Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.

BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer.

BACKGROUND: Annualised figures show an up to 7-fold higher incidence of vascular thromboembolism (VTE) in patients with advanced pancreatic cancer (APC) compared to other common malignancies. Concurrent VTE has been shown to confer a worse overall prognosis in APC. METHODS: One hundred and twenty three APC patients were randomised to receive either gemcitabine 1000 mg/m(2) or the same with weight-adjusted dalteparin (WAD) for 12 weeks. Primary end-point was the reduction of all-type VTE during the study period. NCT00462852, ISRCTN: 76464767. FINDINGS: The incidence of all-type VTE during the WAD treatment period (<100 days from randomisation) was reduced from 23% to 3.4% (p = 0.002), with a risk ratio (RR)of 0.145, 95% confidence interval (CI) (0.035-0.612) and an 85% risk reduction. All-type VTE throughout the whole follow-up period was reduced from 28% to 12% (p = 0.039), RR = 0.419, 95% CI (0.187-0.935) and a 58% risk reduction. Lethal VTE <100 days was seen only in the control arm, 8.3% compared to 0% (p = 0.057), RR = 0.092, 95% CI (0.005-1.635). INTERPRETATION: Weight adjusted dalteparin used as primary prophylaxis for 12 weeks is safe and produces a highly significant reduction of all-type VTE during the prophylaxis period. The benefit is maintained after dalteparin withdrawal although decreases with time.

A prospective study of chemotherapy-induced febrile neutropenia in the South West London Cancer Network. Interpretation of study results in light of NCAG/NCEPOD findings.

BACKGROUND: Chemotherapy-induced febrile neutropenia is a medical emergency complicating the treatment of many cancer patients. It is associated with considerable morbidity and mortality, as well as impacting on healthcare resources. METHODS: A prospective study of all cases of chemotherapy-induced febrile neutropenia in the South West London Cancer Network was conducted over a 4-month period. Factors including demographics, treatment history, management of febrile neutropenia and outcome were recorded. RESULTS AND CONCLUSION: Our results reflect those of the recent National Chemotherapy Advisory Group (NCEPOD, 2008)/National Confidential Enquiry into Patient Outcomes and Death reports (NCAG, 2009) and highlight the need for network-wide clinical care pathways to improve outcomes in this area.

Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study.

BACKGROUND: We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard chemotherapy. METHODS: Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression. RESULTS: In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively). CONCLUSION: Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.

13-cis-Retinoic acid in combination with gemcitabine in the treatment of locally advanced and metastatic pancreatic cancer--report of a pilot phase II study.

AIMS: Adenocarcinoma of the pancreas is a cancer with extremely poor prognosis and limited therapeutic options. Retinoids are derivatives of vitamin A involved in the control of many biological functions, including cell growth and differentiation and the induction of apoptosis. On the basis of pre-clinical evidence and some clinical data, we conducted a phase II study of 13-cis-retinoic acid (13-cis-RA) in combination with gemcitabine in patients with unresectable pancreatic carcinoma. MATERIALS AND METHODS: Patients with histologically confirmed unresectable pancreatic carcinoma were treated with gemcitabine 1000 mg/m2 on days 8, 15, 22 plus 13-cis-RA 1 mg/kg on days 1-14 for six cycles. The end points included the objective response rate and median survival. RESULTS: Thirty patients were recruited, 15 men and 15 women; 20 patients were evaluable. The median age was 65 years (range 44-79 years) and the median Karnofsky performance status was 80% (range 60-100%). The median follow-up was 21 months. One patient achieved a partial remission, seven patients had stable disease and 12 patients developed progressive disease. Toxicity was mainly haematological, with eight cases of grade 3 and four cases of grade 4 neutropenia, thrombocytopenia and anaemia. The median survival was 7.8 months (range 2.6-21.6 months). CONCLUSIONS: The combination of gemcitabine and 13-cis-RA was well tolerated, but we did not see improvement in the response rate. Further studies with other retinoids may be beneficial to patients with unresectable pancreatic cancer.

Gemcitabine and oxaliplatin followed by paclitaxel and carboplatin as first line therapy for patients with suboptimally debulked, advanced epithelial ovarian cancer. A phase II trial of sequential doublets. The GO-First Study.

OBJECTIVES: Gemcitabine and oxaliplatin are active in epithelial ovarian cancer with minimal overlapping toxicity. We studied the efficacy and toxicity of this combination in patients with advanced ovarian cancer when given prior to carboplatin and paclitaxel. METHODS: Chemonaive patients with epithelial ovarian cancer and measurable disease were eligible for the study. Treatment consisted of gemcitabine 1250 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8 every 21 days (GO) for 4 cycles. This was followed by carboplatin AUC = 6 and paclitaxel 175 mg/m2 on day 1 every 21 days (CP) for 4 cycles. RESULTS: Twenty patients, median age 62 years (range 39-78), FIGO stages III (16) and IV (4) received treatment. The response rate (RR) after 4 cycles of GO was 80% (95%CI 61-99%) (4 complete responses (CR), 12 partial responses (PR)). Interval debulking surgery was performed in 7 patients (35%). After CP chemotherapy, RR increased to 85% (95%CI 68-100%) (CR = 13, PR = 4). Median time to progression was 14.5 months. Estimated median overall survival was 31.5 months. Toxicities of GO were mild; grade 3/4 nausea in 3 patients (15%) and vomiting in 2 patients (10%), grade 3/4 neutropenia in 5 patients (25%). Grade 2/3 peripheral neuropathy occurred in 5 patients (25%). After sequential administration of CP, grade 2/3 neuropathy occurred in 13 patients (72%). CONCLUSION: The sequential doublet regimen of GO followed by CP resulted in unacceptable neurotoxicity and is not recommended for further study; however, the doublet gemcitabine and oxaliplatin has significant activity in the first line treatment of patients with ovarian cancer.

A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer.

BACKGROUND: We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of protracted venous infusion (PVI) 5-fluorouracil (5-FU) against the standard bolus monthly regimen of 5-FU/leucovorin (LV) given for 6 months as adjuvant treatment in colorectal cancer (CRC). PATIENTS AND METHODS: Patients with curatively resected stage II and III CRC were randomly assigned to 5-FU/LV [5-FU 425 mg/m(2) intravenously (i.v.) and LV 20 mg/m(2) i.v. bolus days 1-5 every 28 days for 6 months] or to PVI 5-FU (300 mg/m(2)/day for 12 weeks). RESULTS: Between 1993 and 2003, 801 eligible patients were randomised to 5-FU/LV (n=404) or PVI 5-FU (n=397). With a median follow-up of 5.3 years, 231 relapses and 220 deaths have been observed. Five-year relapse-free survival (RFS) was 66.7% [95% confidence interval (CI) 61.6% to 71.3%] and 73.3% (95% CI 68.4% to 77.6%) with bolus 5-FU/LV and PVI 5-FU, respectively [hazard ratio (HR) 0.8; 95% CI 0.62-1.04; P=0.10]. Five-year overall survival (OS) was 71.5% (95% CI 66.4% to 75.9%) and 75.7% (95% CI 70.8% to 79.9%) with bolus 5-FU/LV and PVI 5-FU, respectively (HR 0.79; 95% CI 0.61-1.03; P=0.083). There was a significant survival advantage for patients starting adjuvant chemotherapy within 8 weeks (P=0.044). Significantly less diarrhoea, stomatitis, nausea and vomiting, alopecia, lethargy, and neutropenia (all with P <0.0001) were seen with PVI 5-FU. CONCLUSIONS: There was no OS difference between the two arms, although PVI 5-FU was associated with a trend towards better RFS and OS compared with bolus 5-FU/LV, as well as significantly less toxicity. Based on our results, the probability of 12 weeks of PVI 5-FU being inferior to 6 months of bolus 5-FU/LV is extremely low (P <0.005), and therefore shorter duration of adjuvant treatment should be explored further.

A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year (with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months (patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 micro g of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies.

Twelve weeks of protracted venous infusion of fluorouracil (5-FU) is as effective as 6 months of bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer.

We performed a multicentre randomised trial to compare the efficacy and toxicity of 12 weeks of 5-fluorouracil (5-FU) delivered by protracted intravenous infusion (PVI 5-FU) against the standard bolus regimen of 5-FU and folinic acid (5-FU/FA) given for 6 months as adjuvant treatment in colorectal cancer. A total of 716 patients with curatively resected Dukes' B or C colorectal cancer were randomised to 5-FU/FA (5-FU 425 mg m(-2) i.v. and FA 20 mg m(-2) i.v. bolus days 1-5 every 28 days for 6 months) or to PVI 5-FU alone (300 mg m(-2) day for 12 weeks). With a median follow-up of 19.8 months, 133 relapses and 77 deaths have been observed. Overall survival did not differ significantly (log rank P=0.764) between patients receiving 5-FU/FA and PVI 5-FU (3-year survival 83.2 vs 87.9%, respectively). Patients in the 5-FU/FA group had significantly worse relapse-free survival (RFS, log rank P=0.023) compared to those receiving PVI 5-FU (3-year RFS, 68.6 vs 80%, respectively). Grades 3-4 neutropenia, diarrhoea, stomatitis and severe alopecia were significantly less (P<0.0001) and global quality of life scores significantly better (P&<0.001) for patients in the PVI 5-FU treatment arm. In conclusion, infused 5-FU given over 12 weeks resulted in similar survival to bolus 5-FU and FA over a 6 month period, but with significantly less toxicity.

A multicentre phase II trial of primary chemotherapy with cisplatin and protracted venous infusion 5-fluorouracil followed by chemoradiation in patients with carcinoma of the oesophagus.

BACKGROUND: We undertook a multicentre phase II trial to evaluate the safety and efficacy of primary chemotherapy followed by chemoradiation for localised adenocarcinoma or squamous carcinoma of the oesophagus. PATIENTS AND METHODS: Chemotherapy comprised five 3-weekly cycles of cisplatin and protracted continuous infusion 5-fluorouracil, with conformally planned radiotherapy commencing at the start of the fifth cycle. RESULTS: The planned treatment programme was completed by 39 of 72 patients (54%), and a further 13% completed chemotherapy and proceeded to surgical oesophagectomy. Response rates to chemotherapy and to the entire treatment programme were 47% [95% confidence interval (CI) 34% to 60%] and 56% (CI 43% to 68%). The dysphagia score improved in 54% of patients. The median survival duration was 14.6 months with 1- and 2-year survival rates of 58.7% and 44.1%, respectively. Grade III/IV chemotherapy-related toxicity occurred in 38% of patients, and there were no treatment-related deaths. CONCLUSIONS: This is a feasible and active treatment regimen providing palliative benefits for patients with poor-prognosis localised oesophageal cancer.

Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer.

PURPOSE: We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) (ECF) with the combination of mitomycin, cisplatin, and PVI 5-FU (MCF) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS: Five hundred eighty patients with adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma were randomized to receive either ECF (epirubicin 50 mg/m(2) every 3 weeks, cisplatin 60 mg/m(2) every 3 weeks and PVI 5-FU 200 mg/m(2)/d) or MCF (mitomycin 7 mg/m(2) every 6 weeks, cisplatin 60 mg/m(2) every 3 weeks, and PVI 5-FU 300 mg/m(2)/d) and analyzed for survival, response, toxicity, and quality of life (QOL). RESULTS: The overall response rate was 42.4% (95% confidence interval [CI], 37% to 48%) with ECF and 44.1% (95% CI, 38% to 50%) with MCF (P =.692). Toxicity was tolerable, and there were only two toxic deaths. ECF resulted in more grade 3/4 neutropenia and grade 2 alopecia, but MCF caused more thrombocytopenia and plantar-palmar erythema. Median survival was 9.4 months with ECF and 8.7 months with MCF (P =.315); at 1 year, 40.2% (95% CI, 34% to 46%) of ECF and 32.7% (95% CI, 27% to 38%) of MCF patients were alive. Median failure-free survival was 7 months with both regimens. Global QOL scores were better with ECF at 3 and 6 months. CONCLUSION: This study confirms response, survival, and QOL benefits of ECF observed in a previous randomized study. The equivalent efficacy of MCF was demonstrated, but QOL was superior with ECF. ECF remains one of the reference treatments for advanced esophagogastric cancer.

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer.

Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10-15 microg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82-532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states.

Issues of normal tissue toxicity in patient and animal studies--effect of carbogen breathing in rats after 5-fluorouracil treatment.

Non-invasive magnetic resonance spectroscopy (MRS) can be used in the clinic to monitor the pharmacokinetics of the chemotherapeutic drug 5-fluorouracil (5-FU) and the effects of modifiers. We report two studies of 5-FU toxicity in normal tissue--one with patients and the other an animal study. 1) 19F MRS signals from fluoronucleotides, cytotoxic anabolites of 5-FU metabolism, were observed in the livers of two patients treated with 5-FU for colorectal cancer, shown by computed tomography (CT) and ultrasound (US) to have no liver metastases. This is the first report of non-invasive monitoring of toxic 5-FU metabolites in normal human tissues. 2) In animals, carbogen-breathing enhances tumour uptake and the efficacy of 5-FU, and the method is under trial in patients. This study demonstrates that there were no significant effects of carbogen breathing on the levels of 5-FU and its metabolites in normal rat tissues, or on the histology of the tissues assessed after treatment.

Evaluation of the chemotherapy patient monitor: an interactive tool for facilitating communication between patients and oncologists during the cancer consultation.

Effective communication between oncologists and patients with cancer is of paramount importance. The Chemotherapy Patient Monitor (CPM) is a novel tool designed to assist doctor-patient communication regarding patient concerns and side-effects. Initially, the CPM was assessed in a primary evaluation study of its use during consultations with 26 patients with advanced colorectal cancer (one consultation without, followed by two with, the CPM per patient). This led to a further dissemination/audit of 34 patients attending oncology centres in the UK, who had completed the survey prior to three consultations. The CPM contains a checklist of common side-effects of chemotherapy regimens used in advanced colorectal cancer, and other common concerns of patients with advanced colorectal cancer. The CPM records the presence of side-effects/concerns, the distress caused, whether patients wish to discuss them further, and actions taken as a result. Questionnaires explored the views of patients and oncologists in the UK and Spain regarding the effectiveness of consultations during a baseline visit conducted without the CPM, and then with the CPM in subsequent visits. These data were then complemented by the dissemination/audit study of the CPM across nine centres in the UK. All patients understood the CPM. The CPM was rated as useful by oncologists in 83% of consultations, and did not lengthen 82% of visits. Patients felt it had improved the visit in 95% of cases. Responses from patients (100%) and oncologists (84%) indicated willingness to use the CPM for at least some consultations in the future. The results of the dissemination/audit study supported these conclusions. We conclude that the CPM appears to be a useful new tool for improving patient-doctor communication during cancer consultations.

A phase II study of epirubicin, cisplatin and raltitrexed combination chemotherapy (ECT) in patients with advanced oesophageal and gastric adenocarcinoma.

BACKGROUND: The aim of this study was to evaluate the efficacy of the combination of epirubicin, cisplatin and ralitrexed (Tomudex). ECT, in patients with advanced oesophageal or gastric adenocarcinoma. Efficacy was assessed primarily as response rate and secondarily in terms of toxicity, time to progression and survival. PATIENTS AND METHODS: Twenty-one patients with histologically and/or cytologically proven unresectable (7) or metastatic (14) gastro-oesophageal adenocarcinoma, who had bi-dimensionally measurable disease, with ECOG performance status < or = 2. with adequate haematological, hepatic and renal function received first-line chemotherapy with epirubicin (50 mg/m2). cisplatin (60 mg/m2) and Tomudex (2.5 mg/m2), ECT, at three-weekly intervals. Treatment consisted of three cycles of chemotherapy, with a further three cycles if there was disease response or stabilisation. RESULTS: ECT is an active regimen in the treatment of advanced gastro-oesophageal adenocarcinoma with an overall intention-to-treat response rate of 29% (95% confidence intervals (CI): 11%-52%). In addition, 4 (19%) patients had stable disease. Median time to progression was 19 weeks (95% CI: 7-31 weeks). Median overall survival was 18 weeks (95% CI: 11-24 weeks). Seventeen patients failed to complete the six cycles of treatment due to disease progression (5). toxicity (3), non-toxic death (1 pulmonary embolism, 1 cardiac), severe allergy to epirubicin (1), patient decision (1) and five patients after the study was discontinued early due to toxicity. There were three toxic deaths: two due to sepsis complicating neutropaenia and one due to cardiorespiratory failure following drug induced enteritis. Nine patients experienced grade 3 or 4 neutropaenia, two patients experienced grade 3 or 4 nausea and vomiting and one patient had grade 4 diarrhoea. CONCLUSIONS: The combination of epirubicin, cisplatin and tomudex is active against advanced gastro-oesophageal adenocarcinoma but the toxicity suggests that further evaluation in a randomised comparison to ECF is not appropriate.

Effective treatment of a patient with a high-grade endometrial stromal sarcoma with an accelerated regimen of carboplatin and paclitaxel.

The rarity of endometrial stromal sarcoma (ESS) and its poor response to treatment provides fertile ground for investigational therapies. An accelerated regimen of carboplatin and paclitaxel is investigated. A patient with a recent history of treated tuberculosis of the lung represented with infertility and acute abdominal pain from suspected fibroids, and underwent a laparotomy with a diagnosis of a high-grade ESS. A novel therapeutic approach using a regimen of carboplatin and paclitaxel with the reinfusion of filgrastim-mobilized peripheral blood progenitor cells is described. A partial response was observed following six cycles of chemotherapy. Grade IV thrombocytopenia occurred after the last cycle, with recovery prior to pelvic radiotherapy. The patient remained well 1 year post-diagnosis. High-grade ESS is responsive to combination chemotherapy with paclitaxel and carboplatin, and requires further evaluation. The use of an accelerated regimen may also have contributed to the response and this question awaits randomized trials.

Phase I study of ONO-4007, a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide.

ONO-4007 is a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide, which exhibits antitumor activity by the induction of intratumoral tumor necrosis factor alpha, the potentiation of tumor-infiltrating macrophages, and the inhibition of angiogenesis. Interleukin (IL)-1 alpha, IL-6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cells to up-regulate IFN-gamma and nitric oxide synthase activity. ONO-4007 was given to 24 patients (13 males and 11 females; median age, 53 years) as a 30-min i.v. infusion on day 1, followed on day 15 by a first treatment cycle consisting of three weekly infusions at the same dose, followed by a rest period of 1 week. Cohorts of six patients received up to a maximum of four treatment cycles at increasing dose levels (75, 100, and 125 mg). The maximum tolerated dose was 125 mg, with grade 3 National Cancer Institute Common Toxicity Criteria toxicity (rigors with cyanosis) occurring in two of six patients at this dose level. An additional six patients were treated at 100 mg, the dose below the maximum tolerated dose. Other toxicities included grade 2 National Cancer Institute Common Toxicity Criteria myalgia, nausea, and hypotension. The pharmacokinetics of ONO-4007 appeared to be independent of dose and showed linearity with respect to time. ONO-4007 has a low systemic clearance (approximately 1.3 ml/min) and a small volume of distribution (5-8 liters) with a long t1/2 of 74-95 h. The administration of ONO-4007 was shown to result in a significant increase in circulating levels of tumor necrosis factor alpha and IL-6. No objective antitumor responses were observed. Seven patients maintained stable disease for at least two cycles, whereas five patients maintained stable disease for the full four-cycle duration of the study. Additional studies are required to determine the antitumor activity of ONO-4007.