Recommended Dose Of Irinotecan Research Articles

A Phase I Study of Neoadjuvant Capecitabine, Oxaliplatin, and Irinotecan (XELOXIRI) in Patients with Locally Advanced Rectal Cancer

Objectives: The aim of this study was to determine the recommended dose (RD) of capecitabine combined with oxaliplatin and irinotecan (XELOXIRI) as a neoadjuvant chemotherapy in patients with locally advanced rectal cancer. Method: Patients received irinotecan and oxaliplatin (85 mg/m²) on day 1, and capecitabine (1,000 mg/m² orally twice daily) on days 1–7 of a biweekly schedule. Three dose levels, ranging from 100 to 150 mg/m², were explored for irinotecan in sequential cohorts of 6 patients. Dose-limiting toxicities (DLTs) were assessed in the first cycle to determine the RD. Results: Six patients were enrolled. The DLT was grade 3 febrile neutropenia, which was observed in 2 of the 6 patients at dose level 1. The RD of irinotecan was defined as 150 mg/m². Toxicity was manageable: the most common grade ≥3 toxicities were neutropenia (2 patients), anemia (1 patient), and anorexia (1 patient). Nodal downstaging (cN+ to ypN0) was detected in 2 patients and the T stage was downstaged in 3 patients. Conclusions: XELOXIRI is a feasible and active regimen for patients with locally advanced rectal cancer. Febrile neutropenia was the DLT, and the RD of irinotecan is 150 mg/m².

A dose-finding study for irinotecan, cisplatin, and S-1 (IPS) in patients with advanced gastric cancer (OGSG 1106).

144 Background: In Japan, S-1 plus cisplatin is regarded as one of the standard first line treatment of advanced gastric cancer (AGC). However, the prognosis of AGC remains dismal. The development of more effective chemotherapeutic regimen is thus warranted. A combination of irinotecan, cisplatin, and S-1 (IPS) can be a promising triplet therapy for advanced gastric cancer. We conducted a phase I study of IPS to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and recommended dose (RD), and to assess its safety and antitumor activity in patients with AGC. Methods: This phase I study was designed and conducted in a 3 + 3 manner to determine the recommended dose (RD) of IPS for the subsequent phase II study. Patients received an escalating dose of intravenous irinotecan (level 1: 100/level 2: 125/level 3: 150 mg/m²) on day 1, a fixed dose of intravenous cisplatin (60 mg/m²) on day 1, a fixed dose of S-1 (80 mg/m² b.i.d.) orally on days 1-14, every 4 weeks. Results: Twelve patients were enrolled between June 2013 and February 2017. During the first cycle, one of the six patients in level 1 and two of six patients in level 2 developed the DLT (grade 4 leucocytopenia and grade 3 febrile neutropenia). The MTD of irinotecan was 125 mg/m 2 (level 2) and the RD of irinotecan was considered to be 100 mg/m² (level 1). The most common grade 3 or 4 adverse events included neutropenia 75 % (9/12), anemia 25% (3/12), anorexia 8% (1/12), and febrile neutropenia 17% (2/12). Among six patients with measurable lesions, the response rate was 66.7% (4/6) [95% CI, 33.3-90.7%]. Two patients were performed R0 resection after IPS, with one patient achieved pathological complete response. The median survival time is under analysis. Conclusions: RD of IPS was determined to be 100 mg/m² of irinotecan, 60 mg/m² of cisplatin, and 80 mg/m² of S-1. Our data showed that this regimen provided acceptable antitumor activity and a favorable toxicity profile. Further evaluation of this regimen is warranted. Clinical trial information: UMIN000006864.

A triplet combination with capecitabine/oxaliplatin/irinotecan (XELOXIRI) plus cetuximab as first-line therapy for patients with metastatic colorectal cancer: a dose escalation study.

The addition of cetuximab to triplet chemotherapy can increase treatment efficacy for patients with metastatic colorectal cancer (mCRC). We explored the dose-limiting toxicity and feasibility of a triweekly capecitabine, oxaliplatin, irinotecan, plus cetuximab (XELOXIRI plus cetuximab) regimen in patients with wild-type KRAS mCRC. Patients received oxaliplatin (100mg/m2, day 1), capecitabine (1700mg/m2 per day from day 2 to 15), irinotecan (100, 120, and 150mg/m2 for dose levels 1, 2, 3, respectively, on day 1), and cetuximab (400mg/m2, day 1 and, thereafter, 250mg/m2 every week), repeated every 3weeks. Dose-limiting toxicities (DLTs) were assessed in the first 2 treatment cycles to determine the maximum tolerated dose (MTD) and the recommended dose (RD). Twelve patients received a median of 7 cycles of therapy (range 2-10). The DLT was grade 4 neutropenia, observed in 1 of 6 patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150mg/m2. Most common grade ≥ 3 toxicities were neutropenia (50%), diarrhea (17%), and febrile neutropenia (8%). The response rate was 83% (complete and partial response: 1 and 9 patient(s), respectively), including 4 conversion cases. The combination of XELOXIRI and cetuximab is feasible and has an acceptable toxicity profile; neutropenia was the DLT. The RD of irinotecan is 150mg/m2. The observed response rate was promising and warrants further investigation.

A multicenter phase I study of preoperative chemoradiotherapy with S-1 and irinotecan for locally advanced lower rectal cancer (SAMRAI-1)

Background and purposePreoperative 5-fluorouracil-based chemoradiotherapy is a standard treatment for locally advanced lower rectal cancer (LALRC). We performed a phase I study to develop a new regimen combining irinotecan and S-1. Materials and methodsPatients with LALRC (T3-4, N0-2) were studied. The radiation dose was 45Gy in 25 fractions. S-1 (80mg/m2/day) was administered on days 1–5, 8–12, 22–26, and 29–33. Irinotecan was administered on days 1, 8, 22, and 29. The dose of irinotecan was initially 60mg/m2 (level 1). Surgery was performed 6–10weeks after the chemoradiotherapy. ResultsTwenty patients were enrolled, of whom 18 patients were analyzed. Dose-limiting toxicity (DLT) did not occur in the first 3 patients treated with irinotecan at 80mg/m2 (level 2), but developed in 3 of the 6 patients who received irinotecan at 90mg/m2 (level 3). Then DLT occurred in 3 other patients at level 2. At level 2 or 3, DLT comprised neutropenia, thrombocytopenia, and diarrhea. Level 2 was designated as the maximum tolerated dose, and level 1 as a recommended dose (RD). The pathological complete response rate was 28%, and the down-staging rate was 56%. ConclusionsOur results suggested that the RD of irinotecan when combined with preoperative S-1 and pelvic radiation was 60mg/m2.

A dose-escalation study of oxaliplatin/capecitabine/irinotecan (XELOXIRI) and bevacizumab (bev) as a first-line therapy for patients with metastatic colorectal cancer.

612 Background: In a recent study by Loupakis, F. et al. (ASCO-GI 2013), a FOLFOXIRI and bevacizumab regimen showed promising activity and conversion rate in patients (pts) with metastatic colorectal cancer (mCRC). In order to evaluate a treatment regimen that was easier to administer, we conducted a dose-escalation study to determine the recommended dose (RD) of irinotecan (IRI) in combination with oxaliplatin and capecitabine and bevacizumab (XELOXIRI/bev) in pts with mCRC. Methods: Pts were eligible if they had mCRC (liver and/or other metastases), ECOG PS 0-1, were either negative or heterozygous for UGT1A1*6 or UGT1A1*28 and were not pretreated for metastatic disease. Treatment consisted of oxaliplatin (100 mg/m2 day 1), capecitabine (1700 mg/m2/day from day 2 to 15), IRI (100,120,150 mg/m2 for dose levels 1, 2, or 3, day 1) and bev (7.5 mg/kg, day 1), repeated every 3 weeks. The dose of IRI was escalated if dose limiting toxicities (DLT) were absent in the first three pts per cohort, or if <2 DLTs were observed in six pts. If the MTD was not reached at the planned dose levels, the RD of IRI was defined as 150mg/m2, which is the maximum dosage approved for use in Japan. Results: 12 pts (F/M: 4/8, median age: 58 years, PS 0/1: 11/1) received a median of 6 cycles of therapy (range 2-12). The DLT was grade 4 neutropenia, which was observed in 1 of 6 pts at dose level 2. MTD was not reached at dose level 3. Therefore, the RD of IRI was defined as 150 mg/m2. Most common grade ≥ 3 toxicities were neutropenia (58.3%), anemia (16.6 %), diarrhea (8.3%), and febrile neutropenia (8.3 %). The response rate was 83.3%(95% CI 60-89), including 1 CR, 9 PRs. The disease control rate was 100%(95% CI 80-100). At a median follow-up of 8 months, median PFS was 15 months and median OS was not yet reached. Conclusions: XELOXIRI/bev is a feasible regimen; neutropenia was the DLT; recommended dose of IRI is 150 mg/m². The observed response rate of 83.3% is very promising and warrants further investigation. Clinical trial information: UMIN000005440.

Phase I Trial of Neoadjuvant Preoperative Chemotherapy With S-1 and Irinotecan Plus Radiation in Patients With Locally Advanced Rectal Cancer

To determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan combined with preoperative chemoradiotherapy with S-1 in patients with locally advanced rectal cancer. We gave preoperative radiotherapy (total dose, 45 Gy) to 23 patients with locally advanced (T3/T4) rectal cancer. Concurrently, S-1 was given orally at a fixed dose of 80 mg/m2/day on Days 1-5, 8-12, 22-26, and 29-33, and irinotecan was given as a 90-min continuous i.v. infusion on Days 1, 8, 22, and 29. The dose of irinotecan was initially 40 mg/m2/day and gradually increased to determine the MTD and RD of this regimen. Among the 4 patients who received 90 mg/m2 irinotecan, 2 had Grade 4 neutropenia and 1 had Grade 3 diarrhea. Because dose-limiting toxicity (DLT) occurred in 3 of the 4 patients, 90 mg/m2 irinotecan was designated as the MTD. Consequently, 80 mg/m2 irinotecan was given to 7 additional patients, with no DLT, and this was considered the RD. Of the patients who received irinotecan at the RD or lower doses, 6 (31.6%) had a complete pathologic response (Grade 3) and 9 (47.4%) underwent sphincter-preserving surgery. With our new regimen, the MTD of irinotecan was 90 mg/m2, and the RD of irinotecan for Phase II studies was 80 mg/m2. Although our results are preliminary, this new neoadjuvant chemoradiotherapy was considered safe and active, meriting further investigation in Phase II studies.