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|Ref Type||Journal Article|
|Authors||Lockhart AC, Bauer TM, Aggarwal C, Lee CB, Harvey RD, Cohen RB, Sedarati F, Nip TK, Faessel H, Dash AB, Dezube BJ, Faller DV, Dowlati A|
|Title||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.|
|Journal||Investigational new drugs|
|Abstract Text||Purpose 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, n = 22), carboplatin plus paclitaxel (arm 2, n = 26), or gemcitabine (arm 3, n = 10) in 21-days (arms 1 and 2) or 28-days (arm 3) cycles. A lead-in cohort (arm 2a, n = 6) determined the arm 2 carboplatin dose. Dose escalation proceeded via continual modified reassessment. Results Pevonedistat MTD was 25 mg/m2 (arm 1) or 20 mg/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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|MLN4924||Pevonedistat||MLN-4924||Pevonedistat (MLN4924) binds and inhibits NEDD8, a ubiquitin-like protein, leading to inhibition of NFKB signaling, reduced transcription of target genes, and increased apoptosis in cancer cells with increased NFKB activity (PMID: 24634471, PMID: 29781056, PMID: 32721435).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||Docetaxel + MLN4924||Phase I||Actionable||In a Phase Ib trial, the combination therapy of Pevonedistat (MLN4924) and Taxotere (docetaxel) was well-tolerated and demonstrated safety in advanced solid tumor patients, and resulted in an overall response rate of 16% (3/19), including a partial response in a cholangiocarcinoma patient and in two patients with head and neck cancer (PMID: 29781056; NCT01862328).||29781056|
|Unknown unknown||Advanced Solid Tumor||not applicable||Carboplatin + MLN4924 + Paclitaxel||Phase I||Actionable||In a Phase Ib trial, the combination therapy of Pevonedistat (MLN4924), Taxol (paclitaxel), and Paraplatin (carboplatin) was well-tolerated and demonstrated safety in advanced solid tumor patients, and led to an overall response rate of 35% (8/23), including two complete responses and six partial responses, and a duration of response of 7.4 months (PMID: 29781056; NCT01862328).||29781056|