Phase I clinical and pharmacokinetic trial of dextran conjugated doxorubicin (AD-70, DOX-OXD)

Coupling of anthracyclines to high-molecular-weight carriers may alter drug disposition and improve antitumor effects. We have performed a clinical phase I trial of doxorubicin coupled to dextran (70000 m.w.). The drug was administered as single dose i.v. every 21–28 days. Thirteen patients have received a total of 24 courses (median 2; range 1–3). At the starting dose of 40 mg/m² doxorubicin equivalent (DOXeq), WHO grade IV thrombocytopenia was noted in 2/2 patients. WHO grade IV hepatotoxicity and WHO grade III cardiotoxicity were noted in a patient with preexisting heart disease. Five patients were treated with 12.5 mg/m² DOXeq. Maximal toxicity at this dose level was WHO grade III thrombocytopenia and local phlebitis (WHO grade II) in 1/5 patients, elevation of alkaline phosphatase (WHO grade III) and WHO grade III vomiting in another patient. Subsequently, five patients received 20 mg/m² DOXeq. Hepatotoxicity was noted in 5/5 patients (1 × WHO grade IV, 1 × WHO grade III). Thrombocytopenia was noted in 3/5 patients (1 × WHO grade IV, 2 × WHO grade III). At 12.5 mg/m² DOXeq, a patient diagnosed with a malignant fibrous histiocytoma had stable disease for 4 months. Pharmacokinetic analyses of total and free doxorubicin were performed in plasma and urine. The maximum peak plasma concentration (ppc) for total DOX was 12.3 g/ml at 40 mg/m² DOXeq. The area under the plasma concentration time curve (AUC) ranged from 28.83–80.21 g/ml^*h with dose-dependent elimination half lives (t_1/2: 0.02–0.87 h;_1/2: 2.69–11.58 h;_1/2: 41.44–136.58 h). We conclude that the maximal tolerated dose (MTD) of AD-70 using this schedule is 40 mg/m² DOXeq. The recommended dose for clinical phase II studies is 12.5 mg/m² DOXeq.Abbreviations ALT Alanine Aminotransferase - AST Aspartate Aminotransferase - DOX Doxorubicin - DOXeq Doxorubicin Equivalent - ECG Electrocardiogram - HPLC High Pressure Liquid Chromatography - LD₁₀ Lethal Dose for 10% of individuals - MTD Maximal Tolerated Dose - ppc Peak Plasma Concentration - WHO World Health Organisation     

Multi-targeted-Enzyminhibition in der Tumortherapie

Pemetrexed is a newly developed therapeutic agent which inhibits several key enzymes in the folate metabolic pathway. In phase I trials, this novel multitargeted antifolate showed a broad antitumor activity as a single agent and in combination chemotherapy. Based on these findings, phase III studies have been conducted including patients with malignant pleural mesothelioma (MPM), non-small-cell lung cancer (NSCLC), and colorectal cancer. In a recent phase III trial in MPM, the combination of pemetrexed and cisplatin was significantly more efficacious than cisplatin alone. In addition, vitamin supplementation reduced treatment-associated toxicities with no apparent affect on activity. In patients with NSCLC, a phase III trial showed clinically equivalent efficacy of pemetrexed and docetaxel, but pemetrexed was associated with significantly fewer toxicities in second-line therapy. This review summarizes preclinical and clinical data to define the future role of pemetrexed in the treatment of tumor patients.     

Phase II Trial of Cystemustine,a New Nitrosourea,as Treatment of High-grade Brain Tumors in Adults

This study included 39 patients (37 evaluable, of whom 30 patients with recurrent gliomas and 7 patients with gliomas untreated by radiotherapy); they were enrolled into a phase II trial using a new nitrosourea, cystemustine, administrated every 2 weeks at 60mg/m² as a 15min-infusion. Pathology at inclusion was (WHO classification): 14 glioblastomas, 20 grade 3–4 astrocytomas and 3 grade 3 oligodendrogliomas. Four partial responses have been obtained, giving an overall response rate of 10.8%. Four additional patients had a partial response, which for various reasons was not confirmed 4 weeks later; 12 patients had a stable disease for at least 8 weeks, 15 patients had progressive disease. Of the 4 responses, 2 were with a grade 3 oligodendroglioma and 2 glioblastoma. Toxicity (WHO grading) was mainly hematological: leukopenia (16.2% grade 3–4), neutropenia (29.7% grade 3–4), thrombopenia (27% grade 3–4). No other toxicity greater than grade 2 was observed. In conclusion, cystemustine at 60mg/m² has moderate clinical activity in relapsing glioma. Our results warrant further investigation of this agent with an increased dose or modified scheme.     

Carzelesin phase II study in advanced breast, ovarian, colorectal, gastric, head and neck cancer, non-Hodgkin's lymphoma and malignant melanoma: a study of the EORTC early clinical studies group (ECSG)

Purpose: In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed. Patients and methods: Carzelesin was used as second- or third-line chemotherapy in patients with breast, ovarian, head and neck cancer and non-Hodgkin's lymphoma, and as first-line chemotherapy in patients with colorectal and gastric cancer and melanoma. The drug was given as a bolus infusion at a 4-weekly dose of 150 μg/m². A total of 140 patients were entered and a total of 285 courses were administered. Results: In general, the compound was well tolerated. Myelotoxicity was the most common toxicity. Grade 3 and 4 leukopenia was observed in 18.6% of the courses, neutropenia in 20.3%, thrombocytopenia in 16.2% and anemia in 8.7%. Double nadirs were seen in a total of 41 courses for neutrophils, in 40 for leukocytes and in 3 for platelets. Non-hematological toxicity was very mild. Only one partial response in a patient with melanoma was seen. Conclusions: At this dose and schedule carzelesin did not yield activity in the types of tumors studied. Received: 8 December 1999 / Accepted: 10 April 2000     

Intraspinal distribution and reaction in the grey matter with tetanus toxin of intracisternally injected anti-tetanus toxoid F (ab′)2 fragments

Anti-tetanus toxoid F(ab′)₂ fragments were purified using immune-affinity chromatography on tetanus toxoid-Sepharose. Fragments were labeled with¹²⁵I. Labeled or non-labeled fragments were injected into the intrathecal space of rats. The labeled fragments were found in the spinal cord outside but not inside neurons.Tetanus toxin was injected into a muscle and 36 h later labeled fragments were injected intracisternally. After another 24 h the label was elevated in the spinal cord half segments giving neural supply to the injected muscle and in these half-segments the label was concentrated around some α-motoneurons.[¹²⁵I]Tetanus toxin was injected into a muscle and at different times thereafter non-labeled fragments were injected intracisternally. The development of hindlimb rigidity but not the accumulation of [¹²⁵I]tetanus toxin in α-motoneurons was prevented by early intracisternal injection of fragments. Injection of fragments after the appearance of hindlimb rigidity did not revert the rigidity but prevented the further development of symptoms.It is concluded that an action of tetanus toxin inside α-motoneurons is of no importance for the development of motor symptoms in clinical tetanus. The data suggest that in order to evoke spinal symptoms of toxicity tetanus toxin has to reach interneurons by transneuronal migration. In the very early stages of clinical tetanus the intrathecal injection of fragments may be useful.     

In vitro activity of liposomal N4octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC), a new lipophilic derivative of 1-beta-D-arabinofuranocylcytosine on biopsized clonogenic human tumor cells and hematopoietic precursor cells

N⁴-octadecyl-1--D-arabinofuranosylcytosine (NOAC) is a new lipophilic derivative of1--D-arabinofuranosylcytosine(ara-C) with potent antitumor activityagainst leukemias and solid tumors. In thisstudy the activity of NOAC against freshlyexplanted clonogenic cells from humantumors was determined and compared withconventional antitumor agents. NOAC wasused in two liposomal preparations, astable lyophilized and a freshly preparedliquid formulation. Both formulationsinhibited tumor colony formation equally ina concentration-dependent fashion in bothshort- (1h) and long-term (21-28 d)exposure experiments. NOAC (100 M,long-term exposure) had a significantlybetter activity compared to the clinicallyused drugs cisplatin, doxorubicin,5-fluorouracil, gemcitabine, mitomycin Cand etoposide. The comparison of NOAC withara-C in the long-term exposure experimentshowed that ara-C was more effective at 4and 10 M, whereas at 1 and 100 Mthere was no difference between the twodrugs. NOAC was less toxic in ahematopoietic stem cell assay than ara-Cand doxorubicin by factors ranging from 2.5to 200, indicating that this drug is welltolerated at high doses. The antitumoractivity of NOAC (NSC 685096) was confirmedby the NCI in vitro drug screening programwhere the drug was found to be activeagainst several types of human tumors.Further development of NOAC in phase IIstudies is warranted.     

Results of a phase II trial with cystemustine at 90 mg/m(2) as a first- or second-line treatment in advanced malignant melanoma: a trial of the EORTC Clinical Studies Group

From May 1991 to January 1996, 54 patients with advanced malignant melanoma were enrolled into a phase II trial testing the new nitrosourea cystemustine, administrated intravenously as a 15 min infusion every 2 weeks at 90 mg/m2 for three cycles followed by 60 mg/m2. Out of the 54 enrolled patients, 10 were Ineligible, leaving 44 fully evaluable patients (World Health Organization criteria). Twenty one patients had already received first-line palliative chemotherapy and/or immunotherapy. The median age was 62 years (range 30-74 years) and the median performance status was 0 (grade 0, 19 patients; grade 1, 21 patients; grade 2, 4 patients). Five patients with partial responses (lasting 16-29 weeks, mean duration 24 weeks), nine with stable disease and 28 showing progression were observed, giving an overall response rate of 11% (confidence interval 3.8-24.6%). Toxicity was mild and consisted mainly of neutropenia (39% grade III-IV), thrombocytopenia (42% grade III-IV); febrile aplasia was rare. Cystemustine administered to this schedule appears to have limited clinical activity and acceptable toxicity in untreated or second-line advanced malignant melanoma.     

Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion

BACKGROUND: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethylamino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days. PATIENTS AND METHODS: 45 patients (7 female, 38 male; median age 54 [range 37-73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria. RESULTS: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2gamma) was 14.7 +/- 3.7 h. The AUC at 250 mg/m2 was determined to be 330 +/- 147 microg/mlh, the plasma clearance of NK611 was 16.2 +/- 8.2 ml/min x m2 and the V(ss) was 16.8 +/- 3.3 l/m2. Protein binding of NK611 was 98.7%. CONCLUSION: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.