A phase I study of S-1 and irinotecan combination therapy in previously treated advanced non-small cell lung cancer patients

Background

This phase I study was conducted to evaluate the feasibility and to determine the recommended doses of the combination therapy of S-1 and irinotecan (CPT-11) in patients with advanced non-small cell lung cancer (NSCLC) as second-line treatment.

Methods

Patients with NSCLC who were previously treated with one chemotherapy regimen and had a performance status of 0 or 1 were eligible. CPT-11 was administered at 60 mg/m² (level 1), 80 mg/m² (level 2) on days 1 and 8, and oral S-1 was administered at 80 mg/day for body surface area (BSA) less than 1.25 m², 100 mg/day for BSA 1.25–1.5 m², and 120 mg/day for BSA more than 1.5 m² on days 1–14 every 3 weeks. The dose-limiting toxicity (DLT) was defined as grade 4 leukocytopenia or neutropenia, grade ≥3 neutropenia with fever over 38°C, grade ≥3 thrombocytopenia, or grade ≥3 major nonhematological toxicities.

Results

Nine patients were enrolled in the study. None of 3 patients enrolled in level 1 had any DLT. Of 6 patients in level 2, 2 patients had grade 3 diarrhea and one had grade 3 interstitial pneumonia. Level 1 was declared as the recommended dose.

Conclusion

The feasibility of the combination therapy of S-1 and CPT-11 was shown in the second-line setting for the treatment of advanced NSCLC. The recommended dose of CPT-11 was 60 mg/m² combined with standard dose of S-1 for phase II trials of pretreated advanced NSCLC patients.     

A phase I trial of S-1 with concurrent radiotherapy in patients with locally recurrent rectal cancer

Background

The purpose of this phase I trial of S-1 chemotherapy in combination with pelvic radiotherapy for locally recurrent rectal cancer was to determine the maximum tolerated dose (MTD), recommended dose (RD), and dose-limiting toxicity (DLT) of S-1.

Methods

We enrolled 9 patients between April 2005 and March 2009. Radiotherapy (total dose, 60 Gy in 30 fractions) was given to the gross local recurrent tumor and pelvic nodal metastases using three-dimensional radiotherapy planning. We administered oral S-1 twice a day on days 1–14 and 22–35 during radiotherapy. The dose of S-1 was initially 60 mg/m²/day and was increased to determine the MTD and RD for this regimen.

Results

DLT appeared at dose level 2 (70 mg/m²/day) in 2 patients, who experienced grade 3 enterocolitis and consequently required suspension of S-1 administration for longer than 2 weeks. Hematological toxicity was mild and reversible. At the initial evaluation, complete regression and partial regression were seen in 1 patient (11%) and 2 patients (22%), respectively.

Conclusion

This phase I trial of S-1 chemotherapy with pelvic radiotherapy for locally recurrent rectal cancer revealed that the MTD for S-1 was 70 mg/m²/day and the RD was 60 mg/m²/day.     

Evaluation of S-1 as third- or further-line chemotherapy in advanced non-small-cell lung cancer

Background

No investigation of S-1 monotherapy in previously treated advanced non-small-cell lung cancer (NSCLC) patients has yet been reported. We conducted a retrospective study to evaluate the efficacy and tolerability of S-1 in patients with failure of second- or further-line chemotherapy.

Patients and methods

The records of NSCLC patients who had received S-1 monotherapy between January 2005 and November 2006 with the following eligibility criteria were reviewed: previously treated with at least two regimens including platinum and docetaxel in the case of nonadenocarcinoma patients, and including platinum, docetaxel and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in the case of adenocarcinoma patients. S-1 was administered for 28 consecutive days, followed by a 14-day drug-free period (42 days in one course). The drug was administered in two divided doses daily at 80 mg/day for patients with a body surface area <1.25 m², 100 mg/day for those with a body surface area of 1.25–1.5 m², and 120 mg/day for those with a body surface area ≥1.5 m².

Results

Thirty-five patients were registered. The median number of courses administered per patient was 2 (range 1–9). The toxicity profile was mild, and grade 3 or more severe toxicity was rare. The overall response and disease control rates were 5.7% and 40%, respectively. The median survival time was 208 days.

Conclusion

S-1 exhibits modest activity and acceptable toxicity when used as a third or subsequent line of chemotherapy in patients with advanced NSCLC.     

Phase I and pharmacokinetic study of gefitinib and S-1 combination therapy for advanced adenocarcinoma of the lung

Background

A phase I dose-escalation study was performed to investigate the safety and pharmacokinetics of the combination of S-1 and gefitinib in patients with pulmonary adenocarcinoma who had failed previous chemotherapy.

Methods

Patients received gefitinib at a fixed daily oral dose of 250 mg, and S-1 was administered on days 1–14 every 21 days at doses starting at 60 mg/m² (level 1) and escalating to 80 mg/m² (level 2). The primary end point of the study was determination of the recommended dose for S-1 given in combination with a fixed dose of gefitinib.

Results

Twenty patients were enrolled in the study. Two of the first six patients at dose level 2 experienced a dose-limiting toxicity (elevation of alkaline phosphatase of grade 3 in one patient; elevations of aspartate and alanine aminotransferases of grade 3 in the other). The recommended dose was thus determined as level 2, and an additional 11 patients were assigned to this level. All observed adverse events were well managed. The response rate was 50 % (10 of 20 patients), and the median progression-free survival (PFS) and overall survival times were 10.5 and 21.2 months, respectively. In EGFR mutation–positive patients (n = 9), seven patients achieved an objective response and the median PFS was 12.4 months, whereas none with wild-type EGFR (n = 6) responded. No pharmacokinetic interaction between S-1 and gefitinib was detected.

Conclusions

The combination of S-1 and gefitinib is well tolerated and appears to possess activity against EGFR mutation–positive NSCLC.     

Feasibility study of S-1 adjuvant chemotherapy in patients with colorectal cancer

Background

We evaluated the safety, efficacy, and compliance of 1-year treatment with S-1 in patients with stage II/III resectable colorectal cancer.

Methods

S-1 was administered orally in two divided doses daily. The dose was assigned according to body surface area (BSA) as follows: BSA <1.25 m², 80 mg/day; BSA ≥1.25 to <1.5 m², 100 mg/day; and BSA ≥1.5 m², 120 mg/day. S-1 was given for 28 consecutive days, followed by a 14-day rest. The study objects were the rate of completion of treatment as planned at 1 year, the ratio of the actually administered dose to the planned dose at 1 year, and the total number of days of treatment.

Results

At 1 year, the rate of completion of treatment as planned was 77.7 % (42/54 patients), and the ratio of the actually administered dose to the planned dose was 82.9 %. The mean and median total numbers of days of treatment were 209 and 252, respectively. Grade 3 or higher toxicity (watery eyes) occurred in only 1 patient.

Conclusion

S-1 adjuvant chemotherapy had acceptable compliance, safety, and efficacy in patients with colorectal cancer. S-1 adjuvant chemotherapy is considered a possible standard treatment regimen for colorectal cancer.     

Phase I/II and pharmacokinetic study of S-1 and oxaliplatin in previously untreated advanced gastric cancer

Background

We aimed to determine the maximum-tolerated dose (MTD) of S-1 when given with oxaliplatin, to evaluate S-1 pharmacokinetics, and to determine the efficacy and safety of this regimen as a first-line treatment for advanced gastric cancer (AGC).

Methods

Oxaliplatin was fixed at a dose of 130 mg/m² on day 1 (D1). S-1 was administered from D1 to D14 of a 3-week cycle, and escalated by 10 mg/m² per day from 70 mg/m² per day up to 100 mg/m² per day. Pharmacokinetic analyses were performed following a single dose of S-1 on D-5 and D1 of the first cycle.

Results

In phase I (n = 18), MTD was not defined. In phase II (n = 47) with the planned maximum dose, partial response was achieved in 26 patients (55.3%) and stable disease in 14 patients (29.8%). The median time to progression was 6.6 months (95% CI 4.0–9.2 months) and the median overall survival was 12.5 months (95% CI 9.2–15.9 months). Frequent grade 3/4 toxicities included thrombocytopenia (39%), neutropenia (28%), anemia (17%), and leukopenia (13%). There was one grade 5 febrile neutropenia during the first cycle.

Conclusions

The pharmacokinetics of S-1 was not influenced by oxaliplatin. S-1/Oxaliplatin combination therapy is highly active against AGC and has a favorable toxicity profile.     

Phase I/II study of intraperitoneal docetaxel plus S-1 for the gastric cancer patients with peritoneal carcinomatosis

Purpose

We designed a phase I/II trial of intraperitoneal (IP) docetaxel plus S-1 to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate its efficacy and safety in gastric cancer patients with peritoneal carcinomatosis (PC).

Methods

Patients with PC confirmed by laparoscopy or laparotomy received IP docetaxel on days 1 and 15 and S-1 (80 mg/m²) on days 1–14 every 4 weeks.

Results

In the phase I part (n = 12), each cohort received escalating doses of docetaxel (35–50 mg/m²); the MTD was determined to be 50 mg/m² and the RD was determined to be 45 mg/m². Dose-limiting toxicities included grade 3 febrile neutropenia and grade 3 diarrhea. In the phase II part (n = 27), the median number of courses was 4 (range 2–11). The 1-year overall survival (OS) rate was 70 % (95 % confidence interval 53–87 %). The overall response rate was 22 % and peritoneal cytology turned negative in 18 of 22 (81 %) patients. The most frequent grade 3/4 toxicities included anorexia (19 %), neutropenia (7 %), and leukopenia (7 %).

Conclusion

IP docetaxel plus S-1 is active and safety in gastric cancer patients with PC.     

Phase I clinical and pharmacokinetic/pharmacogenetic study of a triplet regimen of S-1/irinotecan/oxaliplatin in patients with metastatic colorectal or gastric cancer

Purpose

We conducted a phase I study of S-1 combined with irinotecan and oxaliplatin (TIROX) to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety, pharmacokinetics, pharmacogenetics, and preliminary efficacy in patients with metastatic colorectal cancer (MCRC) or metastatic gastric cancer (MGC).

Methods

Patients received escalating doses of S-1 (30–40 mg/m² b.i.d.) orally on days 1–14, an escalating dose of intravenous irinotecan (120–150 mg/m²) on day 1, and a fixed dose of intravenous oxaliplatin (85 mg/m²) on day 1 every 3 weeks.

Results

Twenty-three patients (10 MCRC, 13 MGC; 13 chemonaive, 10 previously treated for metastatic disease) were treated across six dose levels. Because only one patient experienced a dose-limiting toxicity of grade 3 anorexia at the highest dose level (S-1 40 mg/m² b.i.d., irinotecan 150 mg/m², and oxaliplatin 85 mg/m²) (n = 8), the MTD was not obtained, and this level was established as the RD. With a median of 10 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (43 %), diarrhea (13 %), and nausea (13 %). In 22 efficacy-evaluable patients, the objective tumor response rate was 59.1 % (75 % for both MCRC and MGC in the first-line setting) and the disease control rate was 100 %. The exploratory pharmacokinetic/pharmacogenetic study showed that CYP2A6 variants (*4, *7, *9) are associated with a lower metabolic ratio of S-1 (exposure ratio of 5-fluorouracil to tegafur).

Conclusions

The new triplet TIROX regimen has shown promising antitumor activity and a favorable toxicity profile in patients with MCRC and MGC.     

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

Purpose

In our previous randomized controlled trial, the addition of S-1 to gemcitabine for advanced pancreatic cancer did not prolong overall survival (OS) significantly, despite its higher response rate and longer progression-free survival (PFS). Leucovorin is known to enhance efficacy of S-1, and we conducted this phase I trial of combination therapy of gemcitabine, S-1 and leucovorin (GSL).

Methods

Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Gemcitabine was administered at an escalating dose of 600, 800 and 1,000 mg/m² over 30 min on day 1, and oral S-1 at a dose of 40 mg/m² twice daily and oral leucovorin at a dose of 25 mg twice daily on days 1–7, every 2 weeks. A standard “3 + 3” phase I dose escalation design was utilized.

Results

Fifteen patients were enrolled across three dose levels. Three patients developed DLTs: two patients in level 1 (grade 3 anorexia in 1 and grade 3 anorexia, stomatitis and diarrhea in 1) and one patient in level 2 (grade 3 deep vein thrombosis). No DLT was observed in level 3. Response rate and the disease control rate were 33 and 93 %, respectively. The median PFS and OS were 5.4 and 16.6 months. Ten of 12 patients (83 %) with elevated CA19-9 at baseline had a ≥50 % decline.

Conclusions

RD of gemcitabine in GSL was determined as 1,000 mg/m². GSL was well tolerable and showed promising results in advanced pancreatic cancer.     

A phase I trial of concurrent chemoradiotherapy with non-split administration of docetaxel and cisplatin for dry stage III non-small-cell lung cancer (JCOG9901DI)

Purpose

This study aimed to establish the maximum tolerated dose of concurrent chemoradiotherapy (cCRT) with conventional administration of the docetaxel (D) plus cisplatin (P) (conv-DP) regimen.

Methods

Patients (aged ≤70 years) with unresectable dry stage III non-small-cell lung cancer (NSCLC) and having performance status 0 or 1 and adequate organ function were eligible. They received radiotherapy (60 Gy in 30 fractions) once daily starting on day 2. Concurrent P (day 1; 60 mg/m² at Levels 1–3, 80 mg/m² at Level 4) and D (day 1; 30 mg/m² at Level 1, 40 mg/m² at Level 2, 50 mg/m² at Levels 3–4) were administered every 4 weeks for 2–4 courses.

Results

Eighteen patients were enrolled (stage IIIA/IIIB, 5/13 patients). Three cases of dose-limiting toxicity were observed in this study, although another 3 cases were added at Levels 2 and 3. Radiotherapy was completed in 15 patients. Seventeen patients received more than 2 courses of chemotherapy. Neither Grade 3/4 esophagitis nor severe hematological events were observed at Levels 1–4. However, dose escalation to Level 5 (P [80 mg/m²], D [60 mg/m²]) was stopped because the Level 5 dose was the recommended dose (RD) of chemotherapy alone for stage IIIB/IV NSCLC in Japan. Therefore, the RD was determined as D50/P80 mg/m² in this cCRT. The objective response rate was 89 %, and the median survival time was 23.6 months.

Conclusions

cCRT with non-split DP was a tolerable and effective regimen, and RD was 50/80 mg/m² every 4 weeks.     

A dose-finding and pharmacokinetic study of nedaplatin in elderly patients with advanced non-small cell lung cancer

Purpose

Nedaplatin is a second-generation platinum showing favorable activity against non-small cell lung cancer (NSCLC). Dose-limiting toxicity (DLT) is thrombocytopenia, predicted by creatinine clearance (Ccr). This study was conducted to determine the recommended dose, and evaluate the toxicities, pharmacokinetics and efficacy for elderly NSCLC patients.

Methods

Patients ≥70 years were stratified into two groups based on renal functions: Group A, Ccr ≥ 60 and Group B, 40 ≤ Ccr < 60. The initial doses were 80 and 60 mg/m² in Groups A and B, respectively. The doses were escalated in 20-mg/m² increments to 100 mg/m² until DLT.

Results

Chemotherapy-naïve 39 elderly patients (Group A/Group B: 22/17) received a total of 83 cycles. Major toxicities were hematological. In Group A, one of the 15 patients at 100 mg/m² experienced DLT (neutropenia) and the recommended dose was determined at 100 mg/m². In Group B, three of the five patients had DLTs (leukopenia, neutropenia, thrombocytopenia and febrile neutropenia) at 100 mg/m², and the recommended dose was determined at 80 mg/m². The percentage decreases of neutrophil were well correlated with total and free-Pt AUCs. Partial responses were observed in 13 (33%) of the 39 patients, and 12 of the 13 patients who responded had a squamous cell carcinoma.

Conclusions

Nedaplatin was administered simply and feasibly by stratifying renal function and exerted favorable antitumor activity for elderly patients with NSCLC, especially on squamous cell carcinoma.     

A dose escalation and pharmacokinetic study of the biweekly administration of paclitaxel, gemcitabine and oxaliplatin in patients with advanced solid tumors

Purpose

To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of the paclitaxel, gemcitabine, oxaliplatin combination administered biweekly in patients with advanced solid tumors.

Patients and methods

Patients received escalated doses of paclitaxel (starting dose: 100 mg/m²), gemcitabine (starting dose: 800 mg/m²) and oxaliplatin (starting dose: 50 mg/m²) on days 1 and 15 in cycles of every 4 weeks. DLTs were evaluated during the first cycle.

Results

Twenty-seven patients (median age 65 years) with performance status 0–1 were treated on six dose escalation levels. Eleven patients (40.7%) were chemotherapy naïve, six (22.2%) had received 1 prior chemotherapy regimen and ten (37.1%) 2 or more. The DLT level was reached at the doses of paclitaxel 110 mg/m², gemcitabine 1,150 mg/m² and LOHP 70 mg/m². The dose-limiting events were grade 4 neutropenia and grade 3 febrile neutropenia. Neutropenia was the most common adverse event. A median of 3 cycles per patient was administered. One complete and five partial responses were observed in patients with ovarian carcinoma, NSCLC, urothelial cancer, mesothelioma and cancer of unknown primary. No pharmacokinetic drug interactions were detected.

Conclusions

The recommended doses for future phase II studies of this combination are paclitaxel 110 mg/m², gemcitabine 1,000 mg/m² and oxaliplatin 70 mg/m² every 2 weeks. The regimen is generally well tolerated and merits further evaluation.     

Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer

Background

This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS).

Methods

Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m² followed by oxaliplatin 130 mg/m² (maximum 8 cycles) and then S-1 [20 mg/m² (cohort 1) or 25 mg/m² (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2–14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer.

Results

DLT was reported for two of the five patients in cohort 2, defining 20 mg/m² twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m² twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations.

Conclusions

The promising activity of EOS (S-1 dose level, 25 mg/m² twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.

     

Safety, efficacy and pharmacokinetics of S-1 in a hemodialysis patient with advanced gastric cancer

Purpose

The safety and efficacy of S-1 in hemodialysis patients have not been established. We evaluated the safety and efficacy and pharmacokinetics of S-1 in a hemodialysis patient with advanced gastric cancer.

Patient

A 66-year-old Japanese man with chronic renal failure, who had undergone hemodialysis three times a week for 3 years. Based on the diagnosis of stage IV gastric cancer, S-1 therapy was started. S-1 was administered 11 times at a daily dose of 23.5 mg/m² (40 mg/body) after hemodialysis, followed by a rest. One course was a period of 28 days. Blood samples were obtained after the first administration of S-1 and before beginning the fourth course. The concentration of 5-FU was determined by high-performance liquid chromatography.

Results

Area under the concentration–time curve (AUC) of 5-FU was 2647.2 ng h/mL after administration of S-1 of 23.5 mg/m² (40 mg/body). During the S-1 treatment, serious adverse events such as neutropenia were not observed; however, decreases in hemoglobin level were observed (grade 3). The treatment was well tolerated. After the second course of chemotherapy, the primary lesion showed a partial response and lymph node metastases and liver metastases showed stable disease.

Conclusions

Our results suggest that S-1 is an important treatment option for patients with hemodialysis with advanced gastric cancer.     

A phase I trial of combination therapy using gemcitabine and S-1 concurrent with full-dose radiation for resectable pancreatic cancer

Purpose

Use of the fourth-generation oral fluoropyrimidine S-1 together with gemcitabine has shown striking anticancer effects. In this single-arm phase I trial of preoperative combination therapy using gemcitabine and S-1 concurrently with radiotherapy, we verified the safety and feasibility and determined the maximum-tolerated dose of each drug in patients with resectable pancreatic cancer.

Methods

A standard 3+3 dose escalation scheme was used. Patients with cytologically or histologically proven resectable pancreatic ductal adenocarcinoma were administered 30-min intravenous gemcitabine infusions on days 1, 8, 22, and 29 and S-1 orally on days 1–5, 8–12, 22–26, and 29–33. A total radiation dose of 50.4 Gy (1.8 Gy/day, 5 times per week, 28 fractions) was concurrently delivered. Surgical exploration was scheduled 4–7 weeks after the final radiation fraction.

Results

Twenty-one patients were enrolled. No treatment-related deaths occurred during this study. Recommended doses were determined to be 80 mg/m² of S-1 daily and 1,000 mg/m² of gemcitabine. CA19-9 was reduced to <50 % of baseline values in 12 (75 %) of 16 measurable patients. Nineteen of 21 enrolled patients successfully underwent surgical resection.

Conclusions

Preoperative chemoradiotherapy consisting of gemcitabine and S-1 concurrent with full-dose radiation is feasible and well tolerated.     

A phase II study of combination therapy with irinotecan and S-1 (IRIS) in patients with advanced colorectal cancer

Purpose

A combination of irinotecan with continuous infusional 5-fluorouracil (5-FU) is the standard treatment for advanced colorectal cancer. The aim of this study was to determine the efficacy and safety of combining irinotecan and S-1 (IRIS) in patients with advanced colorectal cancer.

Methods

Irinotecan was administered as an intravenous infusion at a dose of 120 mg/m² on day 1 and 15. And S-1 was administered orally on days 1–14 of a 28-day cycle. S-1 was given orally at a dose that did not exceed 40 mg/m² based BSA: BSA < 1.25 m², 40 mg twice daily; 1.25–1.5 m², 50 mg twice daily, and BSA > 1.5 m², 60 mg twice daily, for 14 consecutive days.

Results

A total of 38 patients were enrolled. An intent-to-treat analysis showed a complete response and partial response to occur in 13.2% and 50.0%, respectively. The disease control rate was 84.2%. The median progression-free survival and overall survival were 10.0 months and 29.1 months, respectively. The rates of grade 3/4 toxicity over 4 cycles were the following: neutropenia, 15.8%; leucopenia, 7.9%; anorexia, 15.8%; diarrhea, 10.5%. Conclusion: IRIS is an effective, well tolerated and convenient treatment regimen for patients with advanced colorectal cancer.     

Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma

Purpose

To determine the maximum tolerated dose (MTD), safety and tolerability of sunitinib plus pemetrexed and cisplatin for advanced solid malignancies.

Methods

Using a 3 + 3 dose-escalation design, patients received oral sunitinib (37.5 or 50 mg) qd on a continuous daily dosing (CDD) schedule or Schedule 2/1 (2 weeks on, 1 week off treatment) plus pemetrexed (400 or 500 mg/m² IV) and cisplatin (75 mg/m² IV) q3w up to 6 cycles.

Results

Sunitinib 37.5 mg/pemetrexed 400 mg/m²/cisplatin 75 mg/m² CDD (n = 5) was not tolerated. Lower doses on this schedule were not explored. The Schedule 2/1 MTD (n = 15) was sunitinib 37.5 mg/pemetrexed 500 mg/m²/cisplatin 75 mg/m², based on one dose-limiting toxicity (myocardial infarction) out of six patients. The MTD was further studied in an expansion cohort of 10 non-small cell lung cancer (NSCLC) patients and one mesothelioma patient. There were no clinically significant drug–drug interactions. Cumulative myelosuppression was problematic: the median relative dose intensity (% actual/intended) across all cycles was 61 % for sunitinib, 78 % for pemetrexed, and 74 % for cisplatin. Four of eight NSCLC patients in the dose-escalation and expansion cohorts at the Schedule 2/1 MTD who were evaluable for efficacy had stable disease ≥8 weeks, and the one patient with mesothelioma had a partial response.

Conclusions

In patients with advanced solid malignancies, sunitinib was not tolerated at 37.5 mg CDD with standard pemetrexed and cisplatin doses. Dose reductions were often needed due to cumulative myelosuppression following cycle 1. The MTD showed modest antitumor activity.     

A phase I study of S-1 in combination with <Emphasis Type="Italic">nab</Emphasis>-paclitaxel in patients with unresectable or recurrent gastric cancer

Background

In Japan, S-1, an oral fluoropyrimidine, plus cisplatin is a standard regimen for advanced gastric cancer, whereas nab-paclitaxel is a treatment option. We aimed to evaluate the tolerance, pharmacokinetics, safety, and clinical efficacy of S-1 combined with nab-paclitaxel in patients with advanced gastric cancer in a phase 1 study.

Methods

The primary objective was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 plus nab-paclitaxel. The study was designed in accordance with a standard 3 + 3 method. Patients received 3-week cycles of treatment. S-1 was administered orally at 80 mg/m² twice daily for 14 days, and nab-paclitaxel was administered as an intravenous infusion at 180, 220, or 260 mg/m² on day 1 or 8.

Results

Among the 16 patients enrolled, dose-limiting toxicity was observed in one patient at level 2a (S-1 80 mg/m² twice daily plus nab-paclitaxel 220 mg/m² on day 1). The MTD was not obtained, but the RD was established as level 3a (S-1 80 mg/m² twice daily plus nab-paclitaxel 260 mg/m² on day 1). The most common grade 3–4 toxicity was neutropenia (62.5 %). The overall response rate was 54.5 %. The pharmacokinetic profiles of coadministered S-1 and paclitaxel were comparable to those of nab-paclitaxel or S-1 alone.

Conclusions

Based on the present results, the RD was determined as level 3a (S-1 80 mg/m² twice daily plus nab-paclitaxel 260 mg/m² on day 1). This combination therapy was well tolerated and showed antitumor efficacy in patients with advanced gastric cancer.

     

Phase I study of bevacizumab combined with irinotecan and S-1 as second-line chemotherapy in patients with advanced colorectal cancer

Purpose

The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan has been reported to be a promising regimen for advanced colorectal cancer. However, the safety and efficacy of bevacizumab (BV) to combine with irinotecan and S-1 has not been determined. The aim of the study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BV combined with irinotecan plus S-1, and to observe the safety and efficacy of this regimen as second-line chemotherapy in patients with advanced colorectal cancer.

Methods

This study initially had been planned as a phase I/II study. Eighty mg/m² of irinotecan on days 1 and 8, 80 mg/m² of S-1 for 14 consecutive days, and two doses of BV (Level 1; 10 mg/kg, Level ?1; 7.5 mg/kg) were administered on day 1 every 3 weeks.

Results

Fourteen patients were enrolled in phase I of the study between January 2008 and September 2010. Dose-limiting toxicities were diarrhea, abdominal pain, and infection. The MTD and RD of BV were determined to be 10 mg/kg and 7.5 mg/kg, respectively. The main adverse events were leukopenia, anorexia, and diarrhea. There were no treatment-related deaths. An independent review committee was scheduled to evaluate safety in phase I, but this trial closed early due to toxicity.

Conclusions

This study identified the risk of gastrointestinal toxicity with the combination of irinotecan, S-1 and BV as second-line chemotherapy in patients with advanced colorectal cancer.     

Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study

Background

Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy.

Methods

Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800–1,000 mg/m² gemcitabine on days 1, 8, and 15 and then every 3–4 weeks or 40–80 mg/m²/day S-1 on days 1–28 and every 3–6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm.

Results

Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10 % of DLT, the recommended dose was 1,000 mg/m² gemcitabine biweekly and 80 mg/m²/day S-1 on days 1–28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted.

Conclusion

We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10 %.