Safety,tolerability, and tumor response of IL4-Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma

Summary Purpose: This was an open-label, dose-escalation trial of intratumoral administration of IL-4Pseudomonas 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: 6 μg/ml × 40 ml, 9 μg/ml × 40 ml, 15 μg/ml × 40 ml, or 9 μg/ml × 100 ml 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 6 μg/ml × 40 ml. 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.     

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.     

Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients

Background:Previous work demonstrated that 5-fluorouracil(5-FU) metabolism is a critical factor for treatment tolerability. Inorder to study the predictivity of pharmacokinetics with respect to theoccurrence of 5-FU toxicity, this study investigates the relationshipbetween the pharmacokinetics of 5-FU and its metabolite5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase(DPD) activity in peripheral blood mononuclear cells (PBMNC) andtreatment tolerability. Patients and methods:Pharmacokinetics and metabolismof 5-FU and activity of DPD in PBMNC were examined in110 colorectal cancer patients given adjuvant 5-FU 370mg/m² plus L-folinic acid 100 mg/m² for five daysevery four weeks. Drug levels were examined by HPLC, while toxicitieswere graded according to WHO criteria. Results:DPD activity in patients with mild toxicities (WHOgrade 1) was 197.22 ± 11.34 pmol of 5-FDHU/min/mg of protein,while in five patients with grade 3–4 gastrointestinal toxicity,DPD ranged from low to normal values (range 31.12–182.37pmol/min/mg of protein). In these patients, 5-FU clearance (CL) waslower (range 14.12–25.17 l/h/m²), and the area underthe curve (AUC) was higher (range 14.70–26.20 h×µg/ml)than those observed in 84 patients with mild toxicities (CL, 56.30± 3.60 l/h/m²; AUC, 7.91 ± 0.44h×µg/ml). The severity of adverse events was associated withincreased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and5-FDHU pharmacokinetics were not related to DPD activity. Conclusion:This study shows that DPD activity in PBMNC isunrelated to 5-FU/5-FDHU disposition and patients with severe toxicitydisplay marked pharmacokinetic alterations while a reduction of DPDactivity may not occur.     

A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Purpose: This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 µg/ml for five days (5d) or 1 µg/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease.Patients and methods: EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity.Results: The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%–85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%–42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 × 109/l after 5d and 5.0 × 109/l after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP.Conclusions: Although the number of patients entered into this trial was small, the low activity seen at 1 µg/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration-controlled studies with prolonged EP infusions are required.     

The effects of diphenylhydantoin on murine astrocytoma radiosensitivity

Summary Diphenylhydantoin is a well known anticonvulsant used primarily in the treatment of epilepsy. The prophylactic use of diphenylhydantoin has been suggested for certain cerebral metastases, and it is routinely administered to prevent seizures induced by intracranial neoplasms and/or surgery. Patients with malignant gliomas treated with diphenylhydantoin frequently receive radiation therapy. The effects of a clinical concentration of diphenylhydantoin in combination with gamma radiation was investigated using the C6 astrocytoma cell line in both monolayer and three dimensional multicellular spheroid cultures.Diphenylhydantoin at 7.2 × 10^-5 M (20 µg/ml) significantly increased the doubling time (23%) of the C6 astrocytoma cells in monolayer, but did not affect their survival as measured by plating efficiency. No changes were seen in spheroid growth or plating efficiency of the cells dissociated from spheroids at this concentration.Diphenylhydantoin at the clinical concentration tested was not associated with an alteration in radiation sensitivity of C6 astrocytoma cells in monolayer or three dimensional multicellular spheroid cultures.     

Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients?with?hepatic metastases from colorectal cancer

Background:To determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of oxaliplatin administered as hepatic arterial infusion. Patients and methods:Patients with isolated hepatic metastases from colorectal cancer were treated every three weeks with increasing doses of oxaliplatin (4 hours; starting dose 25 mg/m², escalation in steps of 25 mg/m²) in combination with folinic acid (1 hour, 200 mg/m²) and 5-fluorouracil (2 hour, 600 mg/m²). Results:Twenty-one patients (median age, 61 years) have been entered all of whom are fully evaluable. The DLT has been observed at dose level 6, i.e., at 150 mg/m²/cycle and consisted of leucopenia, obliteration of the hepatic artery, and acute pancreatitis. Overall, toxicity mainly consisted of nausea/vomiting (16 of 21 patients), anemia (16 of 21), upper abdominal pain (15 of 21), sensory neuropathy (10 of 21), diarrhea (9 of 21), and thrombocytopenia (9 of 21). The mean PK parameters were: terminal half-life of ultrafiltrable platin, 17.75 ± 9.29 hours; renal elimination, 48.7% ± 14.1% of the applied dose; renal clearance 135.55 ± 45.32 ml/min. The mean area under the plasma-concentration curve (AUC) increased linearly from 3.22 ± 0.61 µg · h/ml to 18.45 ± 8.90 µg · h/ml through the first five dose levels (P = 0.0004). Ten of eighteen evaluable patients achieved a complete or partial response (59%). Conclusions:The recommended dose for phase II studies is 125 mg/m² oxaliplatin.     

Survival Results from a Phase I Study of Etanidazole (SR2508) and Radiotherapy in Patients with Malignant Glioma

Purpose: To report the survival results from a previous Phase I study of etanidazole (ETA) and radiotherapy in patients with glioblastoma multiforme (GBM n = 50) or anaplastic astrocytoma (AA n = 19) and examine survival according to age, Karnofsky performance status (KPS), and implant status.Patients and Methods: In a previous Phase I study, 70 previously untreated patients (median age 49) with malignant gliomas were accrued. One patient was excluded from analysis because pathology was unverifiable. All had KPS ≥ 70. Prior to initiation of treatment, patients were stratified according to whether they were candidates for interstitial implantation. The implant patients (IMP n = 14) received accelerated fractionation radiotherapy (XRT) 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m² × 6 doses, a 2 week break, and then interstitial implant for an additional 50 Gy (4–7 days) with a continuous infusion of ETA over 90–96 hours. There were 55 patients treated on two sequentially conducted non-implant arms. These patients started with accelerated fractionation XRT 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m² × 4–5 doses/week. Non-IMP1 arm (n = 41) received a 2-week break before standard fractionated boost XRT of 2 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. Non-IMP2 arm (n = 14) did not have the 2-week break. All patients had plasma pharmacokinetic monitoring of ETA. Subsequent follow-up study provided information regarding long-term survival status of this group of patients. The Phase I toxicity evaluation was conducted according to the RTOG toxicity scale and was found well tolerated in both groups. Overall actuarial survival was plotted for all patients, by histologic group, and by implant status. Subset analyses of GBM patients by age (≤ 49 or > 49 years), KPS (≤ 80 or > 80) and implant versus non-implant were also performed.Results: Median survival of GBM patients was 1.1 years and that of anaplastic astrocytoma patients was 3.1 years (p = 0.0001). In GBM patients, KPS > 80, implanted patients, and age ≤ 49 were factors found not to be associated with a statistically improved survival.Conclusion: The results of survival in this Phase I etanidazole study of patients with anaplastic astrocytoma are comparable to the results from other studies using bromodeoxyuridine, iododeoxyuridine, or procarbazine, lomustine (CCNU), and vincristine. The use of etanidazole with accelerated radiotherapy does not appear to improve survival in patients with glioblastoma multiforme compared to those treated with conventional therapies.     

GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon-alpha): A phase I trial in melanoma

Background:Ineffective tumour antigen processing is recognisedas an important cause of failure of immunotherapy in melanoma. GM-CSF mayaugment the cytotoxic lymphocyte response by activating antigen-presentingcells. This study evaluates a schedule combining GM-CSF with biochemotherapy. Patients and methods:Nineteen patients with advanced malignantmelanoma received cisplatin (25 mg/m² days 1–3), dacarbazine(220 mg/m² days 1–3), interleukin-2 (9 MIU/m²/24h)and interferon-2b (5 MIU/m²) both days 6–10 and days17–21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF wasgiven in escalating doses to three cohorts: 1) 450 µg/m² days4–5 and 15–16; 2) as 1) plus 225 µg/m² days6–10 and 17–21; 3) 450 µg/m² days 4–10 and15–21. Each cycle was 28 days. Results:Constitutional side effects were the majornon-haematological toxicity and lymphopaenia the main haematological toxicity.Six patients responded (32%, 95% confidence interval:13%–57%), two patients had complete remission. There wasan apparent trend for increasing responses with increasing GM-CSF dose; zeroof six responses in cohort 1, two of seven in cohort 2 and three of six incohort 3 (P = 0.016). Median overall survival was 6.2 months.Increasing GM-CSF doses significantly increased serum concentrations ofneopterin and TNF-. Conclusions:The combination of GM-CSF with biochemotherapy isfeasible and there appears to be a dose-response relationship with GM-CSF interms of host immunological response, and possibly clinical efficacy.     

Long Term Survival in a Patient with Recurrent Malignantc Glioma Treated with Intratumoral Infusion of an IL4-Targeted Toxin (NBI-3001)

Intratumoral infusion of a recombinant targeted toxin (NBI-3001) consisting of the receptor binding domain of human interleukin 4 (IL-4) and Pseudomonas aeruginosa exotoxin A is an investigational treatment for malignant brain tumors. This 27-year-old male patient presented with a recurrent malignant glioma WHO grade IV after surgery and adjuvant radiation and chemotherapy. The recurrence was treated with intratumoral infusion of NBI-3001 at a dose of 9 microg/ml in 66 ml of infusate. Treatment resulted in long-term survival for 3 years after toxin infusion with a durable tumor response. There were some permanent neurological side effects resulting from toxin infusion. The patient eventually died after a late local recurrence of the known brain tumor. Such clinical evolution of a malignant glioma after a single round of immunotoxin infusion is rather unusual. The late local recurrence may suggest that repeated courses rather than a single infusion of intratumoral toxin are possibly needed for successful long-term tumor control.     

A phase II study of thalidomide and irinotecan for treatment of glioblastoma multiforme

Purpose Irinotecan is a cytotoxic agent with activity against gliomas. Thalidomide, an antiangiogenic agent, may play a role in the treatment of glioblastoma multiforme (GBM). To evaluate the combination of thalidomide and irinotecan, we conducted a phase II trial in adults with newly-diagnosed or recurrent GBM. Patients and methods Thalidomide was given at a dose of 100 mg/day, followed by dose escalation every 2 weeks by 100 mg/day to a target of 400 mg/day. Irinotecan was administered on day 1 of each 3 week cycle. Irinotecan dose was 700 mg/m² for patients taking enzyme-inducing anticonvulsants and 350 mg/m² for all others. The primary endpoint was tumor response, assessed by MRI. Secondary endpoints were toxicity, progression-free survival, and overall survival. Results Twenty-six patients with a median age of 55 years were enrolled, with fourteen evaluable for the primary outcome, although all patients were included for secondary endpoints. One patient (7%) exhibited a partial response after twelve cycles, and eleven patients (79%) had stable disease. The intention to treat group with recurrent disease included 16 patients who had a 6-month PFS of 19% (95% CI: 4–46%) and with newly-diagnosed disease included 10 patients who had a 6-month PFS of 40% (95% CI: 12–74%). Gastrointestinal (GI) toxicity was mild, but six patients (23%) experienced a venous thromboembolic complication. Two patients had Grade 4 treatment-related serious adverse events that required hospitalization. There were no treatment-related deaths. Conclusion The combination of irinotecan and thalidomide has limited activity against GBM. Mild GI toxicity was observed, but venous thromboembolic complications were common. Presented in part at the 8th Annual SNO Meeting in Keystone, CO, November 13–16, 2003.     

Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin

Background:Quercetin is a naturally occurring flavonoid with manybiological activities including inhibition of a number of tyrosine kinases.A phase I, dose-escalation trial of quercetin defined the maximum tolerateddose (MTD) as 1700 mg/m² three weekly, but the vehicle, dimethylsulphoxide (DMSO) is unsuitable for further clinical development ofquercetin. Patients and methods:A water-soluble, pro-drug of quercetin(3(N-carboxymethyl)carbomyl-3,4,5,7-tetrahydroxyflavone), QC12has been synthesised. Six cancer patients received 400 mg of QC12 (equivalentto 298 mg of quercetin), orally on day 1 and intravenously (i.v.) in normalsaline on day 14. Results:Following oral administration of QC12 we were unable todetect QC12 or quercetin in plasma. After i.v. administration, we detectedpeak plasma concentrations of QC12 of 108.7 ± 41.67 µMolar(µM). A two-compartment model with mean t_1/2 of 0.31± 0.27 hours and mean t_1/2 of 0.86 ± 0.78 hoursbest described the concentration-time curves for QC12. The mean AUC was 44.54± 13.0 µM.hour and mean volume of distribution (Vd) of 10.0± 6.2 litres (l). Quercetin was found in all patients following i.v.infusion of QC12, with peak levels of quercetin 19.9 ± 11.8 µM.The relative bioavailability of quercetin was estimated to be20%–25% quercetin released from QC12. Conclusions:QC12 is not orally bioavailable. This water-solublepro-drug warrants further clinical investigation; starting with a formal phaseI, IV, dose-escalation study.     

A first feasibility study of temozolomide for Japanese patients with recurrent anaplastic astrocytoma and glioblastoma multiforme

Background. The efficacy of temozolomide has been evaluated in phase I and phase II trials in patients with recurrent malignant gliomas in the United States and the European Union. We report a feasibility study of the palliative efficacy of temozolomide for patients with recurrent anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Methods. Sixteen patients with at least two prior chemotherapy regimens were enrolled in the study. Nine patients were confirmed to have GBM and 7 patients were confirmed to have AA at the latest pathology review, and all had a Karnofsky performance status (KPS) of over 50%. The median age was 57 years (range, 31–65 years). Results. No cumulative toxicity was observed at any dose level when temozolomide was administered on a once-daily, 5-day schedule. Myelosuppression occurred, with the nadir being mid-late in the cycle (day 14 or 21). National Cancer Institute common toxicity criteria (NCI-CTC) grade 3 or 4 hematological toxicity did not occur. In the 9 GBM patients, the overall response rate (complete response + partial response [CR + PR]) was 0%. The median time to progression (TTP) was 3.5 months, and the rates of progression-free survival (PFS) at 6 and 12 months were 40% and 0%. In the 7 AA patients, the overall response rate (CR + PR) was 29% and median TTP was 9 months, while PFS rates at 6 and 12 months were 80% and 30%. Conclusion. The favorable safety profile and the efficacy of temozolomide in Japanese patients are not incompatible with the results seen with patients in the United States and the European Union.     

Carboplatin pharmacokinetics in young children with brain tumors

 Purpose: The pharmacokinetic parameters and maximal tolerated systemic exposure were determined for carboplatin in young children given in combination with cyclophosphamide and etoposide. Patients and methods: Carboplatin was administered as part of a multiagent chemotherapy regimen to 21 pediatric patients less than 5 years of age with newly diagnosed, malignant central nervous system tumors. Patients received cyclophosphamide, 1.2 g/m², on day 1 and carboplatin on day 2 followed by etoposide, 100 mg/m², each day. Carboplatin doses were calculated to achieve a targeted area under the serum concentration versus time curve (TAUC) of 5, 6.5 or 8 mg/ml . min based on each patient’s measured glomerular filtration rate (GFR). Carboplatin pharmacokinetic parameters were determined after course 1 and then after every third course of therapy. Results: The median carboplatin clearance and GFR after course 1 were 118 and 98 ml/min per m², respectively. Targeted doses based on measured GFR reliably achieved the TAUC for carboplatin. The median (range) carboplatin clearance for four children less than 1 year of age was 76 (66–84) ml/min per m², significantly lower (P=0.05) than the value of 131 (80–158) ml/min per m² for children from 1 to 4 years of age. The mean carboplatin clearance declined by 23% in 12 patients studied from course 1 to course 4 of therapy. The decrease was greater than 20% (range 20–53%) in 7 of the 12 patients studied. Conclusion: Carboplatin clearance for children aged between 1 and 4 years at diagnosis is approximately 45% higher than previously reported for pediatric patients, but declines after four courses of therapy. For children less than 1 year of age, carboplatin clearance per square meter is approximately 40% lower than patients 1 to 4 years of age. There are corresponding differences in GFR that provide a plausible explanation for the age and therapy-related changes in carboplatin clearance. Toxicity was acceptable for patients treated at a TAUC of 6.5 mg/ml . min for carboplatin given with etoposide and cyclophosphamide. The average carboplatin dose required for this AUC was 767 mg/m². Received: 13 July 1995/Accepted: 18 December 1995     

Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the Duke experience

A phase II study of irinotecan (CPT-11) was conducted at Duke University Medical Center, Durham, NC, to evaluate the activity of this agent in children with high-risk malignant brain tumors. A total of 22 children were enrolled in this study, including 13 with histologically verified recurrent malignant brain tumors (glioblastoma multiforme [GBM] 4, anaplastic astrocytoma 1, ependymoma 5, and medulloblastoma/primitive neuroectodermal tumor 3), 5 with recurrent diffuse pontine glioma, and 4 with newly diagnosed GBM. All patients with recurrent tumor had prior chemotherapy and/or irradiation. Each course of CPT-11 consisted of 125 mg/m ( 2 ) per week given i.v. for 4 weeks followed by a 2-week rest period. Patients with recurrent tumors received therapy until disease progression or unacceptable toxicity. Patients with newly diagnosed tumors initially received 3 cycles of treatment to assess tumor response and then were allowed radiotherapy at physician's choice; patients who demonstrated a response to CPT-11 prior to radiotherapy were allowed to continue the drug after radiation until disease progression or unacceptable toxicity. A 25% to 50% dose reduction was made for grade III-IV toxicity. Responses were assessed after every course by gadolinium-enhanced MRI of the brain and spine. Twenty-two patients received a median of 2 courses of CPT-11 (range, 1-16). Responses were seen in 4 of 9 patients with GBM or anaplastic astrocytoma (44%; 95% confidence interval, 11%-82%) (complete response in 2 patients with recurrent GBM lasting 9 months and 48+ months; partial response in one patient with a newly diagnosed midbrain GBM lasting 18 months prior to radiotherapy; and partial response lasting 11 months in 1 patient with recurrent anaplastic astrocytoma), 1 of 5 patients with recurrent ependymoma (partial response initially followed by stable disease lasting 11 months), and none of 5 patients with recurrent diffuse pontine glioma. Two of 3 patients with medulloblastoma/primitive neuroectodermal tumor had stable disease for 9 and 13 months. Toxicity was mainly myelosuppression, with 12 of 22 patients (50%) suffering grade II-IV neutropenia. Seven patients required dose reduction secondary to neutropenia. CPT-11, given in this schedule, appears to be active in children with malignant glioma, medulloblastoma, and ependymoma with acceptable toxicity. Ongoing studies will demonstrate if activity of CPT-11 can be enhanced when combined with alkylating agents, including carmustine and temozolomide.     

Interleukin-13 Receptor-Directed Cytotoxin for Malignant Glioma Therapy: From Bench to Bedside

Central nervous system malignant neoplasias, in particular, glioblastoma multiforme (GBM) have defied all current therapeutic modalities. New therapies involving tumor targeting approach are being explored. This approach relies on the identification of unique or over-expressed cell surface receptors or antigens on tumor cells. In that regard, we have identified receptor for an immune regulatory cytokine, interleukin-13 (IL-13), which is over-expressed on human malignant glioma cell lines and primary tumor cell cultures. To target IL-13 receptors (IL-13R) for cancer therapy, we have developed a recombinant fusion protein composed of IL-13 and a mutated form of Pseudomonas exotoxin (IL13-PE38QQR or IL-13 cytotoxin). The IL-13 cytotoxin was found to be highly selective and potent in killing human GBM cells in vitro while normal cells including immune cells, endothelial cells and normal brain cells were generally spared the cytotoxic effect of IL-13 cytotoxin. This is because these cells either expressed none or expressed low levels of IL-13R.Consistent with in vitro cytotoxic activity, IL-13 cytotoxin mediated remarkable anti-tumor activity to human glioma in animal xenograft models. The direct injection of IL-13 cytotoxin into subcutaneous human GBM tumors grown in nude mice produced complete and durable regression of established tumors. Intravenous and intraperitoneal administration of IL-13 cytotoxin also reduced tumor burden significantly with fewer complete responders. All animals tolerated therapy well with minimal toxicity to vital organs. Pre-clinical safety and toxicity studies were performed in mice, rats and monkeys. Systemic administration of IL-13 cytotoxin appeared to be well tolerated at high doses (up to 50ug/kg). Intrabrain parenchyma administration of IL-13 cytotoxin at doses up to 100ug/ml was very well tolerated without any evidence of gross or microscopic necrosis, whereas at 500ug/ml dose, localized necrosis was observed in normal rat brain. Based on these encouraging pre-clinical studies, three Phase I/II clinical trials in adults with malignant glioma have been initiated. The first clinical trial involves convection-enhanced delivery (CED) of IL-13 cytotoxin into recurrent malignant glioma. This route of IL-13 cytotoxin administration appears to be fairly well tolerated with no neurotoxicity. The second clinical trial involves infusion of IL-13 cytotoxin by CED following tumor resection. The initial stage of the second study assessed histologic effect of drug administered prior to resection. In third one, IL-13 cytotoxin is infused by CED followed by tumor resection. All three clinical trials are currently ongoing.     

Activity and toxicity of GI147211 in breast, colorectal and non-small-cell lung cancer patients: an EORTC-ECSG phase II clinical study.

Background:GI147211 is a water-soluble synthetic analogue ofcamptothecin showing promising in vivoand in vitroantitumor activity and an acceptable toxicity profile. Patients and methods:Between April 1995 and November 1996, 67eligible patients with pretreated breast cancer (25 patients) andchemo-naïve colorectal (19 patients) and non-small-cell lung cancer (23patients) were entered into three multicentric, non-randomized phase IItrials. Treatment schedule consisted of intravenous GI147211 administered ata dose of 1.2 mg/m²/day for five consecutive days every threeweeks. Results:Hematological toxicity was common with grade 3–4neutropenia in 54% of patients and neutropenic fever together or notassociated with infection in 14.5% of patients. Grade 3–4thrombocytopenia and grade 2–4 anemia were observed in 20% andin 68% of patients, respectively. Non-hematological toxicity wasgenerally mild to moderate and consisted mainly of gastrointestinal toxicity,asthenia and alopecia. A dose-escalation to 1.5 mg/m²/d wasfeasible in 17 (25%) patients. The antitumor activity of GI147211 wasmoderate in breast cancer patients (3 partial responses (PRs), response rate(RR) 13%) and minimal in non-small cell lung cancer patients (2 PRs,RR 9%). No objective responses were obtained in colorectal patients. Conclusions:GI147211, at the dose and schedule employed in thisstudy, showed an acceptable safety profile but a modest antitumor activity inthe examined tumor types.     

Prognosis in patients with anaplastic oligoastrocytoma is associated with histologic grade

Background Anaplastic oligoastrocytomas (AOA) are relatively uncommon high-grade gliomas. While oligodendroglial elements are thought to be associated with better outcomes, the magnitude of the difference is not clear. Methods Between 1980 and 1999, Mayo Clinic and the NCCTG conducted 10 trials of radiation therapy and chemotherapy in adults with newly-diagnosed high-grade gliomas. All pathology slides were reviewed by one of the authors (BWS or CG). We grouped patients by cell type and grade, compared survival distributions by the log-rank statistic, and performed multiple variable analyses. Results Of 1368 patients, 68 (5%) had AOA, including 21 Grade 3 (OA3) and 47 grade 4 (OA4), 153 (11%) had anaplastic astrocytoma (AA), and 1147 (84%) had glioblastoma multiforme (GBM). Patients with OA3 survived significantly longer than those with OA4 (P = 0.0001) or AA (P = 0.0044). Patients with OA4 lived significantly longer than those with GBM (P = 0.0005). The same differences were noted for PFS. Prognostic factors for survival identified by multiple variable analysis were histology, age, ECOG performance score, and extent of surgical resection, but not treatment administered. Conclusions Patients with anaplastic oligoastrocytoma have distinct outcomes based upon grade (OA3 vs. OA4) and in comparison with pure astrocytoma (AA or GBM). Future trials which include more than one histologic entity need to report results by cell type and grade and account for the varying prognoses in interpreting treatment outcomes.     

Octreotide in the treatment of severe chemotherapy-induced diarrhea

Background:Chemotherapy-induced diarrhea (CID) is a common sideeffect of a number of chemotherapeutic agents. Conventional therapy for severeCID with opioids or loperamide is moderately effective. A prospective trialwas conducted using octreotide acetate for treatment of severe CID refractoryto loperamide. Patients and methods:Thirty-two patients with grade 2 and 3 CIDrefractory to loperamide were treated with octreotide at a dosage of 100µg subcutaneously 3 ×/day for three days followed by 50µg 3 ×/day for three days. Previous chemotherapy consistedof regimens containing fluorouracil, leucovorin, CPT-11, cyclophosphamide,methotrexate and cisplatin. Primary tumors were colorectal(n = 23), gastric (n = 3), and othercancers (n = 6). Results:Complete resolution of diarrhea was obtainedin 30 of 32 patients (94%); 5 within 24 hours, 14 within48 hours, and 11 within 72 hours of treatment. Nineteenpatients were treated as outpatients. Thirteen were hospitalized for amedian of three days. Response was unaffected by age, gender, performancestatus, previous chemotherapy or primary tumor site. No side effects relatedto octreotide were observed. Conclusions:Octreotide 100 µg subcutaneously3 ×/day for three days is an effective, safe treatment for CIDgiven primarily or as a second-line therapy after loperamide failure.     

A Phase II trial of paclitaxel and topotecan with filgrastim in patients with recurrent or refractory glioblastoma multiforme or anaplastic astrocytoma

Purpose: Therapy for high-grade gliomas remains unsatisfactory. Paclitaxel and topotecan have separately demonstrated activity against gliomas. We conducted a Phase II trial of these agents in combination with filgrastim (G-CSF) in patients with recurrent or refractory glioblastoma multiforme or anaplastic astrocytoma.Patients and Methods: Adult patients with radiographic evidence of recurrent or progressive tumor following primary therapy were eligible for study. Patients received paclitaxel 175 mg/m² IV over 3 h on day 1 and topotecan 1.0 mg/m ² IV over 30 min on days 1–5. Filgrastim 5 g/kg was given days 6–14 for neutrophil support. Treatment cycles were repeated every 21 days.Results: Twenty patients were enrolled on study, and seventeen were considered evaluable for response. Two patients (12/%) exhibited partial remission and seven patients (41/%) exhibited stable disease in response to therapy. Hematologic toxicity was common with 25 /% of patients experiencing grade III or IV leukopenia despite G-CSF support. Two patients died of infectious complications on protocol, prompting suspension of further accrual.Conclusion: Paclitaxel and topotecan with G-CSF support exhibits modest activity in adults with recurrent or refractory glioblastoma and anaplastic astrocytoma. The significant hematotoxicity encountered, however, cannot justify further investigation of this combination in patients with high grade brain tumors.Supported with grant funding from: GlaxoSmithKline Pharmaceuticals Collegeville, PA     

Th1/Th2 cytokine imbalance in meningioma, anaplastic astrocytoma and glioblastoma multiforme patients

The balance between Th1 and Th2 cytokines is thought to be an important factor in terms of tumour prognosis. Serum samples from 61 newly diagnosed patients with brain tumours and 50 age- and sex-matched non-tumour controls were analysed by ELISA for circulating levels of interleukin-12 (IL-12p70 and p40) and interleukin-10 (IL-10); pivotal Th1 and Th2 cytokines, respectively. Patients were divided into various groups depending on their histological diagnosis: meningioma (n=11), anaplastic astrocytoma (n=4) and glioblastoma multiforme (GBM; n=46). Significant reduction in serum IL-12 was seen in all groups as compared with the controls: meningioma, p=0.03; anaplastic astrocytoma, p<0.001; and GBM, p<0.001. Conversely, serum IL-10 was significantly increased in anaplastic astrocytoma, p=0.02, and GBM, p=0.03. The changes in the serum cytokines were not caused by the effects of steroids, as sequential analysis of patients pre- and post-steroid treatment commencement showed no difference. This study shows that patients with advanced primary intracranial malignancies have decreased circulating IL-12 and increased circulating IL-10, demonstrating that brain tumours have a major systemic effect on the immune system.