1537P - A phase I study of pevonedistat plus capeOX in patients with advanced gastric cancer refractory to platinum (NCCH-1811)

Background

Pevonedistat (MLN4924/TAK924), which is an inhibitor of NEDD8 (neural precursor cell expressed developmentally down-regulated protein 8)-activating enzyme (NAE), shows synergistic effects with platinum, suggesting possibility of conquest over platinum-resistance, in preclinical studies. This phase I study was conducted to determine the recommended dose (RD) of pevonedistat in combination with capecitabine plus oxaliplatin (CapeOX) and explore its efficacy and safety as third- or later line treatment in patients (pts) with unresectable advanced gastric cancer (AGC).

Methods

This study consisted of two parts: the dose-finding part, and the expansion part at the RD. In both parts, treatment was started as monotherapy with pevonedistat for a week (Lead-in) and followed by 3-drug combination in a 3-week cycle: Capecitabine (1000 mg/m2/day, twice daily, for 14 days), oxaliplatin (130 mg/m2 on day 1) and pevonedistat (20 mg/m2 in level 1, 15 mg/m2 in level 0, on days 1, 3, and 5). Pharmacokinetics (PK) of pevonedistat was compared between its mono and combination therapy. Translational research for pharmacodynamics and genetic biomarkers were performed.

Results

Between April 2019 and September 2021, 12 pts having prior chemotherapy containing fluoropyrimidine plus platinum were enrolled. The initial 2 pts in the level 1 experienced DLTs (grade 3 elevation in ALT and AST, delay of starting cycle 2). After confirming that six pts in the level 0 showed no DLTs, 4 pts were added in the expansion part. Grade3 AEs included AST increased (25%), ALT increased (17%), and platelet count decreased (17%). No obvious difference in the PK of pevonedistat was observed when combined with CapeOX. Two (17%) and 8 (75%) pts achieved partial response and disease control. The median overall and progression-free survival were 9.3 and 4.4 months. Inhibition of NAE by pevonedistat was confirmed in all patients by positive Cdt1 expression in the post-treatment biopsy. No genetic alterations associated with efficacy were identified.

Conclusions

Pevonedistat plus CapeOX was well tolerated and showed promising efficacy in AGC pts previously treated with platinum containing chemotherapy.

Clinical trial identification

jRCT2031190020.

Editorial acknowledgement

Legal entity responsible for the study

H. Shoji.

Funding

Takeda.

Disclosure

H. Shoji: Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co., Ltd., Zymeworks Inc.; Financial Interests, Institutional, Local PI: Ono Pharmaceutical Co., Ltd., MSD, Astellas, Amgen, Daiichi Sankyo; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co., Ltd., Takeda Pharmaceuticals. H. Hirano: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Ono Pharmaceutical, Teijin Pharma, Novartis; Financial Interests, Personal, Writing Engagement: Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Ono Pharmaceutical, Janssen Pharmaceutical, Merck Biopharma, Bristol Myers Squibb, Pfizer, Eisai, Amgen, Astellas, Seagen, MSD, Incyte, BeiGene, Novartis. K. Yamaguchi: Financial Interests, Personal, Invited Speaker: Taiho Pharm; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Bristol Myers Squibb, Ono Pharm, Eli Lilly Japan; Financial Interests, Institutional, Funding: Taiho. K. Kato: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical, Bristol Myers Squibb, Merck and Co; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical, Bristol Myers Squibb, Merck and Co, Bayer, AstraZeneca, BeiGene, Taiho, Merck Biopharma, Amgen, Novartis, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Ono Pharmaceuticals, Merck & Co; Financial Interests, Institutional, Local PI: Bayer, AstraZeneca, BeiGene, Chugai, Taiho, Oncolys Biopharma, Janssen Pharmaceutical. N. Boku: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Eli Lilly, Ono Pharmaceutical, Taiho, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical, Ono Pharmaceutical. All other authors have declared no conflicts of interest.