Eligible patients are aged 20 years or more Japanese with: 1) histological confirmation of advanced gastric adenocarcinoma; 2) patient with oral intake; 3) Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1; 4) patients with measurable lesions; 5) disease refractory to fluoropyrimidine, platinum and taxane; 6) adequate organ function (Absolute neutrophil count ≥ 1,500/µL, platelet counts ≥ 100,000/mm3, hemoglobin levels ≥ 8.0 g/dL, aspartate aminotransferase and alanine aminotransferase ≤ 2.5 times the upper limit of normal range [ULN] without known liver metastasis or ≤ 5.0 times the ULN with known liver metastasis, total bilirubin ≤ 1.5 mg/dL, Serum creatinine ≤ 1.5 mg/dL); 7) less than grade 2 of diarrhea according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, 8) UGT1A1 gene *6*28 wild type or single hetero; 9) written informed consent. Patients were excluded from the study if they had a treatment history of FTD/TPI or irinotecan; serious illness such as brain metastasis, systemic infection or gastrointestinal bleeding; medical treatment such as major surgery within 4 weeks, systemic chemotherapy within 2 weeks; adverse events due to prior chemotherapy; administration of blood transfusion or granulocyte colony stimulating factor within 2 weeks; severe pulmonary disorder; CTCAE grade 3 or higher of thromboembolism within 6 months.
The study was conducted 4 centers in Japan in accordance with the International Conference of Harmonization of Good Clinical Practice Guidelines and the Declaration of Helsinki, with approval by ethics committees/health authorities of the participating institutions (St. Marianna University School of Medicine, Chiba Cancer Center, Saitama Cancer Center, and National Hospital Organization Shikoku Cancer Center). Independent data monitoring committee (IDMC) was established with two independent experts external to this study. All patients provided their written informed consent. UMIN Clinical Trials Registry: UMIN000031346.
Study design and treatment
The phase I open-label dose finding part was conducted according to 3 plus 3 design to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) in patients with advanced gastric cancer to determine the recommended phase II dose (RP2D), followed by the phase II open-label single arm part to examine the efficacy and safety of RP2D of FTD/TPI and irinotecan. Although the phase II part was initially planned as a dependent cohort of patients receiving RP2D of FTD/TPI and irinotecan, the protocol amendment was performed due to slow recruitment. Finally, this study was amended to a phase Ib study, and the phase II part was conducted to examine the efficacy and safety of FTD/TPI and irinotecan in all enrolled patients.
Patients were enrolled gradually into four levels, Level 1A, 1B, 2A, and 2B, used a deescalated dose of irinotecan with 2 dosage schedules of FTD/TPI (Figure 1A). Regarding FTD/TPI, 35 mg/m2 were administered twice daily, after the morning and evening meal. At level A, taken on days 1–5 and days 8–12 of each 28-day treatment cycle. And at level B, taken on days 1–5 and days 15-19 of each 28-day treatment cycle. Irinotecan, 100 mg/m2 at level 1 or 125 mg/m2 at level 2, was administered by intravenous infusion over at least 90 min on days 1 and 15 in a 28-day schedule (Figure 1B).
Stop or dose reductions of FTD/TPI due to toxicities were not allowed unless dose limiting toxicity was observed during the Cycle 1, and thereafter permitted according to the prespecified criteria. Study treatment was continued until investigator-evaluated progressive disease, adverse events requiring discontinuation, a treatment-free period of >30 consecutive days, withdraw of consent to continue the protocol treatment.
Actual dose intensity (mg/m2/weeks) of FTD/TPI and irinotecan was defined as cumulative dose (mg/m2) divided by the number of weeks from initial treatment to discontinuation. Relative dose intensity (%) was calculated based on the initial planned dose.
Toxicity and dose-finding procedure
Examination of patient’s condition and laboratory tests were repeated weekly. Adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.
An event was considered a dose limiting toxicity if it has a possible causal relationship to study drugs and occurs within the first 28-day treatment period of protocol treatment and meets one of following criteria: ≥ grade 3 non-hematological toxicities (excluding nausea, vomiting and diarrhea showing improvement with supportive treatment, or ≥ grade 3 electrolyte imbalance without clinically significance); grade 4 neutropenia persisting for ≥ 8 days; ≥ grade 3 febrile neutropenia; grade 4 thrombocytopenia; or delay of starting Cycle 2 longer than 28 days due to adverse events.
Dose level was determined based on observed DLTs from at least three subjects in the same cohort who have received investigational therapy according to the designated schedule for 28 days as described in Figure 1. Briefly, if 0 of the 3 patients experienced a DLT, the dose level was escalated to next level. if 1 out of the 3 patients experienced a DLT, 3 more patients were enrolled at the same dose level. The MTD was defined as the dose level at which 2 or more of 3 patients, or at least 2 of 4 to 6 patients, had DLTs during the first 28-day treatment period. All DLTs, MTD, and RP2D was finally judged by the investigators and the IDMC.
Tumor assessments and endpoints
Imaging examination for tumor assessment repeated every 4 weeks until 12 weeks from initiation of treatment or 8weeks later. Disease assessment, including the antitumor efficacy (best overall response), disease control rate (DCR) was evaluated based on response evaluation criteria in solid tumors (Revised RECIST version 1.1). PFS was calculated from enrollment to disease progression or death and OS was calculated from enrollment to death.
Sample size and statistical analysis
The number of patients in each cohort was based on a conventional 3 plus 3 design for dose-modification studies. A maximum of 18 patients were planned to be enrolled in the phase I part. The primary analysis (and all efficacy analyses discussed herein) included the full analysis set (FAS), which was defined as eligible patients treated with FTD/TPI and irinotecan at least each one dose who could be evaluated for DLT. The safety analyses included all treated patients.
The phase II part of the study was designed to evaluate DCR. In the previous study, it was reported that DCR of irinotecan third-line treatment in advanced gastric cancer patients was 21 % (19). It was also reported that DCR of FTD/TPI as second- or third-line treatment was 51.9 % (13). Therefore, we considered a DCR of <20 % to be unacceptable. Thus, based on the sampling distribution for proportions actually follows a binomial distribution, we required 15 patients to evaluate a null hypothesis (a DCR of ≤30 %) with a one-sided α = 0.1 and of power of 75 % to detect a clinically meaningful DCR (≥55 %).