, phase 2 study (Figure) that is being conducted across ~85 sites globally. Eligible patients are those aged ≥18 yrs with morphologically confirmed newly diagnosed AML (World Health Organization criteria 2008) and considered unfit for treatment with cytarabine and anthracycline induction due to age and/or comorbidities. Patients are being randomized 1:1 to receive the combination of pevonedistat 20 mg/m2 intravenously (IV) on days 1, 3, and 5, VEN 400 mg by mouth on days 1-28 in cycle 1 (ramp up schedule of 100 mg on day 1, 200 mg on day 2, 400 mg on days 3-28) and then on days 1-28 (days 1-21 if remission is confirmed; can return to 28-day dosing if well tolerated) in cycle 2 onwards, and AZA 75 mg/m2 (IV or subcutaneously) on days 1-7 or 1-5, 8, and 9, or VEN + AZA, in 28-day cycles until unacceptable toxicity, relapse, or progressive disease. Randomization is stratified by age (18-

Description: BACKGROUND: EBV-positive (EBV+) lymphomas including Hodgkin, B and T cell lymphomas, are generally associated with poor clinical outcomes, particularly for patients (pts) who have relapsed or are refractory (R/R) to standard therapies. There are currently no approved therapies for EBV+ lymphomas and with the exception of adoptive T-cell therapies, no EBV-targeted anti-lymphoma therapeutics are in development. EBV is detectable in cancer cells by in situ hybridization for EBV-encoded RNAs (EBER-ISH). Nstat (VRx-3996), a Class I-selective oral hydroxamate histone deacetylase (HDAC) inhibitor active against HDAC1-3, induces the expression of EBV protein kinases which activate the anti-viral nucleoside analogue VGCV via mono-phosphorylation. This leads to inhibition of both viral and cellular DNA synthesis in EBV+ tumor cells and potentially in surrounding EBV- tumor cells as well (bystander effect), causing apoptosis. This trial is the first to explore the safety and clinical activity of this targeted approach using oral Nstat in combination with oral VGCV in pts with R/R EBV+ lymphomas. Here we present an update of safety and efficacy for all enrolled patients, plus the preliminary safety of the recommended phase 2 doses (RP2D) of Nstat and VGCV (NCT03397706). METHODS: Pts with biopsy-proven EBV+ lymphomas (by EBER-ISH; any positive tumor cell) that had failed ≥1 prior systemic therapy and lacked treatment options by investigator's judgment were eligible for enrollment. Phase 1b used a 3x3 design to determine the RP2D of Nstat + VGCV. Phase 2 pts received the RP2D (Nstat 20 mg days (d) 1-4/7 + VGCV 900 mg orally daily in 28 d cycles) until PD or withdrawal. Primary endpoints were safety/RP2D selection (phase 1b) and ORR (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response (TTR), progression free survival (PFS) and overall survival (OS). Response assessments began after Cycle 2 using Lugano 2014 response criteria. RESULTS: As of 5 July 2020, 43 pts have enrolled (phase 1b: 25; phase 2: 18). Lymphoma subtypes were diffuse large B cell (DLBCL) (6), extranodal NK/T-cell (ENKTL) (6), peripheral T cell, NOS (PTCL-NOS) (3), angioimmunoblastic (AITL) (4), cutaneous T cell (CTCL) (1), Hodgkin (HL) (8), other B cell (2), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (13), including post-transplant lymphoproliferative disorder (PTLD) (4), HIV-associated (5), and other [4: systemic lupus erythematosus (SLE) (2), common variable immunodeficiency/primary immunodeficiency (2)]. Pts had a median of 2 prior therapies (range 1-11); 77% with ≥2 prior therapies, 86% were refractory to their most recent previous therapy and 77% had exhausted standard therapies in the judgment of the investigator. EBER positivity ranged from

Description: Introduction P-2001, a randomized phase 2 trial (NCT02610777), investigated the efficacy and safety of pevonedistat (P), the first small-molecule inhibitor of the NEDD8-activating enzyme, in combination with azacitidine (A) versus A alone in patients (pts) with higher-risk (Revised International Prognostic Scoring System risk 〉3, including intermediate [≥5% blasts], high, or very high risk) myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myeloid leukemia (LB AML) naïve to hypomethylating agents. The P-2001 trial recently demonstrated median event-free survival of 21.0 vs 16.6 months (HR=0.665; P = .076), and overall response rates (complete remission [CR] + CR with incomplete blood count recovery [CRi] + partial response [PR] + hematologic improvement [HI]) of 71% (n=39/55) vs 60% (n=32/53) with P+A compared with A, respectively. Management of MDS can significantly impact quality of life, and measures of high-symptom burden have been associated with worse clinical outcomes. We set out to explore patient-reported outcomes (PRO) as an exploratory endpoint in the study. Methods The study randomized 120 pts (1:1) to receive P+A or A alone in 28-day treatment cycles. The European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire - core 30 items (QLQ-C30) was administered at the first day of each cycle, at the end of treatment (EOT) visit and post-EOT visits. Physical functioning (PF), fatigue (FA), dyspnea (DY) and global health status/quality of life (QL) were identified as key PRO concepts that deserved specific attention in this population. Analyses were carried out to explore the PRO data: description of available PRO data, longitudinal analyses of change in the key PRO scores with repeated measurement mixed models (RMMM), including comparison between treatment arms, and descriptive analysis of the key PRO scores after clinical response depending on the type of response (PR, CR, CRi, or HI), and before and after transformation to AML for pts with higher-risk MDS, independently from the treatment received. Results There were 112 pts in the PRO population (defined as all pts with a PRO assessment at baseline and at least 1 post-baseline); baseline demographics and disease characteristics are presented in Table 1. At least 90% of pts in the study had a PRO available at each cycle. As expected, the amount of available PRO data decreased over the study due to progression, death, or study discontinuations. The RMMMs of the PRO population did not show any statistically significant difference in the change over time in key QLQ-C30 scores (PF, QL, FA, and DY) between P+A versus A alone. Pts who experienced CR (P+A, 40%; A, 29%) showed a nonsignificant improvement in PF and QL, as well as a nonsignificant decrease of FA after CR than at baseline; no differences were noted in DY. Pts for whom best response was PR had less improvement in the key PROs than pts with CR, and those with HI did not show improvement compared with baseline. Among the 12 pts with higher-risk MDS/CMML progressing to AML during the study with available PRO data (P+A, n=4; A, n=8), 6 showed worsening in PF score (vs 2 improving), 6 showed worsening in QL score (vs 1 improving), 7 showed worsening in FA score (vs 1 improving), and 7 showed worsening in DY score (vs none improving). Conclusions Measurement of QL and symptom burden are integral clinical endpoints in assessing new treatments in higher-risk MDS/CMML and LB AML. There was no evidence to suggest that the addition of P to A led to change in the key PROs identified: QL, PF, FA and DY. Achievement of CR was associated with higher PRO scores compared with baseline independently of the treatment received, and progression to AML was associated with worsening QL scores. Additional analyses are planned with the P-2001 PRO data to further explore the impact of P on PROs by evaluating the impact of dropout during the study, comparing findings according to treatment arm, and better understanding the possible effect of adverse events on PROs. Disclosures Zeidner: AbbVie: Honoraria, Other: Independent Review Committee; Agios: Honoraria; AROG: Research Funding; AsystBio Laboratories: Consultancy; Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Genentech: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Forty-Seven: Other: Travel Reimbursement, Research Funding; Merck: Research Funding; Pfizer: Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Reimbursement, Research Funding. Mazerolle:Takeda Pharmaceutical Company: Other: Granted research funding to Modus Outcomes, my employer; Modus Outcomes: Current Employment. Bell:Millennium Pharmaceuticals, Inc.: Current Employment. Cain:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Faller:Phoenicia Biosciences: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Viracta Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment; Briacell Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Dalal:Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmaceutical International Company, Cambridge, MA: Current Employment, Current equity holder in private company. Regnault:Modus Outcomes: Current Employment. Fram:Teva: Current equity holder in publicly-traded company; Baxter: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company; Takeda: Current equity holder in publicly-traded company; Vertex Phamaceuticals: Patents & Royalties: Patent 10/728,114; Takeda Pharmaceuticals Intl. Co.: Consultancy, Current Employment; BeyondSpring Pharmaceuticals Inc.: Consultancy. OffLabel Disclosure: Pevonedistat is the first small molecule inhibitor of the neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme (NAE)

Description: SummaryPevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366.