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. 2018 Mar 13;5:19. doi: 10.3389/fmolb.2018.00019

Table 2.

A non-exhaustive list of clinical studies targeting cullin-RING ubiquitin E3 ligases.

Condition Drug(s) Measurements Phase References or ClinicalTrials.gov identifier
Advanced solid tumors, neoplasms (14C)-Pevonedistat

  1. cumulative excretion of radioactive Pevonedistat in urine and feces/Circulatory and excretory pevonedistat metabolites

  2. Report of TEAEs and SAEs

 I NCT03057366
Recurrent AML, therapy-induced AML, untreated or recurrent AML Pevonedistat plus Decitabine

  1. Safety and tolerability of Pevonedistat added to Decitabine

  2. MTD of pevonedistat in combination to Decitabine

  3. mIR-155 expression, promoter methylation, and mIR-155 target gene expression (SHIP1/PU.1)

  4. NF-kappaB expression and enrichment on mIR-155 promoter

 I NCT03009240
Metastatic melanoma Pevonedistat

  1. MTD of 209 mg/m2

  2. Clinical activity: 3% PR, 48% SD

  3. Pevonedistat plasma concentration increased approximately proportionally with dose from 50 to 278 mg/m2 after Day 1 intravenous infusion

 I NCT01011530 (*) (Bhatia et al., 2016)
Solid tumors

  1. MLN4924 plus Docetaxel

  2. 2.]MLN4924 plus Docetaxel plus Carboplatin

  3. MLN4924 plus Gemcitabine

  1. Number of adverse events

  2. Time course MLN4924 plasma concentration

 I NCT01862328
Advanced solid tumors MLN4924 (schedules A and C) MLN4924 + Dexamethasone (Schedule B)

  1. MTD of 50 mg/m2 (schedule A) 50 and 67 mg/m2 (schedule B and C, respectively)

  2. 11/13 patients with > 20% increase in CDT1 and NRF2 CRLs substrates

  3. 13/14 patients show NEDD8 adducts in tumor biopsies

  4. Clinical activity: 74% SD for schedules B and C

 I NCT00677170 (*) (Sarantopoulos et al., 2016)
AML MLN4924 plus Azacitidine

  1. Safety and tolerability of MLN4924 in combination with Azacitidine

  2. Disease response rate

  3. 30-day and 60-day mortality rate

 I NCT01814826
Advanced solid tumors MLN4924 Fluconazole Itraconazole Docetaxel Carboplatin Paclitaxel

  1. TEAEs and disease response

  2. MLN4924 plasma concentration, blood to plasma ratio. MLN4924 clearance

  3. Clinical response

 I NCT02122770
AML, ALL, MDS MLN4924 Intravenous infusion on days 1, 3, and 5 (schedule A) and 1, 4, 8, and 11 (schedule B)

  1. MTD of 59 (Schedule A) and 83 mg/m2 (Schedule B)

  2. Clinical activity: 17% CR/PR (schedule A); 10% CR/PR (schedule B)

  3. 32/35 patients with NEDD8 adduct in tumor biopsies

  4. Pevonedistat increased within 4–8 h after infusion and returned to baseline within 24 h

 I NCT00911066 (*) (Swords et al., 2015)
Leukemia, MDS, Myeloid, Acute

  1. Pevonedistat

  2. Pevonedistat plus Azacitidine

  1. TEAEs and dose limiting toxicities

  2. Overall and complete responses

  3. Pevonedistat plasma concentration and clearance

 I NCT02782468
Relapsed/refractory multiple Myeloma or lymphoma MLN4924 Intravenous infusion on Week 1, 2, 8, and 9 (schedule A) and 1, 4, 8, and 11 (schedule B)

  1. MTD of 110 mg/m2 (schedule A) and 196 mg/m2 (schedule B)

  2. 11/13 patients with NEDD8 adducts in bone marrow aspirates

  3. CDT1 and NRF2 skin and NRF2 mRNA in blood increased in treated patients

  4. Clinical activity: 1 patient with PR and 71% SD

 I NCT00722488 (*) (Shah et al., 2016)
Multiple myeloma Non-Hodgkin lymphoma TAS4464

  1. Investigate the safety and tolerability of TAS4464; identify TAS4464 MTD

  2. Efficacy of TAS4464, defined as Objective Response Rate (ORR) per IWG criteria (NHL) and IMWG criteria (MM).

 I II NCT02978235
MDS leukemia, CML

  1. Azacitidine

  2. Azacitidine plus Pevonedistat

  1. EVF

  2. OS

 II NCT02610777
Non-small cell lung cancer Pevonedistat plus Docetaxel

  1. Response to treatment

  2. Median progression free survival time, OS time, and patients who achieve stable disease

  3. Toxicities by system organ class

 II NCT03228186
MDS leukemia, CML, AML

  1. Azacytidine

  2. Azacytidine plus Pevonedistat

  1. EVF, OS, partial remission

  2. overall response. 6 months and 1 year survival rate

 II NCT02610777
MDS leukemia, CML

  1. Azacitidine

  2. Azacitidine plus Pevonedistat

  1. Overall response and EVF

  2. OS

  3. Pevonedistat plasma concentration

  4. EVF and OS in participants with TP53 mutations or any adverse cytogenetic risk group

 III NCT03268954

EVF, Event-Free Survival; OS, Overall Survival; AML, Acute Myeloid Leukemia; CML, Chronic Myelomonocytic Leukemia. TEAEs, Treatment Emergent Adverse Events; SAEs, Serious Adverse Events; MDS, Myelodysplastic Syndrome; MTD, maximum tolerated dose. CR, complete response; PR, partial response; SD, Stable diseases.

(*)

Study completed.