Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE)
Abstract Background Patients with advanced gastric cancer (AGC) have poor survival after first-line treatment containing an anti-programmed death-1/ligand 1 (PD-1/PD-L1) antibody. Accumulating evidence suggests rationales for continuing immunotherapy beyond progression, synergistic effects between i...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-02-01
|
| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-025-13591-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823862009074024448 |
|---|---|
| author | Hidekazu Hirano Naoki Takahashi Yusuke Amanuma Nobumi Suzuki Daisuke Takahari Takeshi Kawakami Chie Kudo-Saito Kengo Nagashima Narikazu Boku Ken Kato Hirokazu Shoji |
| author_facet | Hidekazu Hirano Naoki Takahashi Yusuke Amanuma Nobumi Suzuki Daisuke Takahari Takeshi Kawakami Chie Kudo-Saito Kengo Nagashima Narikazu Boku Ken Kato Hirokazu Shoji |
| author_sort | Hidekazu Hirano |
| collection | DOAJ |
| description | Abstract Background Patients with advanced gastric cancer (AGC) have poor survival after first-line treatment containing an anti-programmed death-1/ligand 1 (PD-1/PD-L1) antibody. Accumulating evidence suggests rationales for continuing immunotherapy beyond progression, synergistic effects between immune checkpoint inhibitors and angiogenesis inhibitors, and a preferable combination of steroid-free chemotherapy with immunotherapy. These rationales imply that nanoparticle albumin-bound (nab)-paclitaxel plus ramucirumab in combination with nivolumab (anti-PD-1 antibody) may enhance anti-tumor effects as second-line treatment. Therefore, we hypothesized that this triplet regimen may improve clinical outcomes in patients with AGC who experienced disease progression on first-line treatment including anti-PD-1/PD-L1 antibody. Methods The PADDLE trial, which is sponsored by Ono Pharmaceutical, is an investigator-initiated, multicenter, open-label, single-arm, prospective phase II trial conducted at six institutions in Japan. Key eligibility criteria are as follows: (1) advanced gastric or esophagogastric junction cancer, (2) histologically confirmed diagnosis of adenocarcinoma, (3) refractory to first-line treatment including fluoropyrimidines, platinum, and an anti-PD-1/PD-L1 antibody, (4) performance status of 0–1, and (5) at least one measurable lesion. Patients are to receive nab-paclitaxel (100 mg/m2 weekly, with a 1-week rest after 3 consecutive weeks), ramucirumab (8 mg/kg every 2 weeks), and nivolumab (240 mg/body every 2 weeks). The primary endpoint is 6-month progression-free survival (PFS) rate. The target number of patients was set at 45 based on threshold and expected 6-month PFS rates of 35% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.95. Secondary endpoints include objective response rate, disease control rate, PFS, overall survival, duration of response, time to response, and safety. Biomarker analyses of serial blood and tumor samples are planned to clarify predictive markers and molecular mechanisms underlying treatment resistance by multifaceted analytical methods (e.g., flow cytometry, DNA sequencing [DNAseq]/RNA sequencing [RNAseq]). Recruitment started in November 2022. Discussion The PADDLE trial is expected to clarify the efficacy of nab-paclitaxel plus ramucirumab in combination with nivolumab as second-line treatment in patients with AGC refractory to first-line treatment including an anti-PD-1/PD-L1 antibody and to identify potential biomarkers for predicting clinical responses in patients with AGC undergoing this triplet regimen. Trial registration jRCT2031220448 |
| format | Article |
| id | doaj-art-ddf305482ce843bb8eecad746c210735 |
| institution | Kabale University |
| issn | 1471-2407 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj-art-ddf305482ce843bb8eecad746c2107352025-02-09T12:41:39ZengBMCBMC Cancer1471-24072025-02-012511810.1186/s12885-025-13591-5Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE)Hidekazu Hirano0Naoki Takahashi1Yusuke Amanuma2Nobumi Suzuki3Daisuke Takahari4Takeshi Kawakami5Chie Kudo-Saito6Kengo Nagashima7Narikazu Boku8Ken Kato9Hirokazu Shoji10Department of Gastrointestinal Medical Oncology, National Cancer Center HospitalDepartment of Gastroenterology, Saitama Cancer CenterDepartment of Clinical Trial Promotion, Chiba Cancer CenterDepartment of Gastroenterology, Graduate School of Medicine, The University of TokyoDepartment of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer ResearchDivision of Gastrointestinal Oncology, Shizuoka Cancer CenterDepartment of Immune Medicine, National Cancer Center Research InstituteBiostatistics Unit, Clinical and Translational Research Center, Keio University HospitalDepartment of Gastroenterology, Graduate School of Medicine, The University of TokyoDepartment of Gastrointestinal Medical Oncology, National Cancer Center HospitalDepartment of Gastrointestinal Medical Oncology, National Cancer Center HospitalAbstract Background Patients with advanced gastric cancer (AGC) have poor survival after first-line treatment containing an anti-programmed death-1/ligand 1 (PD-1/PD-L1) antibody. Accumulating evidence suggests rationales for continuing immunotherapy beyond progression, synergistic effects between immune checkpoint inhibitors and angiogenesis inhibitors, and a preferable combination of steroid-free chemotherapy with immunotherapy. These rationales imply that nanoparticle albumin-bound (nab)-paclitaxel plus ramucirumab in combination with nivolumab (anti-PD-1 antibody) may enhance anti-tumor effects as second-line treatment. Therefore, we hypothesized that this triplet regimen may improve clinical outcomes in patients with AGC who experienced disease progression on first-line treatment including anti-PD-1/PD-L1 antibody. Methods The PADDLE trial, which is sponsored by Ono Pharmaceutical, is an investigator-initiated, multicenter, open-label, single-arm, prospective phase II trial conducted at six institutions in Japan. Key eligibility criteria are as follows: (1) advanced gastric or esophagogastric junction cancer, (2) histologically confirmed diagnosis of adenocarcinoma, (3) refractory to first-line treatment including fluoropyrimidines, platinum, and an anti-PD-1/PD-L1 antibody, (4) performance status of 0–1, and (5) at least one measurable lesion. Patients are to receive nab-paclitaxel (100 mg/m2 weekly, with a 1-week rest after 3 consecutive weeks), ramucirumab (8 mg/kg every 2 weeks), and nivolumab (240 mg/body every 2 weeks). The primary endpoint is 6-month progression-free survival (PFS) rate. The target number of patients was set at 45 based on threshold and expected 6-month PFS rates of 35% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.95. Secondary endpoints include objective response rate, disease control rate, PFS, overall survival, duration of response, time to response, and safety. Biomarker analyses of serial blood and tumor samples are planned to clarify predictive markers and molecular mechanisms underlying treatment resistance by multifaceted analytical methods (e.g., flow cytometry, DNA sequencing [DNAseq]/RNA sequencing [RNAseq]). Recruitment started in November 2022. Discussion The PADDLE trial is expected to clarify the efficacy of nab-paclitaxel plus ramucirumab in combination with nivolumab as second-line treatment in patients with AGC refractory to first-line treatment including an anti-PD-1/PD-L1 antibody and to identify potential biomarkers for predicting clinical responses in patients with AGC undergoing this triplet regimen. Trial registration jRCT2031220448https://doi.org/10.1186/s12885-025-13591-5Gastric cancerNanoparticle albumin-bound paclitaxelRamucirumabNivolumabImmunotherapy beyond progression |
| spellingShingle | Hidekazu Hirano Naoki Takahashi Yusuke Amanuma Nobumi Suzuki Daisuke Takahari Takeshi Kawakami Chie Kudo-Saito Kengo Nagashima Narikazu Boku Ken Kato Hirokazu Shoji Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE) BMC Cancer Gastric cancer Nanoparticle albumin-bound paclitaxel Ramucirumab Nivolumab Immunotherapy beyond progression |
| title | Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE) |
| title_full | Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE) |
| title_fullStr | Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE) |
| title_full_unstemmed | Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE) |
| title_short | Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE) |
| title_sort | phase ii trial of nab paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first line treatment including fluoropyrimidine platinum and anti pd 1 pd l1 antibody paddle |
| topic | Gastric cancer Nanoparticle albumin-bound paclitaxel Ramucirumab Nivolumab Immunotherapy beyond progression |
| url | https://doi.org/10.1186/s12885-025-13591-5 |
| work_keys_str_mv | AT hidekazuhirano phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle AT naokitakahashi phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle AT yusukeamanuma phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle AT nobumisuzuki phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle AT daisuketakahari phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle AT takeshikawakami phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle AT chiekudosaito phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle AT kengonagashima phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle AT narikazuboku phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle AT kenkato phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle AT hirokazushoji phaseiitrialofnabpaclitaxelplusramucirumabincombinationwithnivolumabforunresectableadvancedorrecurrentgastriccancerafterprogressiononfirstlinetreatmentincludingfluoropyrimidineplatinumandantipd1pdl1antibodypaddle |