Phase I Trial of Upamostat Combined With Gemcitabine in Locally Unresectable or Metastatic Pancreatic Cancer: Safety and Preliminary Efficacy Assessment
ABSTRACT Aim This study aimed to determine the maximum tolerated dose (MTD) of the urokinase plasminogen activator (uPA) inhibitor upamostat (LH011) in combination with gemcitabine for locally advanced unresectable or metastatic pancreatic cancer. Method Seventeen patients were enrolled and received...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.70550 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841543409958912000 |
|---|---|
| author | Xiuping Lai Di Cheng Huixin Xu Jingshu Wang Xiaozhi Lv Herui Yao Liuning Li Junyan Wu Suiwen Ye Zhihua Li |
| author_facet | Xiuping Lai Di Cheng Huixin Xu Jingshu Wang Xiaozhi Lv Herui Yao Liuning Li Junyan Wu Suiwen Ye Zhihua Li |
| author_sort | Xiuping Lai |
| collection | DOAJ |
| description | ABSTRACT Aim This study aimed to determine the maximum tolerated dose (MTD) of the urokinase plasminogen activator (uPA) inhibitor upamostat (LH011) in combination with gemcitabine for locally advanced unresectable or metastatic pancreatic cancer. Method Seventeen patients were enrolled and received escalating doses of oral LH011 (100, 200, 400, or 600 mg) daily alongside 1000 mg/m2 of gemcitabine. Safety profiles, tumor response (including response rate and progression‐free survival), pharmacokinetics, and changes in CA199 and D‐dimer levels were assessed. Results During the study period (Day0–Day49), no patients achieved partial response. Stable disease (SD) was observed in 12 patients (70.6%), while four patients (23.5%) experienced progressive disease (PD). One patient withdrew due to a serious adverse event (SAE) on D47. Pharmacokinetic analysis revealed a dose‐related increase in LH011 and its metabolite WX‐UK1 exposure from 100 to 400 mg but not in the 600 mg group. Hematological toxicity, mainly attributable to gemcitabine, was the predominant grade 3 or 4 adverse event, with additional occurrences of loss of appetite, rash, and interstitial lung disease. Sinus bradycardia possibly linked to LH011 rather than gemcitabine was noted. The MTD was not reached. Conclusion Combining LH011 at doses ranging from 100 to 600 mg with gemcitabine every 21 days demonstrated manageable safety and tolerability. However, tumor response did not significantly differ among the dose groups, suggesting the need for further investigation. Trial Registration NCT05329597 |
| format | Article |
| id | doaj-art-7766d559f7994992b559e970649f518d |
| institution | Kabale University |
| issn | 2045-7634 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-7766d559f7994992b559e970649f518d2025-01-13T13:22:38ZengWileyCancer Medicine2045-76342025-01-01141n/an/a10.1002/cam4.70550Phase I Trial of Upamostat Combined With Gemcitabine in Locally Unresectable or Metastatic Pancreatic Cancer: Safety and Preliminary Efficacy AssessmentXiuping Lai0Di Cheng1Huixin Xu2Jingshu Wang3Xiaozhi Lv4Herui Yao5Liuning Li6Junyan Wu7Suiwen Ye8Zhihua Li9Phase I Clinical Trial Center Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University Guangzhou ChinaDepartment of Medical Oncology Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University Guangzhou ChinaDepartment of Medical Oncology Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University Guangzhou ChinaDepartment of Medical Oncology Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University Guangzhou ChinaPhase I Clinical Trial Center Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University Guangzhou ChinaPhase I Clinical Trial Center Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University Guangzhou ChinaDepartment of Medical Oncology GuangDong Province Hospital of Chinese Medicine, the Second Clinical Medical Collage, University of Guangzhou Traditional Chinese Medicine Guangzhou ChinaPhase I Clinical Trial Center Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University Guangzhou ChinaPhase I Clinical Trial Center Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University Guangzhou ChinaDepartment of Medical Oncology Sun Yat‐sen Memorial Hospital, Sun Yat‐sen University Guangzhou ChinaABSTRACT Aim This study aimed to determine the maximum tolerated dose (MTD) of the urokinase plasminogen activator (uPA) inhibitor upamostat (LH011) in combination with gemcitabine for locally advanced unresectable or metastatic pancreatic cancer. Method Seventeen patients were enrolled and received escalating doses of oral LH011 (100, 200, 400, or 600 mg) daily alongside 1000 mg/m2 of gemcitabine. Safety profiles, tumor response (including response rate and progression‐free survival), pharmacokinetics, and changes in CA199 and D‐dimer levels were assessed. Results During the study period (Day0–Day49), no patients achieved partial response. Stable disease (SD) was observed in 12 patients (70.6%), while four patients (23.5%) experienced progressive disease (PD). One patient withdrew due to a serious adverse event (SAE) on D47. Pharmacokinetic analysis revealed a dose‐related increase in LH011 and its metabolite WX‐UK1 exposure from 100 to 400 mg but not in the 600 mg group. Hematological toxicity, mainly attributable to gemcitabine, was the predominant grade 3 or 4 adverse event, with additional occurrences of loss of appetite, rash, and interstitial lung disease. Sinus bradycardia possibly linked to LH011 rather than gemcitabine was noted. The MTD was not reached. Conclusion Combining LH011 at doses ranging from 100 to 600 mg with gemcitabine every 21 days demonstrated manageable safety and tolerability. However, tumor response did not significantly differ among the dose groups, suggesting the need for further investigation. Trial Registration NCT05329597https://doi.org/10.1002/cam4.70550LH011maximum tolerated dosepancreatic cancerupamostaturokinase inhibitor |
| spellingShingle | Xiuping Lai Di Cheng Huixin Xu Jingshu Wang Xiaozhi Lv Herui Yao Liuning Li Junyan Wu Suiwen Ye Zhihua Li Phase I Trial of Upamostat Combined With Gemcitabine in Locally Unresectable or Metastatic Pancreatic Cancer: Safety and Preliminary Efficacy Assessment Cancer Medicine LH011 maximum tolerated dose pancreatic cancer upamostat urokinase inhibitor |
| title | Phase I Trial of Upamostat Combined With Gemcitabine in Locally Unresectable or Metastatic Pancreatic Cancer: Safety and Preliminary Efficacy Assessment |
| title_full | Phase I Trial of Upamostat Combined With Gemcitabine in Locally Unresectable or Metastatic Pancreatic Cancer: Safety and Preliminary Efficacy Assessment |
| title_fullStr | Phase I Trial of Upamostat Combined With Gemcitabine in Locally Unresectable or Metastatic Pancreatic Cancer: Safety and Preliminary Efficacy Assessment |
| title_full_unstemmed | Phase I Trial of Upamostat Combined With Gemcitabine in Locally Unresectable or Metastatic Pancreatic Cancer: Safety and Preliminary Efficacy Assessment |
| title_short | Phase I Trial of Upamostat Combined With Gemcitabine in Locally Unresectable or Metastatic Pancreatic Cancer: Safety and Preliminary Efficacy Assessment |
| title_sort | phase i trial of upamostat combined with gemcitabine in locally unresectable or metastatic pancreatic cancer safety and preliminary efficacy assessment |
| topic | LH011 maximum tolerated dose pancreatic cancer upamostat urokinase inhibitor |
| url | https://doi.org/10.1002/cam4.70550 |
| work_keys_str_mv | AT xiupinglai phaseitrialofupamostatcombinedwithgemcitabineinlocallyunresectableormetastaticpancreaticcancersafetyandpreliminaryefficacyassessment AT dicheng phaseitrialofupamostatcombinedwithgemcitabineinlocallyunresectableormetastaticpancreaticcancersafetyandpreliminaryefficacyassessment AT huixinxu phaseitrialofupamostatcombinedwithgemcitabineinlocallyunresectableormetastaticpancreaticcancersafetyandpreliminaryefficacyassessment AT jingshuwang phaseitrialofupamostatcombinedwithgemcitabineinlocallyunresectableormetastaticpancreaticcancersafetyandpreliminaryefficacyassessment AT xiaozhilv phaseitrialofupamostatcombinedwithgemcitabineinlocallyunresectableormetastaticpancreaticcancersafetyandpreliminaryefficacyassessment AT heruiyao phaseitrialofupamostatcombinedwithgemcitabineinlocallyunresectableormetastaticpancreaticcancersafetyandpreliminaryefficacyassessment AT liuningli phaseitrialofupamostatcombinedwithgemcitabineinlocallyunresectableormetastaticpancreaticcancersafetyandpreliminaryefficacyassessment AT junyanwu phaseitrialofupamostatcombinedwithgemcitabineinlocallyunresectableormetastaticpancreaticcancersafetyandpreliminaryefficacyassessment AT suiwenye phaseitrialofupamostatcombinedwithgemcitabineinlocallyunresectableormetastaticpancreaticcancersafetyandpreliminaryefficacyassessment AT zhihuali phaseitrialofupamostatcombinedwithgemcitabineinlocallyunresectableormetastaticpancreaticcancersafetyandpreliminaryefficacyassessment |