A phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies.

BBR 2778 is a novel aza-anthracenedione with no cardiotoxicity in preclinical models. This Phase I dose escalation trial of BBR 2778 was conducted to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetic profile of BBR 2778 in patients with advanced solid tumors. BBR 2778 was given in three consecutive weekly 30-min i.v. infusions over a 4-week cycle (cy). Thirty patients (pts) were treated with BBR 2778 at doses ranging from 5 to 150 mg/m2/week. The dose levels 5, 10, 16.5, 25, 37.5, 75, 112.5, and 150 mg/m2/week were investigated in 4 pts (9 cy), 3 pts (3 cy), 3 pts (5 cy), 6 pts (9 cy), 1 pt (1 cy), 4 pts (9 cy), 6 pts (18 cy), and 3 pts (4 cy), respectively. The dose-limiting toxicity was neutropenia, typically occurring at day 14. Other toxicities were mild to moderate and were principally thrombocytopenia, lymphopenia, alopecia, nausea, and vomiting and blue coloration of the skin and urine. No significant cardiac toxicity was observed. The plasma dose concentration curve fitted a biexponential profile, with a rapid distribution phase followed by a prolonged elimination phase (mean t1/2,z, 12 h). BBR 2778 displayed a large volume of distribution (range, 9.7-29.7 l/kg) with a high plasma clearance rate (0.75-1.31 l/h/kg). Less than 10% of the dose was recovered in urine as unchanged drug. The maximum tolerated dose was 150 mg/m2/week for 3 weeks, every 4 weeks. On the basis of this study, the recommended dose for Phase II studies is 112.5 mg/m2/week days 1 and 8 with individual optional administration at day 15, every 4 weeks. Antitumor activity was observed in patients with breast, small cell lung carcinoma, and facial cylindroma. This trial showed that BBR 2778 has a manageable toxicity profile on a weekly schedule. This lead compound of the aza-anthracenedione family shows promising antitumor activity and deserves Phase II investigation in patients with high risk of cumulative cardiotoxicity, such as anthracycline-pretreated breast cancer patients.     

Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers

Purpose: To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated. Methods: Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography. Results: Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1–2 μmol/kg occurred between 4 and 6 h after MGd infusion. Conclusion: Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.     

Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies.

SU5416 is a small molecule antiangiogenic agent that inhibits vascular endothelial growth factor (VEGF) stimulation of the KDR tyrosine kinase receptor. In this Phase I dose escalation trial, a weekly dose schedule of SU5416 was tested whereby an initial 5-day loading dose was followed by weekly maintenance infusions. The start dose was 20 mg/m(2) for the loading dose followed by 65 mg/m(2) for the weekly infusions. Dose escalations occurred at 33% until a final dose of 65 mg/m(2) (loading dose) and 190 mg/m(2) (weekly infusion) was obtained. Twenty-two patients were treated at five dose levels; tumor types included gastrointestinal (8), breast (3), lung (4), sarcoma (2), and other (5). The most common serious drug-related toxicity was headache, often associated with nausea and vomiting. Grade 1 and 2 toxicities included headache, nausea, vomiting, asthenia, pain at the infusion site, phlebitis, change in voice, and fevers. Of 19 evaluable patients, 4 obtained clinical benefit as defined by tumor regression (1) or disease stabilization for at least 12 weeks (3). Pharmacokinetic data revealed that the weekly infusion schedule prevented the reported 50-60% induction in SU5416 clearance observed with either daily or twice weekly dosing. Higher baseline levels of urine VEGF were observed in the 4 patients who gained clinical benefit, suggesting this may be a useful marker for predicting response to anti-VEGF therapies. Our results suggest that a weekly schedule of SU5416 shows signs of biological activity and is well tolerated at doses up to 145 mg/m(2).     

A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors.

PURPOSE: Matrix metalloproteinases (MMP) play a fundamental role in cancer development and progression. S-3304 is a potent, orally active, noncytotoxic inhibitor of MMPs, primarily MMP-2 and MMP-9, that prolongs survival in mice xenografts and is well tolerated in healthy volunteers. EXPERIMENTAL DESIGN: The aims of this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and intratumoral MMP inhibitory activity of single-agent S-3304 in advanced and refractory solid tumors. MMP activity was determined by film in situ zymography (FIZ). Patients had tumor biopsies before and after S-3304 administration and were also evaluated for response and survival. RESULTS: Four dose levels were explored [DL1-DL4 or 800, 1,600, 2,400, and 3200 mg twice daily (BID), respectively], and 32 patients were enrolled. Toxicities were mostly gastrointestinal. The maximum tolerated dose was not reached, but dose escalations beyond DL4 were impractical (number of capsules needed). S-3304 steady-state concentrations were reached by day 8, and day 1 mean C(max) and AUC(0-8) increases were less than dose proportional. After S-3304 administration, 17 of 18 patients experienced inhibition of MMP activity by FIZ. Strong mean inhibition of MMP activity was observed in DL1 to DL3. The negative mean inhibitory activity calculated for DL4 was due to one patient with a 397% MMP activity increase. CONCLUSION: S-3304 is safe, well tolerated, and achieves plasma concentrations above those required to inhibit MMP-2 and MMP-9. Its intratumoral MMP inhibitory activity has been shown using FIZ, which is useful as a biomarker with this and other MMP inhibitors.     

A phase I and pharmacokinetic study of novel taxane BMS-188797 and cisplatin in patients with advanced solid tumours

This phase I study investigated the maximum tolerated dose and pharmacokinetics of a 3-weekly administration of BMS-188797, a paclitaxel derivate, at three dose levels (DLs) (80, 110 and 150 mg m(-2) DL), combined with cisplatin (standard dose 75 mg m(-2)). In 16 patients with advanced malignancies treated, one patient experienced dose-limiting febrile neutropenia, sepsis and severe colitis at the 150 mg m(-2) DL; at the 110 mg m(-2) DL one episode of dose-limiting grade 3 diarrhoea/nausea occurred. Grade 3/4 haematological toxicities were leucopenia/neutropenia; grade 3 nonhaematological toxicities were neuropathy, nausea, diarrhoea and stomatits. Objective response was seen in four patients, with three complete remissions in ovarian and cervical cancer patients. Pharmacokinetics of BMS-188797 appeared linear through the 110 mg m(-2), but not through the 150 mg m(-2) DL. The mean+/-SD values for clearance, distribution volume at steady state and terminal half-life during cycle 1 were 317+/-60 ml min(-1) m(-2), 258+/-96 l m(-2) and 30.8+/-7.7 h, respectively. The maximum tolerated and recommended phase II dose for BMS-188797 was 110 mg m(-2) (1-h infusion, every 3 weeks) combined with cisplatin 75 mg m(-2).     

A Phase I and pharmacokinetic study of squalamine, an aminosterol angiogenesis inhibitor.

PURPOSE: The purpose of this study was to assess the feasibility and characterize the pharmacokinetics of squalamine administered as a continuous i.v. infusion daily for 5 days every 3 weeks. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of squalamine as a 5-day continuous i.v. infusion every 3 weeks. Doses were initially escalated in 100% increments from a starting dose of 6 mg/m(2)/day, with a single patient treated at each dose level until moderate toxicity was observed, at which time additional patients were treated. RESULTS: Thirty-three patients were treated with 73 courses of squalamine at 13 dose levels ranging from 6 to 700 mg/m(2)/day. Hepatotoxicity, characterized by brief, asymptomatic elevations in transaminases and hyperbilirubinemia, was the principal dose-limiting toxicity of squalamine. At 700 mg/m(2)/day, two of three patients developed grade 4 hyperbilirubinemia, which precluded further dose escalation. At 500 mg/m(2)/day, one of seven patients experienced dose-limiting grade 4 hyperbilirubinemia and grade 3 neurosensory changes, which resolved soon after treatment. Squalamine pharmacokinetics were dose-proportional. At 500 mg/m(2)/day, the mean (percentage coefficient of variation) clearance, half-life, and volume of distribution of squalamine were 2.67 liters/h/m(2) (85%), 9.46 h (81%), and 36.84 liters/m(2) (124%), respectively, and steady-state concentrations [20.08 micro g/ml (13%)] were well above those that inhibit angiogenesis in preclinical models. CONCLUSIONS: At the recommended Phase II dose of 500 mg/m(2)/day, squalamine is well tolerated and results in plasma concentrations at least an order of magnitude higher than those required for prominent antiangiogenic effects in preclinical studies.     

A phase I study of docetaxel with ketoconazole modulation in patients with advanced cancers

PURPOSE: The aims were to determine the maximum tolerable dose (MTD) of docetaxel with CYP3A inhibition by ketoconazole, and to correlate the pharmacokinetics of docetaxel with midazolam phenotyping of CYP3A activity. METHODS: Forty-one patients with refractory metastatic cancers were treated with an escalating dose of intravenous docetaxel once in every 3 week of 10 mg/m(2), concurrently with oral ketoconazole 200 mg twice daily for 3 days starting 2 days before the administration of docetaxel. Midazolam phenotyping test with ketoconazole modulation was performed before the first cycle of docetaxel. Docetaxel and midazolam pharmacokinetics were compared to our previous study of docetaxel treatment without ketoconazole modulation. RESULTS: Neutropenia was the dose-limiting toxicity. The maximum tolerated dose was 70 mg with mean AUC at 70 mg similar to 75 mg/m(2) of docetaxel without ketoconazole. The plasma clearances of docetaxel and midazolam were reduced by 1.7- and 6-fold, respectively. The variability of midazolam AUC was reduced from 157 to 67%, but variability of docetaxel clearance was not reduced by CYP3A inhibition. Docetaxel clearance correlated with renal function and maximum concentration of ketoconazole, but not midazolam clearance or other variables of hepatic function. CONCLUSION: Fixed dosing was found to be feasible, without increased variability of clearance or neutrophil toxicity compared to BSA-based dosing. With ketoconazole modulation, docetaxel clearance correlated with renal function but not CYP3A phenotype.     

A phase I and pharmacokinetic study of exisulind and docetaxel in patients with advanced solid tumors.

PURPOSE: Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non-small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study. EXPERIMENTAL DESIGN: This study evaluated the toxicity and pharmacokinetics of combining exisulind (150-250 mg) given orally twice daily and docetaxel (30-36 mg/m2) administered intravenously on days 1, 8, and 15 of a 4-week cycle. RESULTS: Twenty patients with a range of advanced solid tumors (median age, 59 years; age range, 35-77 years; median performance status, 1) received a total of 70 courses. Observed adverse events were mild to moderate, and there was no dose-limiting toxicity at any level. Grade 3 gastrointestinal toxicities were present in 10 of the 70 cycles (10%) and included nausea, vomiting, dyspepsia, and elevated alkaline phosphatase. Neutropenia was present in four cycles in patients treated with a docetaxel dose of 36 mg/m2. Pharmacokinetic analysis did not demonstrate a clear effect of exisulind on docetaxel pharmacokinetics and vice versa. Relationships were evident between the plasma concentration of exisulind and the development of grade 2 or greater toxicities. One third of patients maintained stable disease for 3 to 12 cycles, but no objective responses were observed. CONCLUSIONS: The combination of docetaxel (36 mg/m2, weekly) and exisulind (500 mg/d) was reasonably well tolerated, and it is undergoing phase II testing in patients with non-small-cell lung cancer.     

A phase I and pharmacokinetic study of losoxantrone and paclitaxel in patients with advanced solid tumors.

A Phase I and pharmacological study was performed to evaluate the feasibility, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the anthrapyrazole losoxantrone in combination with paclitaxel in adult patients with advanced solid malignancies. Losoxantrone was administered as a 10-min infusion in combination with paclitaxel on either a 24- or 3-h schedule. The starting dose level was 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel (as a 24- or 3-h i.v. infusion) without granulocyte colony-stimulating factor (G-CSF). Administration of these agents at the starting dose level and dose escalation was feasible only with G-CSF support. The following dose levels (losoxantrone/paclitaxel, in mg/m2) of losoxantrone and paclitaxel as a 3-h infusion were also evaluated: 50/135, 50/175, 50/200, 50/225, and 60/225. The sequence-dependent toxicological and pharmacological effects of losoxantrone and paclitaxel on the 24- and 3-h schedules of paclitaxel were also assessed. The MTD was defined as the dose at which >50% of the patients experienced DLT during the first two courses of therapy. DLTs, mainly myelosuppression, occurring during the first course of therapy were noted in four of six and five of eight patients treated with 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel over 24 and 3 h, respectively, without G-CSF. DLTs during the first two courses of therapy were observed in one of six patients at the 50/175 (losoxantrone/paclitaxel) mg/m2 dose level, two of four patients at the 50/200 mg/m2 dose level, one of four patients at the 50/225 mg/m2 dose level, and two of five patients at the 60/225 mg/m2 dose level. The degree of thrombocytopenia was worse, albeit not statistically significant, when 24-h paclitaxel preceded losoxantrone, with a mean percentage decrement in platelet count during course 1 of 80.7%, compared to 43.8% with the reverse sequence (P = 0.19). Losoxantrone clearance was not significantly altered by the sequence or schedule of paclitaxel. Cardiac toxicity was observed; however, it was not related to total cumulative dose of losoxantrone. An unacceptably high rate of DLTs at the first dose level of 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel administered as either a 24- or 3-h i.v. infusion precluded dose escalation without G-CSF support. The addition of G-CSF to the regimen permitted further dose escalation without reaching the MTD. Losoxantrone at 50 mg/m2 followed by paclitaxel (3-h i.v. infusion) at 175 mg/m2 with G-CSF support is recommended for further clinical trials.     

A phase I study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors

Purpose

MN-029 (denibulin HCl) is a novel vascular-disrupting agent that reversibly inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor vascular endothelial cells. This study determined the safety, pharmacokinetics, and acute anti-vascular effects of MN-029.

Methods

Patients were treated with escalating doses of MN-029 (4.0?C225?mg/m²) administered IV at 3-week intervals. This first-in-human study followed an accelerated titration design, with intra-patient dose escalation. Plasma samples were assayed to determine PK parameters. DCE-MRI scans were acquired at baseline and at 6?C8?h post-dose.

Results

Thirty-four patients received 151 infusions of MN-029. The most common toxicities of MN-029 included nausea and vomiting (which appeared to be dose related), diarrhea, fatigue, headache, and anorexia. No clinically significant myelotoxicity, stomatitis or alopecia was observed. There was no evidence of cumulative toxicity in patients receiving multiple courses of therapy. The cohort at 180?mg/m² was expanded to six patients due to a reversible episode of acute coronary ischemia, without sequelae and with preservation of myocardial function. Two dose-limiting toxicities occurred at 225?mg/m², a transient ischemic attack and grade 3 transaminitis, thus ending dose escalation. Pharmacokinetic data indicated dose-related increases in C _max and AUC values, although substantial inter-subject variability was observed. No objective responses were noted; however, five patients had stable disease ??6?months. A significant linear correlation was found between reduction in K ^trans and exposure to MN-029.

Conclusions

MN-029 was generally well tolerated and showed decrease in tumor vascular parameters. The maximum tolerated dose was 180?mg/m².     

A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors

Purpose

Nimotuzumab is a humanized IgG₁ monoclonal antibody to the epidermal growth factor receptor (EGFR) and has demonstrated the absence of severe dermatological toxicity commonly caused by other EGFR-targeting antibodies. We conducted a phase I study to assess toxicities, pharmacokinetics, pharmacodynamics, and predictive biomarkers of nimotuzumab administered in Japanese patients with advanced solid tumors.

Methods

Three dose levels, 100, 200, and 400 mg, of weekly i.v. nimotuzumab were given until disease progression or drug intolerability. Four patients with solid tumors were enrolled in each dose level. The expression and gene copy number of EGFR or its downstream transducers were investigated using skin biopsy samples and tumor specimens.

Results

Planned dose escalation was completed without dose-limiting toxicity, and maximum tolerated dose was not reached. No allergic reaction and hypomagnesaemia were observed, and grade 3 or 4 toxicity did not occur. The common toxicity was skin rash (58 %); however, all of them were grade 1 or 2. In skin biopsies, no correlation was shown between doses and the phosphorylation of EGFR or its downstream signal transducers. Of 11 evaluable patients, no objective response was obtained, while 8 patients had stable disease (73 %). Patients with a higher-EGFR gene copy number level measured by FISH showed a longer time to progression.

Conclusions

Nimotuzumab administered weekly was feasible and well tolerated up to 400 mg in Japanese patients. A low dermatological toxicity could be a notable advantage as anti-EGFR mAb, and further evaluation is warranted.     

A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer

Combretastatin A-4 phosphate (CA4P) is a novel antitumor vascular targeting agent, the first agent of this class of compounds to enter the clinic. We performed a Phase I trial to determine the maximum-tolerated dose, safety, and pharmacokinetic profile of CA4P on a single-dose i.v. schedule. We also obtained preliminary data on its effect on tumor blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) techniques and cell adhesion molecules at the higher-dose levels. Twenty-five assessable patients with advanced cancer received a total of 107 cycles over the following dose escalation schema: 18, 36, 60, 90 mg/m(2) as a 10-min infusion and 60 mg/m(2) as a 60-min infusion at 3-week intervals. There was no significant myelotoxicity, stomatitis, or alopecia. Tumor pain was a unique side effect, which occurred in 10% of cycles, and there were four episodes of dose-limiting toxicity at dosages > or =60 mg/m(2), including two episodes of acute coronary syndrome. Pharmacokinetics revealed rapid dephosphorylation of the parent compound (CA4P) to combretastatin A4 (CA4), with a short plasma half-life (approximately 30 min). A significant (P < 0.03) decline in gradient peak tumor blood flow by DCE-MRI in six of seven patients treated at 60 mg/m(2) was observed. A patient with anaplastic thyroid cancer had a complete response and is alive 30 months after treatment. The toxicity profile is consistent with a drug that is "vascularly active" and devoid of traditional "cytotoxic" side effects. Dosages < or =60 mg/m(2) as a 10-min infusion define the upper boundary of the maximum-tolerated dose.     

Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers.

PURPOSE: To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of lexatumumab (HGS-ETR2), a fully human agonistic monoclonal antibody which targets and activates the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: In this phase 1, open label study, patients with advanced solid malignancies were treated with escalating doses of lexatumumab administered i.v. over 30 to 120 min every 21 days. A cohort of four patients, which could be expanded to six patients, was studied at each dose level. The dose-limiting toxicity (DLT) dose was defined as the dose at which the incidence of DLT in the first two cycles was >or=33%. The maximum tolerated dose was defined as the highest dose at which <33% of subjects experienced DLT. The pharmacokinetics and immunogenicity of lexatumumab were also characterized. Tumor specimens from historical or current biopsies, when available, were stained for TRAIL-R2 using immunohistochemistry techniques. RESULTS: Thirty-seven patients received 120 cycles of lexatumumab at doses ranging from 0.1 to 20 mg/kg every 21 days as of May 2006. The 20 mg/kg dose was identified as the DLT dose based on DLTs in three of seven patients treated with this dose; DLTs included asymptomatic elevations of serum amylase, transaminases, and bilirubin. The 10 mg/kg dose cohort was expanded to 12 patients and the 10 mg/kg dose was identified as the maximum tolerated dose. The mean (+/-SD) clearance and apparent terminal half-life values at the 10 mg/kg dose averaged 6.0 (2.9) mL/d/kg and 16.4 (10.9) days, respectively. Twelve patients had durable stable disease that lasted a median of 4.5 months, including three patients with sarcoma having prolonged stable disease (>or=6.7 months). Immunohistochemistry for TRAIL-R2 showed specific staining in >10% of tumor cells for 16 of the 20 evaluable specimens submitted (80%). CONCLUSIONS: Lexatumumab was safe and well tolerated at doses up to and including 10 mg/kg every 21 days. Lexatumumab was associated with sustained stable disease in several patients. Pharmacokinetics were linear over the dose range studied, and consistent with a two-compartment model with first-order elimination from the central compartment. Additional evaluation of this novel apoptosis-inducing agent, particularly in combination with chemotherapy agents, is warranted and ongoing.     

A phase I and pharmacokinetic study of oral uracil,ftorafur, and leucovorin in patients with advanced cancer

 A phase I and pharmacokinetic study of oral uracil, ftorafur, and leucovorin was performed in patients with advanced cancer. Uracil plus ftorafur (UFT) was given in a 4:1 molar ratio in three divided doses for 28 consecutive days. Patient cohorts were treated at 200, 250, 300, and 350 mg/m² of UFT daily. For all patients, 150 mg of leucovorin was given daily in three oral doses. A 1-week rest period followed each 28-day treatment course. Gastrointestinal toxicity, characterized by diarrhea, nausea, and vomiting, was dose-limiting at 350 mg/m² UFT in patients who had received prior chemotherapy. Mild fatigue and transient hyperbilirubinemia were also common. In previously untreated patients, UFT at 350 mg/m² was well-tolerated, suggesting this as an acceptable phase II dose in this schedule with leucovorin. Two of eight previously untreated patients with advanced colorectal cancer had partial responses with UFT (350 mg/m²) plus leucovorin. Pharmacokinetic parameters [ftorafur, uracil, 5-fluorouracil (5-FU), 5-methyltetrahydrofolate] showed wide interpatient variations. Plasma levels of 5-FU (C_max 1.4±1.9 μM) were comparable to those achieved with protracted venous infusions, and folate levels (C_max 6.1±3.6 μM) were sufficient for biochemical modulation. Ongoing study will determine if this convenient oral regimen will compare favorably in terms of efficacy, toxicity, and cost with intravenous fluoropyrimidine programs. Received: 20 January 1995/Accepted: 29 June 1995     

A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma

Purpose

We studied the safety and effectiveness of TSU-68, an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor and fibroblast growth factor receptor, in patients with advanced hepatocellular carcinoma (HCC).

Methods

Patients with unresectable or metastatic HCC were eligible for enrollment. In phase I, the safety, tolerability and pharmacokinetics were assessed in patients stratified based on liver function, from no cirrhosis to Child?CPugh class B. The safety and effectiveness were assessed in phase II at the dose determined in phase I.

Results

Twelve patients were enrolled in phase I. Dose-limiting toxicities were found with TSU-68 at the dose of 400?mg bid in Child?CPugh B patients, and 200?mg bid was established as the phase II dose. Phase II included 23 additional patients, and the safety and efficacy were evaluated in a total of 35 patients. One patient (2.9%) had a complete response. Two patients (5.7%) had a partial response, and 15 patients (42.8%) showed a stable disease. The median time to progression was 2.1?months, and the median overall survival was 13.1?months. Common adverse events were hypoalbuminemia, diarrhea, anorexia, abdominal pain, malaise, edema and AST/ALT elevation. The analysis of angiogenesis-related parameters suggests that serum-soluble vascular cell adhesion molecule-1 is a possible marker to show the response.

Conclusions

TSU-68 at a dose of 200?mg bid determined by stratification into liver function, showed promising preliminary efficacy with a high safety profile in patients with HCC who had been heavily pre-treated.     

A Phase I and pharmacokinetic study of VNP40101M, a novel sulfonylhydrazine alkylating agent, in patients with refractory leukemia.

PURPOSE: VNP40101M is a novel sulfonylhydrazine alkylating agent with broad antitumor activity in animal models. As alkylating agents are important antileukemia drugs, a Phase I and pharmacokinetic study of VNP40101M was conducted in patients with refractory or relapsed leukemias or poor-risk myelodysplastic syndromes (MDS). EXPERIMENTAL DESIGN: VNP40101M was given as a single i.v. infusion over 15-70 min on day 1. Courses were repeated every 4 weeks according to antileukemic activity. The starting dose of 220 mg/m(2) was escalated by approximately 33% in cohorts of 3-6 patients until a maximum-tolerated dose was established. One additional cohort was treated with the maximum-tolerated dose divided over days 1 and 8. RESULTS: Thirty-eight patients, including 28 with acute myeloid leukemia and 5 with MDS, received 52 courses of treatment. Nondose-limiting, reversible infusion-related toxicities were the most frequent adverse event, occurring in 24 (63%) patients on the first course. Dose escalation was terminated at 708 mg/m(2) for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m(2) was selected as the recommended Phase II dose, with no significant extramedullary toxicity at this dose level. Two patients, 1 with MDS treated with 300 mg/m(2) and 1 with acute myeloid leukemia treated with 600 mg/m(2), achieved complete remission. CONCLUSIONS: VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.     

A phase I and pharmacokinetic study of melphalan using a 24-hour continuous infusion in patients with advanced malignancies.

The objectives of the present study were to determine the following: (a) the maximum tolerated dose (MTD) of melphalan using a 24-h continuous infusion; (b) the clinical toxicity; and (c) the pharmacokinetic characteristics of melphalan at each dose level. Twenty-one patients with refractory solid tumors were enrolled in the study. Melphalan, packaged in 3% sodium chloride, was administered i.v. over a 24-h period. Patients were assigned to one of three escalating dose levels of melphalan: (a) 20 mg/m2 (n = 5); (b) 30 mg/m2 (n = 7); and (c) 40 mg/m2 (n = 6). Each patient underwent pharmacokinetic evaluation during the first cycle of treatment. Melphalan concentrations in plasma were determined by high-performance liquid chromatography. Toxicity was evaluated after each course of chemotherapy. All of the patients were assessable for toxicity and pharmacokinetics, and 20 patients were assessable for response analysis. A total of 50 courses of melphalan was studied. The MTD was 30 mg/m2. The dose-limiting toxicity was neutropenia and thrombocytopenia. Hematotoxicity was reversible (nadir, 14-15 days; recovery, 3.5 and 12.5 days for 30 and 40 mg/m2, respectively), cumulative, and related to the administered dose and to the history of previous therapy. There were six episodes of neutropenic sepsis. Individual pharmacokinetic parameters were estimated using a Bayesian approach and linear elimination kinetics. Data were compatible with a one-compartment model. Relationships have been found between the area under the plasma concentration-time curve and doses and between Css and doses. Moreover, clearance, t1/2 elimination, and volume of distribution did not change statistically with dose, which suggests linear kinetics. Two partial responses were observed in patients with ovarian carcinoma or adenocarcinoma of unknown primary origin, and another patient had stabilization disease. In conclusion, melphalan MTD was determined to be 30 mg/m2 when administered as a 24-h infusion. Hematological toxicity was the dose-limiting toxicity. The most important nonhematological toxicity encountered was nausea and vomiting. The recommended dose for Phase II studies was 30 mg/m2.     

A phase I study of bizelesin, a highly potent and selective DNA-interactive agent, in patients with advanced solid malignancies.

BACKGROUND: The aim of this study was to assess the feasibility of administering bizelesin, a cyclopropylpyrroloindole with extraordinarily high potency as a bifunctional DNA-damaging agent and selectivity for specific AT-rich DNA sequences, as a single i.v. bolus injection every 4 weeks in patients with advanced solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) of bizelesin, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of bizelesin as an i.v. bolus injection every 4 weeks. The selection of the specific starting dose, 0.1 micro g/m(2), which was equivalent to one-tenth the toxic dose low in dogs, factored in large interspecies differences in myelotoxicity as gauged using an ex vivo hematopoietic colony-forming assay. Due to concerns about the high potency of bizelesin and the large interspecies differences in toxicity, a conservative dose-escalation scheme was used for dose-level assignment to determine the MTD levels for both minimally pretreated (MP) and heavily pretreated (HP) patients. A variety of analytical assays were assessed to reliably measure bizelesin concentrations in plasma. RESULTS: Sixty-two patients were treated with 185 courses of bizelesin at eight dose levels ranging from 0.1 to 1.5 micro g/m(2). Myelosuppression, principally neutropenia that was always brief, was the most common toxicity observed. Thrombocytopenia and anemia were uncommon and severe non-hematological effects were not observed. Severe neutropenia alone and/or associated with fever was consistently experienced by HP and MP patients at doses exceeding 0.71 and 1.26 micro g/m(2), respectively. These doses also resulted in functionally non-cumulative myelosuppression as repetitive treatment was well-tolerated. A 40% reduction in measurable disease lasting 24 months was noted in a patient with advanced ovarian carcinoma. Various analytical methods were evaluated but none demonstrated the requisite sensitivity to reliably quantify the minute plasma concentrations of bizelesin and metabolites resulting from administering microgram quantities of drug. CONCLUSIONS: The highly potent and unique cytotoxic agent, bizelesin can be feasibly administered to patients with advanced solid malignancies. The recommended doses for phase II studies of bizelesin as a bolus i.v. injection every 4 weeks are 0.71 and 1.26 micro g/m(2) in HP and MP patients, respectively. The characteristics of the myelosuppression, the paucity of severe toxicities with repetitive treatment, the preliminary antitumor activity noted, and, above all, its unique mechanism of action as a selective DNA-damaging agent and high potency, warrant disease-directed evaluations of bizelesin in solid and hematopoietic malignancies and consideration of its use as a cytotoxic in targeted conjugated therapeutics.     

A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors.

PURPOSE: HMN-214 is an oral prodrug of HMN-176, a stilbene derivative that interferes with the subcellular spatial location of polo-like kinase-1, a serine/threonine kinase that regulates critical mitotic events. We conducted a dose escalation study of HMN-214 in patients with advanced cancer to assess the safety profile and pharmacokinetics of HMN-214 and to establish the maximum tolerated dose. EXPERIMENTAL DESIGN: Thirty-three patients were enrolled onto four dosing cohorts of HMN-214 from 3 to 9.9 mg/m2/d using a continuous 21-day dosing schedule every 28 days, with pharmacokinetic sampling during cycle 1. RESULTS: A severe myalgia/bone pain syndrome and hyperglycemia were dose-limiting toxicities at 9.9 mg/m2/d. A dose reduction and separate enrollment by pretreatment status (lightly versus heavily pretreated) was undertaken, with one dose-limiting toxicity (grade 3 bone pain) at 8 mg/m2/d. The maximum tolerated dose was defined as 8 mg/m2/d for both treatment cohorts. Dose-proportional increases were observed in AUC but not Cmax. There was no accumulation of HMN-176, the metabolite of HMN-214, with repeated dosing. Seven of 29 patients had stable disease as best tumor response, including 6-month stable disease in a heavily pretreated breast cancer patient. A transient decline in carcinoembryonic antigen in a patient with colorectal cancer was noted. CONCLUSIONS: The maximum tolerated dose and recommended phase II dose of HMN-214 when administered on this schedule was 8 mg/m2/d regardless of pretreatment status. Further development of HMN-214 will focus on patient populations for which high expression of polo-like kinase-1 is seen (i.e., prostate and pancreatic cancer patients).