Phase II study of oral S-1 with irinotecan and bevacizumab (SIRB) as first-line therapy for patients with metastatic colorectal cancer

Fluorouracil (5-FU) plus irinotecan combined with bevacizumab has significant activity in metastatic colorectal cancer (mCRC), but S-1 has become a substitute for continuous infusion of 5-FU and has a very low incidence of hand-foot syndrome. With the S-1 plus irinotecan regimen (SIR), the response rate was 62.5%, and the progression-free survival was 8.0 months. We report here on an update of efficacy and safety of the SIR plus bevacizumab (SIRB) regimen as first line treatment for mCRC patients. Fifty-one eligible patients with histologically confirmed advanced or recurrent colorectal cancer received this treatment. S-1 was administered orally on days 1-14 of a 21-day cycle. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg, 50 mg, or 60 mg. Irinotecan (150 mg/m(2)) plus bevacizumab (7.5 mg/kg) were administered by intravenous infusion on day 1. Safety analysis identified a grade 3/4 neutropenia rate of 26%. Other grade 3/4 toxicities were diarrhea (8%), nausea (6%), vomiting (2%), and hypertension (8%). The response rate was 67% and the median progression-free survival time was 373 days. The SIRB regimen appears to be highly active and well tolerated as first-line treatment for mCRC.     

A multicenter phase II study of the stop-and-go modified FOLFOX6 with bevacizumab for first-line treatment of patients with metastatic colorectal cancer

Currently, no prospective data exists to support a "stop-and-go" modified FOLFOX6 regimen with bevacizumab in metastatic colorectal cancer (mCRC) patients. This study aimed to evaluate the efficacy and safety of this regimen in first-line mCRC patients. Eligible patients (age ≥20 years) had previously untreated mCRC; Eastern Cooperative Oncology Group performance status of 0-2; and adequate hematologic, hepatic, and renal function. The modified FOLFOX6 regimen and bevacizumab (5 mg/kg) was administered intravenously every 2 weeks. After 8 cycles, patients received maintenance therapy with simplified LV5FU2 and bevacizumab until completion of 8 cycles or disease progression. After maintenance therapy, patients received another 8 cycles of modified FOLFOX6 with bevacizumab until completion of 8 cycles or disease progression. We recruited 50 patients between August 2007 and January 2009. The overall response rate was 48% (80% confidence interval [CI]; 38.2-58) with outcomes as follows: complete response, n?=?1; partial response, n?=?23; stable disease, n?=?21; progression, n?=?1; and not evaluated, n?=?4. Median time to treatment failure was 7.7 months (80% CI: 6.2-8.0), and median progression-free survival was 12.8 months (80% CI: 10.8-14). Grade 3/4 toxicities included neutropenia (40%), nausea (4%), diarrhea (14%), thrombosis (4%), and hypertension (4%) et al. Grade 1, 2, or 3 peripheral neuropathy was reported in 38%, 40%, and 10% of patients, respectively. The stop-and-go modified FOLFOX6 and bevacizumab regimen is effective and well tolerated as first-line chemotherapy for mCRC patients.     

Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

Background To define maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary efficacy of sorafenib plus capecitabine/cisplatin in advanced gastric cancer (AGC) patients. Methods Four dose-level combinations were tested in a standard 3 + 3 dose escalation design. Level 1: sorafenib 400 mg/d, capecitabine 1,600 mg/m²/d, cisplatin 80 mg/m². Level 2: sorafenib 800 mg/d, capecitabine 1,600 mg/m²/d, cisplatin 80 mg/m². Level 3: sorafenib 800 mg/d, capecitabine 2,000 mg/m²/d, cisplatin 80 mg/m². Level 1A: sorafenib 800 mg/d, capecitabine 1,600 mg/m²/d, cisplatin 60 mg/m². Results There were 1 DLT at Level 2, and 2 DLTs at Level 3 (Level 3 was MTD). Since the relative dose intensity (RDI) of sorafenib and capecitabine could not be maintained at Level 2, Level 1A was newly investigated. As no DLT was observed and RDI remained above 80%, Level 1A is the recommended dose for the next clinical trial. Objective response rate was 62.5% (10 of 16 patients, 95% CI; 38.8–86.2%). Median progression-free survival and overall survival were 10.0 months (95% CI; 7.4–13.8) and 14.7 months (95% CI; 12.0–20.0), respectively. Conclusions Sorafenib 400 mg bid daily, capecitabine 800 mg/m² bid (days 1–14), and cisplatin 60 mg/m² (day 1) is recommended for further development in AGC.     

A phase II trial of gefitinib in combination with capecitabine and oxaliplatin as first-line chemotherapy in patients with advanced colorectal cancer

ABSTRACT

Objective: This study was designed as a multicentre phase II trial to assess the efficacy and safety of gefitinib in association with capecitabine and oxaliplatin in patients with untreated metastatic colorectal cancer.

Research design and methods: Patients with metastatic colorectal cancer that had received no prior chemotherapy for advanced disease were treated with oral gefitinib (250?mg daily) plus oral capecitabine (1000?mg/m² twice a day on Days 1–14) and intravenous oxaliplatin (120?mg/m² on Day 1 of each 3?week cycle).

Results: Thirty-five patients were enrolled. In the intention-to-treat analysis, 3 (8.6%) patients experienced a complete response (CR), 14 (40%) a partial response (PR) and 11 (31.4%) had stable disease (SD). The disease control rate (CR + PR + SD) was 80%, the median time to progression was 7.3 months (95%CI: 4.76–9.2) and the estimated median overall survival was 21.9 months (95% CI: 15.1–not reached). The most common grade 3 to 4 toxicities included diarrhoea (31%) and vomiting (5.7%).

Conclusions: The combination of capecitabine, oxaliplatin and gefitinib appears to have promising activity in chemotherapy-naïve metastatic colorectal cancer. A higher disease control rate and an increase in median overall survival were seen compared with previous reports with capecitabine and oxaliplatin in similar patient populations. The tolerability profile appears to be predictable and similar to capecitabine/oxaliplatin regimens.     

Phase II study of gemcitabine as first-line chemotherapy in patients with advanced or metastatic breast cancer

In this phase II study, the efficacy and tolerability of gemcitabine were studied in 42 patients with locally advanced or metastatic breast cancer who had received up to one prior chemotherapy regimen in an adjuvant setting. Ten patients had received adjuvant chemotherapy. Twenty-eight patients (67%) had visceral disease spread at entry. Gemcitabine (1000 mg/m2) was administered weekly on days 1, 8 and 15 of a 28-day cycle. The mean number of completed cycles was 3.9 and the mean dose delivered was 942.2 mg/m2. Ninety-seven percent of injections were administered as assigned. No complete responses were observed, but there were six partial responses and 24 patients with stable disease lasting 2-9 months. The overall response rate was 14.3% (95% CI 5.4-28.5%). The median survival for all patients was 15.2 months. Maximum WHO grade 3 and 4 toxicities were observed in five patients for nausea and vomiting, one patient for diarrhea, one patient for pain, seven patients for alanine transaminase, and eight patients for segmented neutrophils. There were no grade 3 and 4 toxicities for alopecia. These data confirm modest single-agent gemcitabine activity in advanced or metastatic breast cancer. Gemcitabine's favorable toxicity profile makes it an ideal candidate for combination chemotherapy.     

Phase I/II study of biweekly vinorelbine and oxaliplatin as first-line treatment in patients with metastatic breast cancer

The objective of this phase I/II study was to establish the recommended dose of biweekly vinorelbine and oxaliplatin in patients with metastatic breast cancer and to evaluate the efficacy and safety profile of this schedule as first-line treatment. Four different dose levels of vinorelbine and oxaliplatin were selected for the phase I study: (i) 25 and 80 mg/m2; (ii) 25 and 90 mg/m2; (iii) 25 and 100 mg/m2; and (iv) 30 and 90 mg/m2; respectively. At least three patients were treated at each dose level. Overall, 12 patients were included in the phase I trial. No dose-limiting toxicities occurred at any dose level. Therefore, the fourth dose level (30 mg/m2 of vinorelbine and 90 mg/m2 of oxaliplatin) every 2 weeks was selected for the phase II trial. In this part, 44 patients were included and 61% completed the eight 2-week cycles of study treatment. On an intention-to-treat basis, overall response rate was 59%, and median progression-free survival and overall survival were 9.2 months (95% confidence interval: 7.6-10.9) and 18.6 months (95% confidence interval: 14.4-22.9), respectively. The main severe toxicities were neutropenia (46%) and fatigue (14%). We conclude that the biweekly combination of vinorelbine and oxaliplatin at doses of 30 mg/m2 and 90 mg/m2, respectively, is highly active and well tolerated as first-line treatment for patients with metastatic breast cancer.     

A phase I trial of vandetanib combined with capecitabine,oxaliplatin and bevacizumab for the first-line treatment of metastatic colorectal cancer

Background Vandetanib is a tyrosine kinase inhibitor of both the vascular endothelial growth factor (VEGFR) and epidermal growth factor (EGFR) receptors. The primary objectives of this study were to determine the maximum tolerated dose of vandetanib with capecitabine and oxaliplatin, without and with bevacizumab, for the first line treatment of metastatic colorectal cancer (mCRC), and to define the dose limiting toxicities. Materials and methods Three cohorts of patients were studied, with capecitabine at 1,000 mg/m² twice daily p.o. on days 1–14 of a 3 week cycle, with oxaliplatin i.v. at 130 mg/m² on day 1. Vandetanib dosing was 100 mg/day in cohort 1 and 300 mg/day in cohorts 2 and 3. Bevacizumab was added in cohort 3 at 7.5 mg/kg IV on day 1 every 3 weeks. Results Thirteen patients were enrolled and received from one to eight cycles per patient. Grade 4 dermatitis developed in one patient in the first cohort, and the cohort was expanded to six patients with no further dose limiting toxicities (DLT). The second cohort of 3 patients was well tolerated. The third cohort resulted in grade 3 diarrhea, requiring several days of hospitalization and IV hydration, in 3 of the 4 patients. Given the severity and duration of diarrhea, each of these was considered a DLT, and therefore cohort 3 was considered to be above the maximum tolerated dose. Six of the 13 patients achieved a partial or complete remission (46%). The time to progression ranged from 2 to 14 months. Conclusions Vandetanib at doses of 100 mg and 300 mg daily in combination with capecitabine and oxaliplatin was well tolerated. However, the addition of bevacizumab resulted in severe diarrhea in three out of four patients. Bevacizumab was not well tolerated with vandetanib and XELOX in combination.     

贝伐珠单抗联合化疗一二线治疗不可手术转移性结直肠癌临床观察

目的：评估现实治疗环境中贝伐珠单抗与化疗联合治疗转移性结直肠癌（mCRC）的疗效和毒性。方法：收集2010年10月至2013年4月间接受贝伐珠单抗联合化疗治疗的mCRC患者资料,近期疗效评估采用实体瘤疗效评价标准1.1版;Kaplan-Meier法估计生存时间;毒性评估采用国立癌症研究所不良事件标准3.0版。结果：74例患者入组,男性40例,女性34例;年龄31~74岁,中位年龄55.5岁;结肠癌44例,直肠癌30例;一线和二线治疗各37例;63例患者有可测量病灶,一线、二线治疗的客观有效率（ORR）分别为62.8%、28.6%;一线、二线治疗患者的中位无进展生存时间（PFS）和中位总生存时间（OS）分别为8.7个月、4.4个月和25.3个月、14.6个月;奥沙利铂及伊立替康为基础的化疗方案的中位PFS、中位OS分别为8.1个月、5.8个月和21.9个月、17.1个月,组间无统计学差异（P值分别为0.592和0.506）。全组各级高血压的发生率为9.5%、蛋白尿8.1%、静脉血栓形成2.7%、胃肠穿孔2.7%,伤口愈合综合症4.1%,出血17.6%。结论：贝伐珠单抗联合化疗治疗mCRC有效,贝伐珠单抗相关毒性的总体发生率较低。     

Role of the antiangiogenic agent bevacizumab in the treatment of elderly patients with metastatic colorectal cancer

Although major progress has been achieved in the treatment of metastatic colorectal cancer with the employment of biological antiangiogenic agents, several questions remain open for discussion regarding the use of this therapy in elderly patients with metastatic colorectal cancer. In Western countries, the total number of elderly patients with colorectal cancer is expected to increase in the future. As adverse physical or socioeconomic conditions are more common in the elderly, an assessment of the patient's suitability for this therapy should be performed before a treatment decision is made. Most patients in clinical trials of the antiangiogenic drug bevacizumab were aged <65 years and thus the efficacy and tolerability of this agent in older patients has been less well explored. However, this article shows that older and younger patients with metastatic colorectal cancer appeared to derive similar survival benefit from bevacizumab treatment. Elderly patients were also found to have significant prolongation of median progression-free survival with the addition of bevacizumab to their treatment, with a similar magnitude of improvement in this outcome being observed in younger and older patients. It should be emphasized that the patients included in the studies discussed in this article were eligible for clinical trials and therefore may not be representative of a more general elderly population. Careful selection of patients and monitoring of treatment effects are required to optimize use of the antiangiogenic agent bevacizumab in older patients.     

Phase II study of epirubicin plus oxaliplatin and infusional 5-fluorouracil as first-line combination therapy in patients with metastatic or advanced gastric cancer

The purpose of this study was to evaluate the efficacy and safety of an epirubicin, oxaliplatin and infusional 5-fluorouracil combination in patients with advanced gastric cancer. Patients with previously untreated advanced measurable gastric cancer received epirubicin (50 mg/m2, day 1), oxaliplatin (130 mg/m2 2-h infusion, day 1) and 5-fluorouracil (750 mg/m2, 24-h infusion, day 1-3) every 3 weeks. The primary endpoint of this phase II study was the response rate according to Response Evaluation Criteria in Solid Tumors. Out of 48 patients, 46 were evaluable for efficacy and 48 for toxicity. A median of five cycles (range 1-6) was administered. The overall best response rate was 47.8% (95% confidence interval 33-63%) including 2.2% complete responses and 45.6% partial responses. The median time for progression and median overall survival was 5 (95% confidence interval 4.1-5.9) and 11 months (95% confidence interval 8.1-13.9), respectively. Grade 3/4 neutropenia and leukocytopenia were observed in 25 and 12.5% of patients, respectively. Grade 3/4 nonhematological toxicities included nausea (6.3%), vomiting (14.6%), neurological toxicity (10.4%) and mucositis (2.1%). The epirubicin, oxaliplatin and infusional 5-fluorouracil regimen was effective and well tolerated as a front-line chemotherapy for patients with metastatic or advanced gastric cancer, and should be evaluated further.     

Phase II trial of edatrexate in patients with metastatic colorectal cancer

Summary Edatrexate is an analog of methotrexate whichin vitro demonstrated activity against human colon cancer xenografts grown in nude mice. In a phase II trial, 12 patients with metastatic colorectal cancer and no prior chemotherapy were treated with Edatrexate 80 mg/m²/week for an initial period of 8 weeks. No objective responses were observed. Edatrexate is inactive against colon cancer at the dose and schedule used in this trial.     

Phase II trial and pharmacokinetic study of thalidomide in patients with metastatic colorectal cancer

Introduction. This study was designed to estimate the percentage of objective tumor responses, toxicity profile, and obtain additional information about the plasma pharmacokinetics of thalidomide in patients with refractory and progressing metastatic colorectal cancer. Study design. This phase II clinical trial was conducted according to the two-stage Simon method with the inclusion of consecutive patients. The study protocol was approved by the Institutional Review Board (IRB) of the Academic Hospital (HCPA) of the Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Patients and methods. Seventeen patients with previously treated, refractory progressive metastatic colorectal cancer were eligible. Six patients had prior radiotherapy. The patients had a median of one previous chemotherapy regimen. Patients were initially treated with 200mg/day of thalidomide with an increase in dose by 200mg/day every 2 weeks until a final daily dose of 800mg/day was achieved. Patients were evaluated every 8 weeks for response by radiographic criteria. Plasma pharmacokinetics studies were performed in four patients at 200mg level and in one patient at 600mg during the first 24h. Main outcome measures and results. A total of 17 patients were accrued, all of them being evaluable for toxicity and 14 for response. Thalidomide was well tolerated, with constipation, somnolence, dizziness, and dry mouth being the major toxicities. There were no objective response or stable disease. The median survival was 3.6 months. Single-agent thalidomide is a generally well-tolerated drug that showed no antitumor activity in patients with advanced pretreated metastatic colorectal cancer. Although thalidomide did not show antitumor activity in this patient population, future studies of this agent in patients at initial stages of the disease (when its antiangiogenic properties may be more relevant to disease progression) could be considered.