Phase II trial of fazarabine (arabinofuranosyl-5-azacytidine) in patients with advanced pancreatic adenocarcinoma

We conducted a phase II evaluation of fazarabine 1.75–2.0 mg/m²hr over 72 hours every 28 days in 14 previously untreated patients with advanced adenocarcinoma of the pancreas. The intial dose was 1.75 mg/m²/hr in 10 patients, and 2.0 mg/m²hr in 4 patients. The dose was escalated in 8 patients, including all 4 who started at the higher dose level. Toxicity was unexpectedly mild. The median WBC nadir was 4.4 (range: 2.4–15.8)×10³/l, the median absolute neutrophil nadir was 3.2 (range: 0.9–13.0)×10³/l, and the median platelet count was 134.0 (range: 48.0–291.0)×10³/l. Gastrointestinal toxicity was generally mild. No major responses were seen, excluding, with 95% confidence, a response rate in excess of 20%.     

Pharmacokinetics, mass balance, and tissue distribution of a novel DNA alkylating agent, VNP40101M, in rats

VNP40101M (1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(2 methylamino)carbonyl] hydrazine), a novel DNA alkylating agent, is currently under clinical development for the treatment of cancer in Phase I clinical trials. This study investigated the pharmacokinetics, mass balance, and tissue distribution of [¹⁴C]-VNP40101M in rats following a single intravenous dose of 10 mg/kg. After 7 days, the total recovery of radioactivity was 85% for males and 79% for females. Most of the radioactivity was eliminated within 48 hours through urine (70%), with less excreted in feces (6%). Tissue contained relatively high radioactive residues with the highest concentrations in kidneys, liver, lung, and spleen. After 7 days, tissue still contained 9% of the dose. At both 5 minutes and 1 hour post-dose, brain contained relatively high radioactivity (5.9 and 3.3 μg equivalence/g and 50% and 30% of the blood concentration, respectively), suggesting that VNP40101M penetrated the blood-brain barrier. The elimination half-life of VNP40101M was approximately 20 minutes, the peak plasma concentration (Cmax) averaged 11.3 μg/mL, the volume of distribution (Vss) averaged 0.91 L/kg, and the total body clearance (CI) averaged 33.5 mL/min/kg. The metabolite profile in urine was complex, indicating VNP40101M was extensively metabolized. There were no apparent sex differences in pharmacokinetic parameters of VNP40101M in the rat.     

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     

Phase I/II study of gemcitabine and vinorelbine plus cisplatin in non-small cell lung cancer

Purpose. We determine the maximum tolerated dose (MTD) and efficacy ofgemcitabine plus vinorelbine combined withcisplatin in patients with non-small celllung cancer (NSCLC). Patients and methods. Chemo naive patientswith stage IIIA to IV non-small cell lungcancer received outpatient administrationof gemcitabine 1000 mg/m² andvinorelbine 25 mg/m² intravenously ondays 1 and 8 every 21 days. Doses ofgemcitabine and vinorelbine were escalatedby 250 mg/m² and 5 mg/m²,respectively, at each dose level. Cisplatin was administered at a fixed doseof 50 mg/m² on days 2 and 9. Afterthe MTD was reached, the study wascontinued as a phase II trial. Results. From January 1998 to March 1999, sixty-five patients were enrolled. Thefirst 38 patients participated in the phaseI evaluation. After 130 cycles, thedose-limiting toxicities were neutropenia,stomatitis, asthenia, and hepatotoxicityoccurring at the third and fourth doselevels (doses of gemcitabine/vinorelbine of1500/25 and 1000/30 mg/m²).For the subsequent phase II evaluation, 27additional patients, out of a total of 53,receiving the MTD of gemcitabine andvinorelbine (1000–1250/25 mg/m²)followed (24 hours later) by cisplatin50 mg/m². Thirty one (58%) of 53 assessable patients responded. Objectiveresponse for patients with stages III andIV disease, respectively, were 65% and47%. The median time to progression andthe overall survival time were 9 months(95% CI: 5–12) and 11 months (95 % CI:9–13), respectively. World HealthOrganization toxicity grade 3neutropenia was registered in 28 (54%) of52 assessable patients (2% with febrileneutropenia), and grade 3thrombocytopenia in 15 (29%) patients (4%with bleeding). Nausea/vomiting( grade 2) and asthenia (moderate tosevere) occurred in 24 (46%) and 14 (27%)patients, respectively. Conclusion. Gemcitabine1000–1250 mg/m plus vinorelbine25 mg/m² on days 1 and 8, followed bycisplatin 50 mg/m² 24 hours later, issafe for outpatient administration andactive in patients with NSCLC.     

Phase II study of mitozolomide (M & B 39,565) in colorectal and breast cancer

Summary Twenty-two patients with advanced colorectal cancer (CRC) (12 without prior chemotherapy) and fourteen with pretreated breast cancer (BC) were given mitozolomide (MTZ), IV infusion, every six weeks. The starting dose was 90 mg/m². When it was well-tolerated, dose escalation was done up to 100–115 mg/m². Toxicity was mild, limited to thrombocytopenia with a median nadir of 1.27 × 10⁵ (0.20–4.86). No response was observed in these patients. MTZ, according to these schedule and dosage, does not show activity in human CRC and pretreated BC.     

Phase II trial of vinblastine in advanced ovarian carcinoma

Summary A phase II trial of vinblastine in patients with refractory epithelial ovarian adenocarcinoma of the ovary was conducted by the Gynecologic Oncology Group (GOG) between March 9, 1988 and July 7, 1988. Vinblastine was administered in a dose of 9 mg/m² intravenously every three weeks until disease progression or toxicity supervened. Twenty patients were entered initially. One was ineligible due to a previous primary cancer. Thus, 19 patients are evaluable for toxicity and response. All patients had cisplatin-combination chemotherapy and four had prior radiotherapy. Median age was 63 years (range 40–75 years). Thirteen patients had disease in the pelvis and six had extrapelvic metastases. Ten patients had grade 3 lesions and seven had grade 2. A median of two courses (range: 1–6) were administered. Toxicity was moderate. Seven patients (36.8%) experienced GOG grade 3 or 4 leukocytopenia and six had grade 3 or 4 granulocytopenia. Median nadir WBC was 2,000 cells/1 (range 600–3,500) and platelet nadirs for the three patients with thrombocytopenia were 60,000, 116,000, and 147,000. Other toxicity included grade 3 gastrointestinal and renal toxicity in one patient each. Seven patients (36.8%) had stable disease on therapy and 12 had increasing disease. No responses were observed. Vinblastine in this dose and schedule is inactive in patients with resistant epithelial ovarian adenocarcinoma progressing on first-line chemotherapy. Responsible author: Dr. Gregory P. Sutton, Indiana University Medical Center, Section of Gyn. Oncology, Dept. of Obstetrics & Gynecology, 926 West Michigan Street, Indianapolis, IN 46223, USA.     

Toxicological evaluation of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylaminocarbonyl)hydrazine (VNP40101M), a novel alkylating agent with potential antitumor activity, with intravenous administration in rats and dogs

These studies investigated the toxicological effects of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylaminocarbonyl) hydrazine, VNP40101M, a novel alkylating antitumor agent, in animals. Sprague-Dawley rats (2-10/sex/time point at each dose) and Beagle dogs (1-3/sex/time point at each dose) were treated with VNP40101M (0 [vehicle], 1, 3, 10, and 20 mg/kg in rats and 0, 0.3, 1, and 3 mg/kg in dogs), given intravenously (IV, bolus via the tail or slow push via the cephalic or saphenous vein, respectively) once daily for 5 consecutive days. Clinical signs, mortality, body weight, clinical pathology, gross necropsy, organ weights, and histopathology were evaluated for as long as 43 days in rats and 50 days in dogs. In rats, the toxic doses were found to be at 10 and 20 mg/kg, which induced mainly pulmonary toxicity and mortality. The pulmonary toxicity was reflected by an increase in lung weight; clear, pink or red fluid within the thoracic cavity observed at necropsy; and histopathological evidence of alveolar edema, vascular congestion, alveolar histiocytosis, and vascular thrombi. Although some of these effects were observed in rats treated with 3 mg/kg, the incidence was low (approximately 7%-30%) and may be reversible (based on the time-dependent reduction in the magnitude of lung weight increases). Therefore, the maximum tolerated dose (MTD, or the maximum dose that did not induce significant toxicity or induced reversible toxicity) was > or = 3 mg/kg. VNP40101M at 1 mg/kg did not induce any toxicity, other than low incidence of alveolar edema (2/30 rats), and increased incidences of capillary ectasis/congestion and alveolar histocytosis (2-6/30 rats vs. 1/30-36 in control rats). Therefore, the low effect level (LOEL) is considered to be 1 mg/kg in rats when given IV for 5 days. In dogs, LOEL, MTD, and toxic dose levels were comparable (based on a body weight/surface area conversion) to those in rats, except for some gastrointestinal (GI) effects (i.e., red lesion in the ileum) observed at 0.3 mg/kg (equivalent to 1 mg/kg, or similar to the LOEL in rats) and the associated effects (slight body weight loss and inappetence). For dogs treated with 1 mg/kg (equivalent to approximately 3 mg/kg, or MTD, in rats), VNP40101M induced the same GI effects seen in dogs treated with 0.3 mg/kg of VNP40101M. Additionally, a transient reduction in white blood cell counts was also observed. Three mg/kg (equivalent to approximately 10 mg/kg, or toxic dose level, in rats) was toxic to dogs, as reflected by the poor clinical condition of these dogs, which subsequently required euthanasia. In conclusion, VNP40101M, when given IV once daily for 5 consecutive days, has a LOEL of 1 mg/kg, a MTD of 3 mg/kg, and toxic doses at > or = 10 mg/kg in rats. The primary toxicity of VNP40101M was pulmonary toxicity and mortality. Based on an interspecies body weight/surface area conversion, VNP40101M had comparable LOEL (0.3 mg/kg), MTD (1 mg/kg), and toxic doses (> or = 3 mg/kg) in dogs, except that dogs appeared to be more sensitive to the GI effects of VNP40101M.     

A Phase I trial of Cis-diammine-1,1-cyclobutane dicarboxylate platinum II (Carboplatin,CBDCA, JM-8) with a single dose every five week-schedule

Summary Carboplatin, a new platinum analogue, was administered intravenously on a schedule of a single dose every five weeks to 23 patients with advanced malignant solid tumors. Patients were treated at six dosage levels ranging from 200–550 mg/m² every five weeks. Thrombocytopenia was dose-limiting. At 550 mg/m² Carboplatin, the median platelet nadir was 65 000/mm³. Leukopenia was common, but usually of mild to moderate degree. Gastrointestinal upset was commonly seen at all dose levels, but 35% of the patients experienced no vomiting. No significant increase of the serum creatinine following Carboplatin was seen. In 16 patients serial determinations of the creatinine clearance were performed. The median base line creatinine clearance was 87 (50–155) ml/min and dropped to a median lowest creatinine clearance of 69 (23–171) ml/min on day four (p < 0.05). The median creatinine clearance before the next Carboplatin treatment was 89 (42–155) ml/min. No significant proteinuria or electrolyte disturbances were noted. Carboplatin exhibited antitumor activity in ovarian, endometrial, thyroid and gastric carcinomas. The maximally tolerated dose appears to be 550 mg/m² every five weeks. A starting dose of 450 mg/m² seems to be appropriate for Phase II studies. In patients with impaired renal function and/or prior cis-Platin chemotherapy, Carboplatin at doses of 200–500     

An NCIC-CTG phase I dose escalation pharmacokinetic study of the matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin

Background: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin in patients with advanced solid tumours, and to identify the maximum tolerated dose of these agents in combination and the dose for use in subsequent studies. Patients and methods: 14 patients were entered onto 3 dose levels consisting of escalating doses of doxorubicin (50 mg/m², 60 mg/m² and 70 mg/m²) with 800 mg po bid BAY 12-9566. At all three dose levels, patients received doxorubicin alone in cycle one on day 1. Daily oral dosing with BAY 12-9566 was started on day 8 of cycle 1, and thus doxorubicin was given concurrently with BAY 12-9566 in cycle 2. Patients were continued on treatment until a dose limiting toxicity or tumour progression occurred. Results: Pharmacokinetic studies from cycles 1 and 2 from the patients treated in the first three dose levels demonstrated that the addition of BAY 12-9566 increased the AUC_0-12h levels of doxorubicin by a median of 48%. No effects were seen on the BAY 12-9566 pharmacokinetic values. Two dose limiting toxicities were seen at the third dose level. One patient experienced grade 3 stomatitis in cycle 2, and another patient experienced grade 4 granulocytopenia in cycle 1 and grade 4 thrombocytopenia in cycle 2. Thus the maximum tolerated dose of 60 mg/m² was declared. These toxicities were those that would have been expected from doxorubicin alone. Conclusions: BAY 12-9566 can be safely administered with full doses of doxorubicin without evidence of clinical interaction. The recommended dose of doxorubicin to be combined with BAY 12-9566 800 mg po b.i.d is 60 mg/m², however, further development of BAY 12-9566 has been abandoned.This study was supported by Bayer Inc.     

Phase I study of high dose etoposide phosphatase with filgrastim (G-CSF) in the treatment of advanced refractory malignancies

Purpose: To define the maximum tolerated dose of etoposide phosphate when used with G-CSF in the treatment of patients with refractory malignancies.Patients and methods: Eleven patients with advanced cancer refractory to standard therapy were treated with etoposide phosphate given over 1–2 hours on three consecutive days. The first cohort of patients received a total dose of 1596 mg/m² (equivalent to etoposide 1400 mg/m²); doses were escalated in subsequent patient cohorts. G-CSF 5 µg/kg was administered subcutaneously from day 4 until the total leukocyte count rose to > 10,000/µL. Two courses were given at 28 day intervals.Results: Toxicity produced by high dose etoposide phosphate included myelosuppression and mucositis. Three of five patients treated at the 2280 mg/m² dose level (equivalent to etoposide 2000 mg/m²) had dose limiting toxicities (grade 4 leukopenia for 7 days, 2 patients; grade 4 mucositis + leukopenia, 1 patient). In addition, median days with severe thrombocytopenia (< 50,000/µL) rose to six days at this dose. Other toxicity was uncommon.Conclusions: In pretreated patients, the maximum tolerated dose of etoposide phosphate with G-CSF is 1938 mg/m² (equivalent to etoposide 1700 mg/m²). Dose-limiting toxicities were myelosuppression and mucositis, as with high dose etoposide. Etoposide phosphate can be substituted for etoposide in high dose regimens; due to its greater solubility, administration can be more rapid, requires less fluid volume, and is not associated with acidosis.     

Pharmacokinetics,mass balance,and tissue distribution of a novel DNA alkylating agent,VNP40101M,in rat

VNP40101M (1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(2 methylamino)carbonyl] hydrazine), a novel DNA alkylating agent, is currently under clinical development for the treatment of cancer in Phase I clinical trials. This study investigated the pharmacokinetics, mass balance, and tissue distribution of [14C]-VNP40101M in rats following a single intravenous dose of 10 mg/kg. After 7 days, the total recovery of radioactivity was 85% for males and 79% for females. Most of the radioactivity was eliminated within 48 hours through urine (70%), with less excreted in feces (6%). Tissue contained relatively high radioactive residues with the highest concentrations in kidneys, liver, lung, and spleen. After 7 days, tissue still contained 9% of the dose. At both 5 minutes and 1 hour post-dose, brain contained relatively high radioactivity (5.9 and 3.3 micro g equivalence/g and 50% and 30% of the blood concentration, respectively), suggesting that VNP40101M penetrated the blood-brain barrier. The elimination half-life of VNP40101M was approximately 20 minutes, the peak plasma concentration (Cmax) averaged 11.3 micro g/mL, the volume of distribution (Vss) averaged 0.91 L/kg, and the total body clearance (Cl) averaged 33.5 mL/min/kg. The metabolite profile in urine was complex, indicating VNP40101M was extensively metabolized. There were no apparent sex differences in pharmacokinetic parameters of VNP40101M in the rat.     

The pharmacokinetics,toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor

Summary Background FK866 is a potent inhibitor or NAD synthesis. This first-in-human study was performed to determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics on a 96-h continuous infusion schedule. Materials and methods Twenty four patients with advanced solid tumor malignancies refractory to standard therapies were treated with escalating doses of FK866 as a continuous, 96-h infusion given every 28 days. Serial plasma samples were collected to characterize the pharmacokinetics of FK866. Further blood samples were collected for the measurement of plasma VEGF levels. Results There were 12 women and 12 men with a median age of 61 (range 34-78) and a median KPS of 80%, received a 4-day of infusion of FK866 at dose levels of 0.018 mg/m²/h (n = 3), 0.036 mg/m²/h (n = 3), 0.072 mg/m²/h (n = 3), 0.108 mg/m²/h (n = 4), 0.126 mg/m²/h (n = 6), and 0.144 mg/m²/h (n = 5). Thrombocytopenia was the dose limiting toxicity, observed in two patients at the highest dose level and one patient at the recommended phase II dose of 0.126 mg/m2/h No other hematologic toxicities were noted other than mild lymphopenia and anemia. There was mild fatigue and grade 3 nausea; the latter was controlled with antiemetics and was not a DLT. C_ss (the mean of the 72 and 96 h plasma concentrations) increased in relation to the dose escalation. The study drug did not significantly affect plasma concentrations of VEGF. There were no objective responses, although four patients had stable disease (on treatment for 3 months or greater). Conclusions The recommended phase II dose is 0.126 mg/m²/h given as a continuous 96-h infusion every 28 days. The dose limiting toxicity of FK866 is thrombocytopenia. Pharmacokinetic data suggest an increase in the plasma C_ss in relation to the escalation of FK866.     

A phase I study of T900607 given once every 3 weeks in patients with advanced refractory cancers; National Cancer Institute of Canada Clinical Trials Group (NCIC–CTG) IND 130

Background: T900607 is a novel tubulin active agent which disrupts microtubule polymerization by a unique mechanism of action. This phase I trial was conducted to determine the maximum tolerated dose, recommended phase II dose, pharmacokinetic properties and toxicities of this agent. Patients and methods: Patients with advanced and/or metastatic solid malignancies were enrolled, for an open dose escalation of T900607 administered intravenously over 30 minutes every 21-days. Results: Thirty patients were enrolled on 7 dose levels ranging from 15 to 270 mg/m². No DLTs were seen until 270 mg/m², the sixth dose level, with 1 patient experiencing Grade 3 thrombocytopenia, 1 grade 4 troponin increase and 1 grade 5 myocardial infarction in an expanded cohort of 6 patients. The dose was decreased to 180 mg/m² with increased cardiac monitoring and at this dose 3/4 patients experienced cardiac toxicity. Further animal cardiotoxicity studies failed to reveal any cardiac effects and the study was reopened at 130 mg/m²; of 6 enrolled patients, 1 had grade 3 drug related lethargy considered to be a DLT and this dose was considered the RP2D. No objective responses were seen but stable disease was reported in 7/20. Pharmacokinetic analysis showed that AUC and C_max increased with dose with considerable intrapatient variability, a short half life of < 1 hour, and no apparent dose dependency clearance. Conclusions: The recommended phase II dose for T900607 is 130 mg/m² given as an intravenous infusion over 60 minutes on a 21-day cycle. Cardiac toxicity was seen with this schedule.This study was supported by grants from the National Cancer Institute of Canada and Tularik Inc., 1120 Veterans Blvd, San Francisco, CA 94080.     

Phase I clinical and pharmacokinetic study of an one-hour infusion of ormaplatin (NSC 363812)

Ormaplatin (NSC 363812, tetraplatin) is a stable platinum (IV) analog which has exhibited activity against cisplatin-resistant cell lines. A phase I trial of ormaplatin administered as a 1-h infusion every 4 weeks was performed. Forty-one patients received 101 cycles of drug over the dose range 4–128 mg/m². The dose-limiting toxicity was reversible thrombocytopenia and granulocytopenia. Minimal myelosuppression was observed at dose levels 78 mg/m², while grade 3 or 4 myelosuppression (thrombocytopenia and/or granulocytopenia) was seen in 4/8 patients at 98 mg/m² and 4/5 patients at 123 mg/m². Nausea and vomiting was observed at all dose levels but was controlled with antiemetic premedication. Neurotoxicity was observed in 5/41 patients and the incidence appeared related to cumulative dose rather than to dose level or drug clearance. Platinum was measured by furnace atomic absorption spectrophotometry. Ormaplatin-derived plasma ultrafilterable platinum (UF-Pt) exhibited linear pharmacokinetics over the dose range studied. The mean total body clearance of UF-Pt was 135 ml/min/m² and the mean elimination half-life (t_1/2) was 13.6 h. Ormaplatin exhibited a high degree of protein binding, with more than 70% of platinum protein bound by the end of the infusion. Urinary excretion of platinum accounted for 37% of the total dose of ormaplatin in 24 hours. A phase II dose of 98 mg/m² is recommended for testing in a patient population with cisplatin-refractory disease.     

Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma

We conducted a phase II evaluation of edatrexate in 17 previously untreated patients with advanced adenocarcinoma of the pancreas; 14 patients had at least one month of therapy. The initial dose was 80 mg/m²iv. Treatment was administered weekly for 5 weeks, then every other week. Toxicity was generally mild. The median WBC nadir was 5.4 (range 0.6–7.4)×10³/l, and the median platelet nadir was 164.0 (range 62.0–341.0)×10³/l. One patient died with sepsis and gastrointestinal bleeding associated with pancytopenia. Five patients had a mild rash. Nausea occurred in 6 patients, including 3 who had vomiting. In addition, 11 patients complained of vague malaise which seemed to begin within 24–48 hours after administration of edatrexate, and lasted for 2 to 3 days, resolving within 6 days of drug administration. Median survival was 85 days. Although 5 patients had stable disease, including one with relief of pain, no major responses were seen, excluding, with 95% confidence, a response rate in excess of 20%.     

BBR 3438, a novel 9-aza-anthrapyrazole, in patients with advanced gastric cancer: A phase II study group trial of the central European Society of Anticancer-Drug Research (CESAR)

BBR 3438, a member of the 9-aza-anthrapyrazole family designed to decrease anthracycline dependent cardiotoxicity and to improve efficacy provided high in vivo activity in gastric carcinoma xenograft models. The present study was carried out to assess the efficacy and safety of BBR 3438 applied at a dose of 50 mg/m² four-weekly as an 1-hour infusion to pretreated patients with gastric cancer. Twenty-seven patients received at least one administration of BBR 3438. Lymph nodes and liver were the most common sites of metastases. A total of 94 cycles were administered (median 2, range 1–6). The main toxicity consisted of (worst per patient [%]; NCIC CTC grades 1/2/3/4) neutropenia 7/7/19/52 (one case of febrile neutropenia), stomatitis 15/19/4/-, nausea 22/26/7/-, vomiting 19/7/7/-, alopecia 15/33/-/-. Neutrophil nadir (520/μl) was reached after a median 15 days. The median time to recovery to ≤grade 1 neutropenia was 13.5 days. The median average cumulative dose of BBR 3438 was 166.8 mg, and the median dose intensity was 48.8 mg/m². Left ventricular ejection function (LVEF) was monitored with multiple-gated angiography (MUGA). Median LVEF values at baseline and at the end of cycle 2 were 67.5% and 65%, respectively, and no patient showed a relevant decrease of LVEF. In 25 patients evaluable for response no remission was observed. Four patients (16%) had stable disease. Median time to progression was 51 days, median overall survival was 64 days. In all, the feasibility and tolerability of BBR 3438 applied 4-weekly at a dose of 50 mg/m² was confirmed and neither relevant LVEF decreases nor hints of cardiac toxicity were observed. In terms of antitumor activity, BBR 3438 was found to be ineffective in the treatment of gastric cancer.     

Phase I/II study of amrubicin,a novel 9-aminoanthracycline,in patients with advanced non-small-cell lung cancer

Purpose: Amrubicin is a novel, totally synthetic 9-aminoanthracycline. The present phase I/II study was performed to define its maximum-tolerated dose (MTD), efficacy and toxicity in the treatment of previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Chemonaive patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and adequate organ functions. Amrubicin was administered by daily intravenous injection for 3 consecutive days every 3 weeks. Results: In a phase I study, four patients were enrolled at dose level 1 (40 mg/m²/day) and four at dose level 2 (45 mg/m²/day). No dose limiting toxicity (DLT), which was defined as toxicity consisting of grade 4 neutropenia and leukopenia lasting four days or more, and grade 3 or 4 toxicity other than neutropenia, leukopenia, anorexia, nausea/vomiting, and alopecia, was observed at these dose levels. Subsequently, at dose level 3 (50 mg/m²/day), 3 of 5 patients experienced DLTs (leukopenia, neutropenia, thrombocytopenia, or gastrointestinal complications). The MTD and recommended dose (RD) were determined to be 50 mg/m²/day and 45 mg/m²/day, respectively. Three partial responses (PRs) were achieved in 13 patients (response rate, 23.1%) in a phase I study. In a phase II study, 15 patients were assessable for efficacy and toxicity at the RD, and four PRs were obtained (response rate, 26.7%). The major toxicities were leukopenia and neutropenia, while non-hematologic toxicities were mild. The overall response rate in the combined patient population of the phase I/II study was 25.0% (7 PRs in 28 patients), with a 95% confidence interval of 10.7% to 44.9%. Conclusion: Amrubicin exerted promising antitumor activity on NSCLC with acceptable toxicity.     

nab-Paclitaxel in patients with advanced solid tumors and hepatic dysfunction: a pilot study

Objective: This pilot open-label clinical study evaluated the safety and pharmacokinetics of albumin-bound paclitaxel (nab-paclitaxel) in patients with advanced solid tumors and hepatic dysfunction.

Research design/methods: Dosing was determined according to baseline bilirubin levels as described in the package insert for Taxol^® (paclitaxel), and patients received 130, 200 or 260 mg/m² nab-paclitaxel every 3 weeks.

Results: Thirty patients with elevated baseline bilirubin and aspartate aminotransferase levels received nab-paclitaxel. The most commonly-occurring grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 neutropenia occurred in 10, 30 and 30% of patients receiving 130, 200 and 260 mg/m² nab-paclitaxel, respectively. Grade 3 fatigue presented in 50 and 30% patients receiving 130 and 200 mg/m² nab-paclitaxel, respectively (no grade 4 event). Only one (10%) patient had a grade 3 sensory neuropathy in the 260 mg/m² nab-paclitaxel arm. Treatment-related grade 3 bilirubinemia and elevated aspartate aminotransferase was observed in patients receiving 130 mg/m² (30 and 10%, respectively) and 260 mg/m² nab-paclitaxel (20 and 10%, respectively). One patient had a grade 4 bilirubinemia in the 200 mg/m² nab-paclitaxel arm. Total bilirubin levels were inversely correlated to paclitaxel clearance (p < 0001).

Conclusions: nab-Paclitaxel has an acceptable tolerability profile in patients with solid tumors and hepatic dysfunction. The safety and pharmacokinetic results support the same dose modification scheme recommended for cremophor-based paclitaxel.     

Gemcitabine and mitoxantrone in metastatic breast cancer: A phase-I-study

Background: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. Patients and methods: Patients with metastatic breast cancer were treated with gemcitabine (1000–1400 mg/m²) on days 1, 8 and 15 and mitoxantrone (10–14 mg/m²) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. Results: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m² gemcitabine and 14 mg/m² mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m² based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. Conclusion: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m².     

Phase II study of fazarabine (NSC 281272) in patients with metastatic colon cancer

Summary Fazarabine (Arabinofuranosyl-5-azacytosine) is a synthetic pyrimidine nucleoside which combines the arabinose sugar of cytosine arabinoside with the triazine base of 5-azacytidine. It has demonstrated activity against a variety of human solid tumor xenografts including colon, lung and breast cancers. Eighteen patients with refractory metastatic colon cancer were enrolled in a phase II trial of fazarabine. The drug was administered as a 72 hr continuous infusion every 3–4 weeks; the starting dose was 2 mg/m²/hr as established in a previous phase I study. The major toxicity was neutropenia, as predicted from the phase I study. The median time to nadir for cycle 1 was 20 days, with a median granulocyte count of 437/l (range 36–1600/l); recovery was within 2–4 days, with only one incidence of fever and neutropenia in 42 cycles. Especially noted for their absence were thrombocytopenia, nausea, vomiting and stomatitis. No objective clinical responses were seen; one patient had stabilization of rapidly growing liver metastases for a period of 7 months. In view of fazarabine's narrow range of toxicities, future dose intensification trials utilizing fazarabine in combination with hematopoietic growth factors are worthy of consideration.