Phase 2 Study of S-1 in Advanced or Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether S-1 is effective in slowing tumor activity in participants with locally advanced or metastatic pancreatic cancer who have not had chemotherapy. The study is also looking at the safety of S-1.

Detailed Description
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Locally advanced or metastatic pancreatic cancer is relatively unresponsive to chemotherapy. This is true for the nucleoside analogue gemcitabine, with a response rate of approximately 10%, as well as for 5-fluorouracil (5-FU). Even when gemcitabine is combined with other chemotherapeutic drugs or biological agents, the overall tumor response rate remains basically unchanged. S-1 is a new generation oral fluoropyrimidine that combines Tegafur (5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione [FT]), an oral prodrug of 5-FU, with two modulators, Gimeracil (5-chloro-2,4-dihydroxypyridine [CDHP]), which inhibits 5-FU degradation by dihydropyrimidine dehydrogenase (DPD) inhibition, and Oteracil potassium (Oxo), which inhibits 5-FU phosphorylation in the digestive tract. This combination of 3 compounds is designed to achieve enhanced antitumor activity while decreasing gastrointestinal toxicity.

Official Title
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An Open-Label, Non-Randomized, Multicenter, Two-Stage, Phase 2 Study of S-1 in Chemotherapy-Naïve Patients With Locally Advanced or Metastatic Pancreatic Cancer

Conditions
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Locally Advanced or Metastatic Pancreatic Cancer

Intervention / Treatment
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* Drug: S-1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has provided written informed consent. Has histologically or cytologically confirmed locally advanced, unresectable or metastatic adenocarcinoma of the pancreas not amenable to curative radiotherapy or surgery. Has measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (ie, lesions that can be accurately measured in at least one dimension with the longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm using spiral computed tomography [CT] scan). Is able to take medications orally. Is 18 years of age or older. Has a Karnofsky Performance Status (KPS) ≥ 70%. Has a life expectancy of ≥ 12 weeks. Has adequate organ function as defined by the following criteria: Transaminases AST (SGOT) and ALT (SGPT) ≤ 2.5 times the upper limit of normal (ULN). If liver function abnormalities are due to underlying liver metastasis, then AST (SGOT) and ALT (SGPT) may be ≤ 5 times ULN. Total serum bilirubin ≤ 3.0 times ULN (if due to underlying liver metastasis, then total bilirubin may be ≤ 5 times ULN). Absolute granulocyte count ≥ 1,500/mm3 (ie, ≥ 1.5 x 109/L by International Units [IU]). Platelet count ≥ 100,000/mm3 (IU: ≥ 100 x 109/L). Hemoglobin value ≥ 9.0 g/dL. Calculated creatinine clearance ≥ 60 mL/min (based on serum creatinine) (Cockcroft-Gault85 formula) Is willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Exclusion Criteria: Has had treatment with any of the following within the specified time frame prior to study drug administration: Any prior anticancer chemotherapy. Radiation therapy to a target lesion unless there was evidence of PD after radiotherapy (and this target lesion must not be the only site of measurable disease). Any radiotherapy within the previous 3 weeks. Any investigational agent received either concurrently or within the last 30 days. Current enrollment in another clinical study with an investigational agent. Patients participating in surveys or observational studies are eligible to participate in this study. Major surgery within the previous 3 weeks. Symptomatic brain metastasis not controlled by corticosteroids. Leptomeningeal metastasis. Previous or concurrent malignancy other than pancreatic cancer except adequately treated carcinoma in-situ of the cervix or non-melanoma skin cancer. Uncontrolled ascites requiring drainage at least twice a week. Other serious illness or medical condition(s) including, but not limited to, the following: Uncontrolled congestive heart failure (New York Heart Association [NYHA] Class III or IV), angina pectoris, arrhythmias, or hypertension. Active infection. Known (at time of entry) gastrointestinal disorder, including malabsorption, chronic nausea, vomiting, or diarrhea, present to the extent that it might interfere with oral intake and absorption of study medication. Poorly controlled diabetes mellitus. Psychiatric disorder that may interfere with consent and/or protocol compliance. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study. Is receiving a concomitant treatment with drugs interacting with S-1. The following drugs are prohibited because there may be an interaction with S-1: Sorivudine, uracil, cimetidine, folinic acid, and dipyridamole (may enhance S-1 activity). Allopurinol (may diminish S-1 activity). Phenytoin (S-1 may enhance phenytoin activity). Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 and flucytosine activity). Is a pregnant or lactating female. Has known sensitivity to 5-FU. Is a patient with reproductive potential who refuses to use an adequate means of contraception (including male patients).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S-1 30 mg/m^2<br>Participants received 30 milligrams per meter square (mg/m^2) of S-1 orally twice daily (BID) for 2 weeks (i.e., Day 1 to 14), followed by 1 week recovery period (i.e., Day 15 to 21; one cycle equaled 21 days), treatment was repeated every 3 weeks until death, progression of disease, occurrence of intolerable side effects, withdrawal of consent, or removal by Investigator, whichever comes first. | Drug: S-1<br>* All participants received S-1 orally at a dose of 30 mg/m2 BID for 14 days followed by a 1-week recovery period, repeated every 3 weeks. The trial was planned to proceed to the second stage only if sufficient efficacy was demonstrated in Stage 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Tumor Response Rate (ORR) | ORR was defined as the percentage of participants with objective evidence of partial response (PR) or complete response (CR) and was based on the best overall response across all cycles for each participant. Tumor response was assessed according to the Response Evaluation Criteria In Solid Tumors (RECIST). For target lesions response, CR was defined as the disappearance of all target lesions for at least 3 weeks and PR was defined as at least a 30% reduction in the sum of the longest diameters of the target lesions, taking as a reference the baseline sum of the longest diameters for at least 6 weeks. For non-target lesions, CR was defined the disappearance of all non-target lesions and normalization of tumor marker level for at least 6 weeks. | From first dose of study medication until disease progression, permanent discontinuation of study treatment, or death due to any cause, assessed up to 2 years 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) | DCR was defined as the percentage of participants with objective evidence of CR, PR or stable disease (SD) determined according to RECIST. For target lesions, stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) taking as a reference the smallest sum of the longest diameters since the treatment started for at least 6 weeks. For non-target lesions, stable disease was defined a persistence of greater than or equal to (>=) 1 non-target lesions and/or maintenance of tumor marker level above the normal limits for at least 6 weeks. | From first dose of study medication until disease progression, permanent discontinuation of study treatment, or death due to any cause, assessed up to 2 years 5 months | 
| Duration of Response (DR) | DR was calculated as date of first progressive disease (PD) or death, date after the first response of CR or PR minus date of first CR or PR plus 1. Participants who did not die and were without progressive disease were censored at last evaluable tumor response assessment. Analysis was performed by Kaplan-Meier method. | From first dose of study medication until disease progression, permanent discontinuation of study treatment, or death due to any cause, assessed up to 2 years 5 months | 
| Time to Tumor Progression (TTP) | TTP was calculated as date of first PD minus date of first dose of study medication plus 1. Participants without progressive disease were censored at last evaluable tumor response assessment. Analysis was performed by Kaplan-Meier method. | From first dose of study medication until disease progression, permanent discontinuation of study treatment, or death due to any cause, assessed up to 2 years 5 months | 
| Overall Survival (OS) | OS was calculated as date of death minus date of first dose of study medication plus 1. In the absence of death confirmation, OS was censored at the date of last study follow-up. Analysis was performed by Kaplan-Meier method. | From first dose of study medication until disease progression, permanent discontinuation of study treatment, or death due to any cause, assessed up to 2 years 5 months | 
| Progression-free Survival (PFS) | PFS was defined as date of first PD or date of death minus date of first dose of study medication plus 1. Participants who did not die and were without PD were censored at their last evaluable tumor response assessment. Analysis was performed by Kaplan-Meier method. | From first dose of study medication until disease progression, permanent discontinuation of study treatment, or death due to any cause, assessed up to 2 years 5 months | 
| Number of Participants With Karnofsky Performance Status (KPS) Score - Shift From Baseline Score to Final Assessment Score | KPS classified participant's as per their functional impairment. The KPS ranged from 0percent (%) to 100%, (100= no signs of disease, 90% = few symptoms or signs of disease, 80%=some symptoms or signs, 70% = not capable of normal activity or work, 60% = can take care of most personal requirements, 50% = requires frequent medical care, 40% = disabled, 30% = severely disabled, hospital admission indicated but no risk of death, 20% = very ill, requires supportive measures or treatment, 10% = moribund, rapidly progressive fatal disease processes, and 0% = death), where higher values represented better outcomes. Participants with baseline KPS >=70% were included in study. Final assessment was the participant's last assessment. Participants with available data were only presented in the below data table. | Baseline, at end of treatment (up to 2 years 5 months) | 
| Change From Baseline in Pain Intensity | Pain intensity was graded from 0 (least possible pain) to 100 (worst possible pain) on a visual analog scale (VAS). The higher score on VAS scale indicated more pain. Final assessment was the last assessment of participant's. | Baseline, at end of treatment (up to 2 years 5 months) | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAE) | An AE was defined as any untoward medical event in a participants administered any dose of a study medication which may or may not have a causal relationship with the use of the study medication. An SAE was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. | From the first dose of study medication up to 30 days after the last dose of study medication, or until additional antitumor therapy had been introduced, whichever came first (approximately up to 2 years 6 months) |