A phase I trial of gemcitabine, S-1 and LV combination (GSL) therapy in advanced pancreatic cancer

14047 Background: While gemcitabine (GEM) is the standard drug for chemotherapy against advanced pancreatic cancer, the development of multidrug therapies for improved outcome is important. We conducted multicentric combined chemotherapy with GEM and S-1 and report the results of the phase I trial. Methods: The subjects had unresectable pancreatic ductal cancer. The method of administration was single administration of GEM on the first day of the week from Level 1 to Level 4 at 400 to 1000 mg/m2, with concurrent administration of S-1 at 40 to 100 mg/day × 7 days, repeated every other week as a collaborative trial conducted at 3 facilities. The purpose was to determine the optimal dose with adverse events as an indicator. Results: Eighteen patients were enrolled (3 each at Levels 1, 2, 3 and 4’, 6 at Level 4). Average age was 60.9 years (38 - 71 years). There was no dose limiting toxicity (DLT) up to Level 3. Level 4 was the maximum tolerated dose since DLT was observed in 4/6 patients (mucositis 2, rash 1, anorexia 1), and no DLT was observed in 3 additional patients at Level 4’. The resulting recommended dose was Level 4 (GEM 1000 mg/m2, S-1 100 mg/day). For reference, partial response was observed in 5 patients, and median survival time at this stage is 336±39 days. Conclusions: The recommended dosage of GEM + S-1 combined chemotherapy for unresectable advanced pancreatic cancer was determined in a phase I trial. We intend to proceed to a phase II trial. No significant financial relationships to disclose.

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Tolerability and safety of a replication-competent adenovirus-mediated double suicide gene therapy (Ad5-yCD/mutTK(SR39)rep-ADP) with chemotherapy in locally advanced pancreatic cancer: Phase 1 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15761 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15761-e15761

Author(s):

Jong-Chan Lee ◽

Dong Woo Shin ◽

Se Yeol Yang ◽

Min Jae Kim ◽

Jae Hyup Jung ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Trial ◽

Gene Therapy ◽

Phase I ◽

Phase I Trial ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Suicide Gene ◽

Evaluation Period ◽

Double Suicide

e15761 Background: Up to 35% of pancreatic cancers are considered ‘locally advanced’ (LAPC) at the time of diagnosis. Replication-competent adenovirus-mediated double suicide gene therapy (Ad5-yCD/mutTK(SR39)rep-ADP) showed an anti-cancer effect in prostatic cancer patients in previous studies. We aimed to investigate tolerability and safety of Ad5-yCD/mutTK(SR39)rep-ADP in combination with gemcitabine in patients with LAPC. Methods: In this single-center, open label, dose-escalation phase I trial, we recruited adult patients (≥18 years) with newly diagnosed LAPC. Patients with histologically confirmed pancreatic ductal adenocarcinoma with good performance were enrolled. We injected Ad5-yCD/mutTK(SR39)rep-ADP into pancreatic mass with EUS-FNB needle in combination with oral 5-fluorocytosine 500mg qd, oral valgancyclovir 450mg qd, and standard gemcitabine (1000mg/m2, day 1-8-15 infusion every 4 weeks). In the three-stage dose-escalation scheme with traditional 3+3 design, the dose of Ad5-yCD/mutTK(SR39)rep-ADP in each cohort was 1x1011, 2x1011, and 1x1012 vp/mL, respectively. Every patient has been evaluated adenovirus-induced toxicity in 8 weeks and tumor response in 12 weeks. The primary aim is to establish the maximum tolerated dose (MTD) of Ad5-yCD/mutTK(SR39)rep-ADP, as assessed by dose-limiting toxicities (DLT). Results: From 2016 to 2018, we enrolled 11 patients and analyzed nine patients for the final cohort. Two were dropped out by withdrawal of consents. In the first evaluation period (8 weeks), any of patients did not experience dose-related serious adverse event. Only one patients of in 3rd cohort experienced transient grade II fever. In the second evaluation period (12 weeks), two patients showed partial response (PR) and seven showed stable disease (SD). Adenovirus DNA fragments disappeared in median 50 days (range 20 – 139). After the gemcitabine periods, five patients received 2nd-line chemotherapy with FOLFIRINOX, and overall survival was median 14.9 months (range 8.9 – 21.9). Conclusions: In this phase I trial, Ad5-yCD/mutTK(SR39)rep-ADP has been well-tolerated without dose-related severe adverse events, and no MTD reached in locally advanced pancreatic cancer. Phase II clinical trial is needed for evaluating clinical efficacy. Clinical trial information: NCT02894944.

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