A Phase II Study of KRN8602(MX2), a Novel Morpholino Anthracycline Derivative,in Patients with Recurrent Malignant Glioma

KRN8602(MX2) is a newly developed morpholino-anthracycline that has been found to cross the blood–brain barrier and be distributed in brain tissue after intravenous administration and to be effective against human glioma cells and the intracerebrally transplanted tumors in vivo. In order to confirm these promising preclinical observations clinically, we performed a phase II trial of KRN8602 in patients with recurrent malignant glioma.The 44 patients enrolled received at least 2 cycles of KRN8602 35mg/m2/day at 3–4 week intervals by intravenous bolus. Of the 44 patients, 37 could be evaluated for response, and 39 for toxicity. One patient with anaplastic astrocytoma had a complete response (1/37, 3%), and 2 patients with anaplastic astrocytoma and 1 with brain stem glioma had a partial response (3/37, 8%). The overall response rate was 11% (4/37). All patients who responded had received prior chemotherapy that included nitrosoureas. No response was observed in the patients with glioblastoma.Myelosuppression was moderately severe, with 72% of patients developing grade 3 or 4 leukopenia. Severe nausea/vomiting was observed in 31% of the patients. No severe cardiotoxicity was observed.The results indicate that KRN8602 has modest activity against recurrent malignant glioma with relatively severe, but manageable toxicity. It seems to be worthwhile to further assess the efficacy and toxicity of KRN8602 against malignant glioma, which is generally less sensitive to chemotherapy.     

MX2; 3'-deamino-3'-morpholino-13-deoxy-10-hydroxycarminomycin (KRN8602) in Refractory Metastatic Breast Cancer: Results of a Preliminary Phase II Trial

We performed a preliminary phase II clinical trial of MX2; 3'-deamino-3'-morpholino-13-deoxy-10-hydroxycarminomycin (KRN8602) in patients with metastaticbreast cancer who had failed to respond to previous chemotherapeuticregimens after clinical evidence of systemic disease. Twelvepatients at a single institute received KRN8602 at a dose of35 mg/m2 intravenously once every three weeks. All the patientswere folio wed-up until their disease progressed. There wasone complete response lasting 17 weeks and one partial responselasting eight weeks. Among the 12 patients, World Health Organization(WHO) grades 3 and 4 neutropenia were observed in five and twopatients, respectively. Grade 3 anemia was observed in threepatients but severe thrombocytopenia was not observed. Grade3 nausea/vomiting was observed in eight patients. Alopecia wasnot observed. The results of this preliminary phase II trialsuggest a need for further testing of the anti-tumor activityof KRN8602 in patients with metastatic breast cancer.     

Intrathecal Chemotherapy with MX2 for Treating Glioma Dissemination in vivo

We examined whether the intrathecal MX2 chemotherapy for treating dissemination of malignant glioma would be a feasible therapy. In the toxicity study, physiological and histological neurotoxicity was not observed in the rats treated with less than 100g/kg of MX2 administered intracisternally. But physiological side effects were observed in the treatment group of more than 200g/kg and histological brain toxicity was in the treatment group of more than 1000g/kg. Dissemination models were induced in rats by intracisternal inoculation of C6 glioma cells. The median survival times of the rats treated with 100g/kg of intrathecal MX2 on day 1, 3, or 7 after tumor inoculation were prolonged by 52.4% (p=0.0006), 31.5% (p=0.0007), and 7.1% (p=0.0180), respectively, compared to that of untreated control animals. Intrathecal MX2 treatment also cured 33.6% of rats in the treatment group. These findings suggested that there was a possibility that intrathecal MX2 would be a safe and effective method for treating dissemination of malignant glioma.     

Antitumor Activity and Pharmacokinetics of a Morpholino-anthracycline Derivative (KRN8602) against Human Breast Carcinoma Xenografts Serially Transplanted into Nude Mice

The antitumor activity and pharmacokinetics of (7 R , 8 S , 10 S )-10-((3-deamino-3-(4-morpholino)-2,3,6-trideoxy-α- l - lyxo -hexopyranosyl)oxy)-8-ethyl-7,8,9,10-tetrahydro-1,6,7,8,11-pentahydroxy-5,12-naphthacenedione hydrochloride (KRN8602) were evaluated using five human breast carcinoma xenografts in nude mice. The maximum non-toxic dose of KRN8602 was 2 mg/kg by q4d×3 intraperitoneal and peroral administration. KRN8602 showed significant antitumor activity against MX-1, which is less sensitive to adriamycin, with the chemotherapeutic indices of 13.0 for po administration and 9.5 for ip injection. Although KRN8602 also inhibited the growth of T-61 significantly, the antitumor activity of this agent against the other three breast carcinoma xenografts was limited. To elucidate this discrepancy, pharmacokinetic analysis and MTT assay were conducted using the KRN8602-sensitive MX-1 and KRN8602-insensitive R-27. While no differences were observed in the area under the curve and the peak concentration of KRN8602 for each tumor, a difference in the sensitivity of the tumor strains was obvious in MTT assay. The efficacy of this agent seemed to depend on the sensitivity of each type of tumor cell rather than the concentration of agent in tumor tissues. If it were possible to select patients with sensitive tumor cells to this agent by the MTT assay, the phase II trial might be completed within a short period by reducing the number of studied patients.     

Second Line Chemotherapy with Docetaxel in Patients with Recurrent Malignant Glioma: A Phase II Study

The objective of the study was to assess the efficacy of docetaxel in recurrent supratentorial malignant gliomas. The sample size of the study was determined by the Gehan's method for a response rate of 20% and a error of 5%. In the first step 14 patients (age 27–69, median 50; Karnofsky index 50–90, median 75) with recurrent malignant glioma after surgery, radiotherapy and nitrosourea, were enrolled (12 glioblastomas, 2 anaplastic astrocytomas). Docetaxel at the initial dose of 80mg/m² was administered every 3 weeks until progression or unacceptable toxicity. A total of 41 cycles was administered. Patients received a median of two cycles (range 1–6). No complete or partial response was observed. Therefore, according to the design of the study, no additional patients were enrolled and the trial was terminated. Two stabilizations were observed (14 and 15 weeks). Median TTP was 7 weeks (44 days). Median overall survival from recurrence was 26.5 weeks (6.4 months). Grade 3–4 neutropenia was observed in 8 patients (57%) but no life-threatening toxicity was observed. Other toxicities were uncommon and mild. Dose reduction was performed in 5 patients. This study suggests that docetaxel displayed no significant activity in patients with malignant recurrent gliomas.     

Intra-arterial Cisplatin Plus Oral Etoposide for the Treatment of Recurrent Malignant Glioma: A Phase II Study

Twenty-five adults with recurrent malignant glioma were enrolled into a phase II clinical study. All patients had undergone surgical resection and had failed radiotherapy and first-line treatment with nitrosourea-based chemotherapy; five had failed second-line chemotherapy. Our objective was to test the efficacy of combining intra-arterially (IA) infused cisplatin and oral etoposide. Using conventional angiographic technique to access anterior/posterior cerebral circulation, cisplatin 60mg/m² was administered by IA infusion on day 1 of treatment. Oral etoposide 50mg/m²/day was given days 1–21, with a 7day rest interval between courses. Response to treatment was evaluated in 20 patients. Two patients with anaplastic astrocytoma had partial responses (PR) and six patients experienced stable disease (SD) for an overall response rate (PR + SD) of 40%. The median time to disease progression (MTP) following treatment for the responder subgroup was 18weeks. The median survival time from treatment (MST) for the responders (n=8) and non-responders (n=12) was 56.5weeks and 11weeks, respectively. Combined IA cisplatin and oral etoposide was well-tolerated, but produced an objective response in only a minority of patients. Those considered responders (PR + SD) experienced significant survival advantage when compared to the non-responders. Nonetheless, IA delivery of chemotherapy is an expensive and technologically burdensome treatment for most patients to access, requiring proximity to a major center with neuro-oncological and neuroradiological clinical services. This is of special concern for patients suffering recurrent disease with progressive neurological symptoms at a time in their course when quality of life must be safeguarded and palliation of symptoms should be the therapeutic goal. Despite the efforts of previous investigators to use this combination of agents to treat recurrent malignant glioma, we cannot recommend the use of IA chemotherapy for salvage treatment of thisbreak disease.     

Phase II study of KRN8602, 3′-deamino-3′-morpholino- 13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 · HCl in patients with metastatic breast cancer

Purpose: KRN8602 (3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 · HCl) is a newly developed anthracycline that has been found to be effective against multidrug-resistant tumor cells in vitro and in vivo. In order to clinically confirm these promising preclinical observations, we performed a phase II trial of KRN8602 in patients with anthracycline-resistant metastatic breast cancer. Methods: Of 41 patients registered with metastatic breast cancer, 37 were eligible and were given at least two cycles of KRN8602 15 mg/m² per day at 3–4 week intervals by intravenous bolus injection on days 1, 2, and 3. Results: Of the 37 patients, 6 (16.2%, with a 95% confidence interval of 4.3–28.1%) had a partial response (PR). No complete responses (CRs) were observed. The difference between response rates according to prior history of anthracycline administration was not significant. Myelosuppression was moderately severe, with grade 3 or 4 leukopenia occurring in 65%. Severe nausea/vomiting was observed in 44% of the patients. Conclusions: The results indicate that KRN8602 has modest activity in refractory metastatic breast cancer and is associated with relatively severe toxicity. Furthermore, the preclinical finding that KRN8602 overcomes anthracycline resistance was not reliably reproduced in this clinical phase II trial. Received: 20 May 1998 / Accepted: 15 October 1998     

AKT1 and AKT2 Promote Malignant Transformation in Human Brain Glioma LN229 Cells

OBJECTIVE To confirm the role played by AKT1 and AKT2 in the β-catenin/Tcf-4 signaling pathway in promoting malignant transformation of glioma cells. METHODS LN229 cells were divided into five groups:a control group, acetone(ACE)group, acetylsalicylic acid(ASA; aspirin)group,ASA+AKT1 plasmid group and ASA+AKT2 plasmid group. Western blot and PCR were used to detect the expression of AKT1 and AKT2 after dealing with ASA and transferring AKT1/2 genes into LN229 cells. Cell proliferation was determined by flow cytometry, cell invasion was evaluated by transwell assay and cell apoptosis was detected with annexin V staining. The molecules regulating proliferation and invasion were examined by western blot analysis.RESULTS Aspirin down-regulates AKT1 and AKT2 expression by modulating R-catenin/Tcf-4 activity.AKT1 and AKT2 can enhance cell proliferation and invasion by up-regulating the expression of cyclin-D and matrix metal loprotein-9(MMP-9)in LN229 glioma cells. CONCLUSION AKT1 and AKT2 play an important role in the β-catenin/Tcf-4 signaling pathway promoting malignant transformation; AKT1 is more effective than AKT2.AKT1 and AKT2 may be potential targets for brain glioma therapy and an effective way to prevent metastasis of gliomas.     

Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although a wide range of therapeutic options is available, the efficacy of these methods and the prognosis of patients with HCC remain very poor. This study was conducted to evaluate the efficacy and safety of viscum fraxini-2 in patients with chemotherapy-na?ve, advanced hepatocellular carcinoma. 23 patients with unrespectable HCC who had received no prior systemic chemotherapy with objectively measurable tumors were enrolled on this study. The mistletoe preparation for the study is an aqueous injectable solution. It contains one milliliter of viscum fraxini in dilution stage-2 (15 mg extract of 20 mg mistletoe herb from ash tree, diluted in di-natrium-mono-hydrogen phosphate, ascorbic acid and water) which is equivalent to 10 000 ng/ml injection ampoules. 2 ampoules of viscum fraxini-2 were administered subcutaneously once weekly. As assessed by conventional imaging criteria, 3 (13.1%) patients have achieved complete response, 2 (8.1%) patients have achieved a partial response. 9 (39.1%) had progressive disease while 9 (39.1%) patients didn't have evaluation of response due to early death. The median overall survival time for all patients was 5 months (range 2-38 months), for those who achieved a CR was 29 months (range 12-38 months) and, for those who achieved a PR was 6.5 months (range 6-7 months). The median progression free survival for all patients was 2 months (range 1-38 months), for those who achieved a CR, it was 29 months (range 8-38 months) and for those who achieved a partial response, it was 5 months (range 4-6 months). No hematologic toxicity has been encountered. The spectrum of non-hematologic toxicity was mild. The WHO toxicity criteria grade 3-4 were 34.8% drug related fever, 13.1% erthyma at injection site and 17.4% pain at the site of injection. No drug related discontinuation or toxic deaths have occurred. Viscum fraxini-2 seems to be particularly promising in patients with advanced HCC, it shows antitumor activity and low toxicity profile. Further studies in combination with other active agents are clearly warranted.     

Phase II Trial of Cisplatin Plus Temozolomide, in Recurrent and Progressive Malignant Glioma Patients

We report a phase II trial of cisplatinum and temozolomide (TMZ) combination in recurrent malignant glioma patients. The DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGAT) is important in glioblastoma resistance to alkylating antitumor agents. In vitro, cisplatin (CDDP) decreases MGMT activity in a time- and dose-dependent manner. Thirty-three recurrent malignant glioma patients (20 GBM-13 AA) were treated at recurrence or progression with a CDDP and TMZ association. On days 1 and 2, iv CDDP (40 mg/sqm) was administered. TMZ (at the dose of 200 mg/sqm) was administered as a single oral daily-dose on days 2-6 (starting 24 h after the first CDDP dose), the cycle was repeated every 4 weeks. All patients had been previously treated with surgery followed by radiotherapy and CDDP + BCNU chemotherapy. The primary endpoint of the study was progression free survival at 6 months (PFS-6). Secondary endpoints included radiological response and toxicities. Thirty-three patients received a total of 113 courses (median 3 range 1-11). Complete responses were not observed, partial responses were 18.8% with an additional 39.9% of stable disease. For the whole group of patients the PFS at 6 and 12 months was 52% and 15% with a median TTP of 33 weeks. PFS-6 for GBM and Anaplastic astrocytoma (AA) were 35% and 69%, respectively. PFS-12 for GBM and AA were 13.8% and 17.3%, respectively. Median TTP was 21.3 and 39.5 weeks, respectively. The principal toxic effects of the regimen were: neutropenia (5 WHO grade IV), thrombocytopenia (4 WHO grade IV), nausea and vomiting.     

Safety, Tolerability, and Tumor Response of IL4-Pseudomonas Exotoxin (NBI-3001) in Patients with Recurrent Malignant Glioma

Purpose: This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. Patients and methods: A total of 31 patients with histologically verified supratentorial grades 3 and 4 astrocytoma were studied. Of these, 25 patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma. Patients were over 18 years of age and had Karnofsky performance scores 60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6µg/ml×40ml,9µg/ml×40ml,15µg/ml×40ml, or 9µug/ml×100ml of NBI-3001 administered via convection-enhanced delivery intratumorally using stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. Results: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6µug/ml×40ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. Conclusions: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.     

Interstitial Docetaxel (Taxotere), Carmustine and Combined Interstitial Therapy: a Novel Treatment for Experimental Malignant Glioma

Docetaxel (Taxotere) is a hemisynthetic, anti-cancer compound with good preclinical and clinical activity in a variety of systemic neoplasms. We tested its activity against malignant gliomas using local delivery methods. Antitumor activity was assessed in vitro against human (U87 and U80 glioma) and rat brain-tumor (9L gliosarcoma and F98 glioma) cell lines. For in vivo evaluation, we incorporated docetaxel into a biodegradable polymer matrix, determined associated toxicity in the rat brain, and measured efficacy at extending survival in a rat model of malignant glioma. Also, we examined the combined local delivery of docetaxel with carmustine (BCNU) against the experimental intracranial glioma. Rats bearing intracranial 9L gliosarcomas were treated 5 days after tumor implantation with various polymers (placebo, 5% docetaxel, 3.8% BCNU, or 5% docetaxel and 3.8% BCNU combination). Animals receiving docetaxel polymers (n = 15, median survival 39.1 days) had significantly improved survival over control animals (n = 12, median survival 22.5 days, P = 0.01). Similarly, animals receiving BCNU polymers (n = 15, median survival 39.3 days, 13.3% long-term survivors) demonstrated an increase in survival compared to the controls (P = 0.04). Animals receiving the combination polymers demonstrated a modest increase in survival compared to either chemotherapeutic agent alone (n = 14, median survival 54.9 days, 28.6% long-term survivors) with markedly improved survival over controls (P = 0.003). We conclude that locally delivered docetaxel shows promise as a novel anti-glioma therapy and that the combination of drug regimens via biodegradable polymers may be a great therapeutic benefit to patients with malignant glioma.     

Phase II Study of Weekly Dose-intensified Cisplatin Chemotherapy with Oral Etoposide in Recurrent Glioma

Background. In most patients with recurrent glioma chemotherapy is the only remaining treatment option. In general results of chemotherapy in these patients are poor, and trials on new regimens are indicated. Because relatively good results have been achieved with combinations of platin compounds and etoposide, we investigated a dose-intensified cisplatin regimen with oral etoposide.Methods. Eligible patients, with recurrent glioma after surgery and radiation therapy were treated with two four week-cycles with cisplatin 70 mg/m² on days 1, 8 and 15, combined with oral etoposide 50 mg daily on days 1–15. In responding or stabilized patients, treatment was continued with six four week-cycles of oral etoposide 50 mg/m² on days 1–21. Toxicity was assessed using the NCI Common Toxicity Criteria, a 50% decrease in contrast enhancing area on MRI scan was considered a partial response. Time to progression was measured from the start of chemotherapy.Results. Sixteen patients were included, 11 were progressive during or immediately after the induction cycles. Two patients achieved a partial response with a time to progression of 42 and 58 weeks. Three patients were stable for 11, 14 and 15 weeks respectively. Toxicity was modest.Discussion. This dose-intensified cisplatin regimen did not result in a significant number of objective responses and even the number of stable disease was small. Given the low response rate of this intensive treatment, we consider this intensive regimen inappropriate for these patients.     

Phase II study of XR5000 (DACA) administered as a 120-h infusion in patients with recurrent glioblastoma multiforme.

BACKGROUND: XR5000 is a tricyclic carboxamide that intercalates DNA and inhibits both topoisomerase I and II. The aim of this study was to evaluate the efficacy and tolerability of XR5000 in patients with recurrent glioblastoma multiforme previously untreated with chemotherapy at relapse. PATIENTS AND METHODS: Patients received XR5000 at a dose of 3010 mg/m2 as a 120-h central venous infusion every 3 weeks. An independent panel assessed response every two cycles using McDonald's criteria (tumour size, steroid intake and neurological status); toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria, version 2.0. RESULTS: Sixteen patients were enrolled (one ineligible patient was excluded from efficacy evaluation). Performance status was zero (five patients), one (nine patients) or two (one patient). They received 30 cycles of XR5000 (median 2, range 1-5). Haematological toxicity was mild, with only one patient experiencing grade 3 neutropenia. Other related grade 3/4 adverse events included chest pain (one patient), axillary vein thrombosis (one patient) and rigors/fever in the absence of neutropenia (one patient). There were no objective responses, 14 patients progressing on XR5000 and one having stable disease. CONCLUSIONS: Although XR5000 was generally well tolerated, these results do not support further evaluation in patients with glioblastoma multiforme using this dose and schedule.     

NCIC-CTG phase II study of gemcitabine in patients with malignant glioma (IND.94).

Purpose:We conducted a phase II multicentre study of gemcitabinein patients with anaplastic astrocytoma and glioblastoma multiforme at firstrelapse. Patients and methods:Patients with anaplastic astrocytoma orglioblastoma multiforme receiving a stable dose of steroids and ECOGperformance status 3 were eligible for this study at the time of firstrelapse. One adjuvant chemotherapy regimen was permissible. Patients receivedgemcitabine 1000 mg/m² i.v. weekly × 3, repeated on afour-weekly cycle. Results:Of 20 patients enrolled, 15 were evaluable for response,19 for non-hematological toxicity and 18 for hematological toxicity. Sevenpatients had anaplastic astrocytoma (AA) and twelve glioblastoma multiforme(GBM). Age ranged from 28–71 years (median 50). Fifteen patientsdiscontinued therapy due to disease progression. The median number of cyclesadministered was 1 (range 1–11); only two patients received more thanthree cycles. Hematologic toxicity was acceptable and no grade 4 toxicity wasseen. One patient developed Pneumocystispneumonia and eventualpulmonary embolism; one died of gastric hemorrhage related to steroid therapy.No objective responses were seen. Nine patients had stable disease (medianduration 2.7 months, range 0.9–11.2). Conclusions:Gemcitabine given in this dose and schedule seemswell tolerated but is not active in patients with recurrent high-gradegliomas.     

A Phase II Study with Teniposide (VM26) in Patients with Progressed or Relapsed Small Cell Lung Cancer (SCLC)

Summary

Sixteen patients with advanced small cell lung cancer who relapsed or progressed under first-line therapy, were treated with second-line chemotherapy consisting of: teniposide, 60 mg/m², i.v. days 1-5, every 3 weeks until further progression.

The response rate was: 3 minor responses, 6 stable disease, 5 progressive disease, 1 early death and 1 not evaluable. After the introduction of teniposide, median survival was 4.5 (range 1-11) months, compared to the median survival (2 months, range 1-11) observed in 40 contemporary patients of our series, who relapsed or progressed and subsequently received no treatment. The assessment of the difference was significant: chi-square = 4.05, P<0.05. In addition a particular comparison was performed with 15/40 patients who matched according to the major predictive parameters of disease. These patients experienced 2 months (range 1-7) of median survival which was significantly shorter than that of the teniposide treated group (chi-square = 4.48, P< 0.05). On these bases, teniposide appeared to be effective, but the small size of the study suggests caution in evaluating the results.     

Phase I/II study of gemcitabine in association with vinorelbine for metastatic breast cancer

Background. Gemcitabine (G) and vinorelbine (V) have favorable safety profile and antitumor activity in metastatic breast cancer. To exploit their different mechanism of action and lack of overlapping toxicity, we performed a phase I and II study of G and V in combination. Patients and methods. Fifty-three patients with metastatic breast cancer were treated. In the dose-finding phase, seven cohorts of patients (22 women) received increasing doses to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the combination. Patients recruited in the phase II portion of the study (31 women) received the dose level immediately below the one defined as MTD (i.e., G 1200mg/m², V 30mg/m², on day 1 and day 8, every 3 weeks). Results. Dose escalation was discontinued at G 1400mg/m² and V 30mg/m² because of toxic death due to thrombocytopenia and CNS hemorrage. No other limiting toxicities were observed, and tolerability was similar at all dose levels studied in the escalation portion of the study. The main toxicity was granulocytopenia of grade 3/4 in 36 and 48% of the patients on phase I and II respectively, without episodes of neutropenic fever. Thrombocytopenia was uncommon. Other side effects were usually mild to moderate. In 46 evaluable patients, the response rate was 24% (complete response 7%, partial response 17%). Disease stabilization was observed in further 17%. The median duration of response was 12 months (range 5–14) and the median survival was 20 months (range 1 to 45+). Conclusions. G and V, on day 1 and 8 of 3-weekly cycles, can safely be administered to patients with metastatic breast cancer at the dose of 1200 and 30mg/m², respectively. The antitumor activity of G and V in combination was similar to that reported when using either drug as single agent.     

Phase II study of S-1 in patients with advanced biliary tract cancer

The aim of this study was to investigate the efficacy and safety of an oral fluoropyrimidine derivative, S-1, in patients with advanced biliary tract cancer. Patients with pathologically confirmed advanced biliary tract cancer, a measurable lesion, and no history of radiotherapy or chemotherapy were enrolled. S-1 was administered orally (40 mg m(-2) b.i.d.) for 28 days, followed by a 14-day rest period. A pharmacokinetic study was performed on day 1 in the initial eight patients. In all, 19 consecutive eligible patients were enrolled in the study between July 2000 and January 2002. The site of the primary tumour was the gallbladder (n=16), the extrahepatic bile ducts (n=2), and the ampulla of Vater (n=1). A median of two courses of treatment (range, 1-12) was administered. Four patients achieved a partial response, giving an overall response rate of 21.1%. The median time-to-progression and median overall survival period were 3.7 and 8.3 months, respectively. Although grade 3 anorexia and fatigue occurred in two patients each (10.5%), no grade 4 toxicities were observed. The pharmacokinetic parameters after a single oral administration of S-1 were similar to those of patients with other cancers. S-1 exhibits definite antitumour activity and is well tolerated in patients with advanced biliary tract cancer.     

A Phase II Study of Recombinant Granulocyte Macrophage Colony Stimulating Factor in Patients with Non-Hodgkin's Lymphoma

Myelosuppression is often the major limiting factor that prevents timely administration of cytotoxic chemotherapeutic agents, particularly in chemoresponsive malignancies. A study was designed to assess the role of GM-CSF in preventing myelosuppression in patients with intermediate-grade non-Hodgkin's lymphoma receiving combination chemotherapy (Cyclophosphamide, Vincristine, Prednisone and Epirubicin or Mitozantrone, ± Bleomycin). A total of 24 patients were entered and data collated from 20 of them are amenable to analysis.

All patients received the first chemotherapy cycle without GM-CSF and the second with GM-CSF (250 mg/m² subcutaneously twice daily for 5 days commencing on the 5th day following chemotherapy). By entering only those patients who had suffered myelosuppression following chemotherapy, an internal control was established. GM-CSF administration significantly reduced the degree of neutropenia and leucopenia. The mean nadir white blood cell (WBC) and absolute neutrophil counts (ANC) were 2.88 × 10⁹/L and 0.97 × 10⁹/L in cycle 1 as compared to 5.95 × 10⁹/L and 2.92 × 10⁹/L respectively, in cycle 2 (p = 0.05 and 0.02, respectively). Eight patients (40%) had febrile neutropenias and 13 patients (65%) experienced a treatment delay by a median of 8 days during cycle 1. Six patients (30%) had febrile neutropenias and 2 patients (10%) had a treatment delay of 3 days during cycle 2. Reversible toxicity was seen in the majority of patients: bone pains (60%), skin rashes (35%), arthralgias (25%), and altered taste sensation (10%). No patient developed the capillary leak syndrome. This study demonstrates the efficacy of GM-CSF in preventing chemotherapy-induced myelosuppression.     

应用GM-CSF治疗恶性肿瘤化疗后白细胞减少的临床研究

本文研究总结了北医联合生物工程公司研制的GM-CSF，应用于恶性肿瘤化疗引起的白细胞减少12例，其白细胞减少时间较对照组缩短5天。对合并感染的病人有较明显的抗感染作用，降低了抗生素的作用时间，临床应用常规剂量未发生明显副作用。是肿瘤根治性化疗的抢救、保驾药品。