Homoharringtonine: a phase I evaluation

Summary Homoharringtonine is one of several Cephalotaxine esters which have shown experimental antineoplastic activity as well as anti-leukemia effects in patients in China. In a Phase I trial of homoharringtonine administered daily × 5 by bolus intravenous injection, the dose limiting toxicity was hypotension and the maximum tolerated dose was 3.5 mg/m²/d × 5. Evidence of drug induced cardiac irritability with resulting ventricular and atrial dysrhythmias was seen. Minimal myelosuppression was seen at this dose. Treatment of patients by 5 day continuous intravenous (rather than bolus) infusion resulted in more pronounced myelosuppression and clinically significant but tolerable hypotension. Significant reduction of white blood cell and platelet counts occurred at a dose of 3.5 mg/m²/day. Further investigations of the hypotensive and cardiac effects of homoharringtonine and Phase II trials using continuous infusion are indicated.     

Taxol administered as a 120 hour infusion

Summary A Phase I trial of Taxol administered as a 120 h infusion once every 3 weeks was conducted in 20 patients with advanced cancer. The initial dose was 5 mg/m²/d (25 mg/m² total dose) and patients received 10 mg/m²/d, 25 mg/m²/d, 30 mg/m²/d and 36 mg/m²/d. Forty-four courses of taxol were administered and all patients were evaluable for toxicity. Grade 4 leukopenia was the dose limiting toxicity observed in 50% of patients treated with 36 mg/m²/d. Significant mucositis was also observed at 30 and 36 mg/m²/d. All toxicity resolved within three weeks of treatment and no cumulative toxicity was observed. No neurotoxicity or cardiotoxicity was observed and no episodes of hypersensitivity reaction were noted. We conclude that 30 mg/m²/d is an appropriate dose for phase II testing of this schedule.     

Clinical phase I and pharmacokinetic trial of the new titanium complex budotitane

Budotitane [cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] is a novel inorganic metal complex. Preclinical studies in established screening models indicate considerable antitumor activity. We have performed a clinical Phase I and pharmacokinetic trial with budotitane administered as i.v. infusion twice weekly. The starting dose of 100 mg/m² was derived from a prior single dose Phase I study. Eighteen patients with solid tumors refractory to all other known treatment modalities were entered. 17 patients had receivedprior chemotherapy. Dose levels ranged from 100 mg/m² to 230 mg/m², with a total of 122 budotitane infu sions administered. Neither leukonor thrombocytopenia were observed. 2/5 pts at 180 mg/m² and 2/4 pts at 230 mg/m² developed a 3-fold increase of reticulocytes without signs of hemolysis or bleeding. Nonhematologic toxicity was moderate at doses of 180 mg/m². Fifteen patients reported loss of taste at the day of infusion. At 230 mg/m², 2/4 pts developed WHO grade 3 cardiac arrhythmias with polytope premature ventricular beats and nonsustained ventricular tachycardia. A limited pharmacokinetic analysis was performed at dose levels 180 mg/m² and 230 mg/m². At 180 mg/m², C_max was 2.9 ± 1.2 g/ml, t_1/2 78.7 ± 24.4 h, Cl_tot 25.3 ± 4.6 ml/min and AUC 203 ± 71.5 h·g/ml. At 230 mg/m², C_max was 2.2 ± 0.8 g/ml, t_1/2 59.3 ± 12.1 h, Cl_tot 44.9 ± 23.6 ml/min and AUC was 183 ± 90.4 h·g/ml. No objective tumor response was observed. We conclude that the maximum tolerated dose of budotitane administered twice weekly is 230 mg/m², the dose limiting toxicity is cardiac arrhythmia. Further evaluation of the nature of the cardiac toxicities observed is warranted. Using this schedule, 180 mg/m² is a safe dose for subsequent clinical studies.     

A phase I trial of ametantrone acetate (NSC-287513)

Ametantrone acetate is an intensely blue anthracenedione undergoing clinical trials in man. In this Phase I study, 20 patients received 39 courses of drug as a single IV dose given daily for five days and repeated every three weeks (21 days). Dosage escalations proceeded from 15 mg/m² to 35 mg/m². Predictable and reversible leukopenia was the dose limiting toxicity. One previously untreated patient with renal cell carcinoma metastatic to the lungs and right arm experienced a partial response of 51 days duration. Nine patients had pharmacokinetic studies performed during the study. Ametantrone was extensively distributed (apparent volume of distribution, 26.3 1/m²) and demonstrated a short half-life (harmonic mean half-life, 0.38 hour). The maximum tolerated dose in this study was 35 mg/m². Recommended doses for Phase II trials are 30 mg/m² in good risk patients and 25 mg/m² in poor risk patients. Because of the partial response seen in one patient with renal cell carcinoma, Phase II trials should include this tumor category in order to better define the activity of ametantrone in this disease. In addition, since the total amount of drug that could be given to patients receiving the five day schedule (125–150 mg/m²) was approximately the same amount that could be administered as a single dose (140 mg/m²), it would appear that the only advantage of the daily times five day dosage schedule would be in the lower incidence of bluish skin discoloration.     

Phase I trial of Idarubicin (4-demethoxydaunorubicin) in adult acute leukemia

Summary Idarubicin (IDR) is a new analog of Daunorubicin (DNR) selected for clinical trials because of its outstanding activity in experimental leukemias of mice and in several experimental models when compared to DNR and Doxorubicin. This Phase I trial was designed to determine the maximal tolerated dose in adult patients with acute leukemia refractory to prior treatment, using intravenously (I.V.) daily treatments for 5 consecutive days.Eleven patients were entered in this study. The initial dose of IDR was 4 mg/m²/d × 5 I.V. The highest dose given was 8 mg/m²/d × 5 I.V. Dose limiting toxicity were gastrointestinal side effects at the 8 mg/m²/d × 5 level (mucositis-diarrhea). Antileukemic activity has been detected in acute non-lymphoblastic leukemia not pretreated with anthracyclines. For Phase II adult leukemia studies using this schedule, it is recommended that the IDR dose should be 7 mg/m²/d.     

Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia

Summary Purpose: This Phase I dose escalation study was based on the hypothesis that the addition of 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) to cytarabine would enhance cytarabine cytotoxicity. The primary objective of the study was to establish the maximum tolerated dose of 3-AP when given in combination with a fixed dose of cytarabine. Experimental design: Twenty-five patients with relapsed or refractory myeloid leukemia were enrolled to three dose levels of 3-AP. Cytarabine was administered as a 2 h infusion at a fixed dose of 1,000 mg/m²/day for 5 consecutive days. Escalating doses of 3-AP as a 2 h infusion were administered on days 2 through 5. The 3-AP infusion preceded the start of the cytarabine infusion by 4 h. Results: In general, the toxicities observed with the combination were similar to the expected toxicity profile for cytarabine when utilized as a single agent at this dose and schedule. However, two of three patients developed dose-limiting methemoglobinemia at the highest 3-AP dose studied (100 mg/m²). Transient reversible methemoglobinemia was documented in 11 of 15 patients enrolled at the 75 mg/ m² dose level. Objective evidence of clinical activity was observed in four patients. Conclusions: The combination of 3-AP and cytarabine given on this schedule is feasible in advanced myeloid leukemia. The recommended Phase II dose is 75 mg/m²/day of 3-AP on days 2–5 given prior to cytarabine administered at a dose of 1,000 mg/m²/day over 5 consecutive days. Methemoglobinemia is a common toxicity of this combination and requires close monitoring.     

Phase I Study of N1-N11-Diethylnorspermine (DENSPM) Administered TID for 6 Days in Patients with Advanced Malignancies

This was a dose escalation Phase 1 trial designed todetermine the maximum tolerated dose (MTD) and dose-limitingtoxicities (DLT) of DENSPM. Methods: Adult patientswith refractory solid tumors were treated with DENSPMadministered by intravenous infusion in 100 ml of normalsaline over 30 minutes. The daily dose of DENSPM was dividedinto three equal doses administered approximately every eighthours for six days. Courses were repeated every 28 days.Results: Twenty-eight patients were enrolled in thestudy. Dose levels of DENSPM explored were 25mg/m²/day (3 patients), 50 mg/m²/day (9patients), 60 mg/m²/day (5 patients), 75mg/m²/day (6 patients), 94 mg/m²/day (3patients) and 118 mg/m²/day (2 patients). The DLTfor DENSPM was central nervous system toxicity characterizedby aphasia, ataxia, dizziness, vertigo and slurred speechoccurring at dose levels 94 mg/m²/day, whichwas also the MTD. Safety: The most frequent drug-relatedadverse events were asthenia (9 patients), injection sitereaction (6 patients) and anemia (6 patients). One patient wasremoved from the study due to CNS toxicity. There were notreatment-related deaths. No trends were observed regardinghematologic toxicities, biochemical changes or changes invital signs. Efficacy: Nineteen of the 28 patients enrolled inthe study were assessed for response. No objective responseswere observed. Five patients had stable disease as the bestresponse to therapy. Conclusions: Because the DLT wasCNS and because of the relatively low doses that could besafely administered on this schedule as compared with aonce-a-day schedule, this regimen was not recommended forPhase 2.     

Phase I clinical trial of 5-fluoro-pyrimidinone (5FP), an oral prodrug of 5-fluorouracil (5FU)

Purpose: 5-Fluoro-Pyrimidinone (5FP)is an oral pro-drug of 5-Fluorouracil(5FU), and is converted to 5FU by hepaticaldehyde oxidase. Preclinically, 5FPdemonstrated anti-tumor activity againstcolon 38 and P 388 leukemia models in mice. Using an accelerated titration trial designwith one patient cohorts and initial 100%escalations, a Phase I trial was conductedto determine the maximum tolerated dose(MTD) of 5FP and describe its toxicity andpharmacokinetic profile. Patients and methods: 5FP was administered orally oncedaily for 5 days every 4 weeks. The initialdose level was 23 mg/m²/d. Usingsingle patient cohorts, escalationproceeded according to acceleratedtitration 4B design, initially by 100% andsubsequently 30–35% escalations (exactescalation determined by pill size) untildose limiting toxicity was observed. Atotal of 19 patients were enrolled with amedian age of 56 years and medianperformance status of 1. Most patientswere heavily pre-treated with chemotherapy,radiation therapy, or both, and patientpopulation included a wide variety of tumortypes. Results: Dose escalationproceeded rapidly to 1715 mg/m²/d withthe only toxicities observed being nauseaand vomiting. The large number of pillsnecessary at that point required aformulation change, which resulted inappreciable hematologic toxicity. This ledto rapid de-escalation of dose insubsequent patients, with the MTD finallybeing determined to be 625 mg/m²/d. The DLTs observed were grade 4 neutropeniafor greater than 5 days and grade 3 anemia. Other toxicities included nausea, vomiting,fatigue, constipation and mucositis. Pharmacology studies confirmed that 5FP wasconverted to 5FU in humans at all doselevels. However, the extent of conversiondecreased over the five daily treatments,but returned for the subsequent cycle. Thehematologic toxicity was not related to 5FUexposure per course. Conclusion: 5FPis a tolerable oral outpatient therapy. Accelerated titration was an efficient wayof conducting this phase I trial. Therecommended phase 2 dose is625 mg/m²/d orally for 5 days every 28days.     

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors

Purpose: This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. Patients and methods: Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m². Pharmacokinetic studies were performed in patients at all dose levels. Result: Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m². One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m², and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m². Six patients were treated at the 18 mg/m² dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t_1/2) for TTI-237 was 25–29 h, and the mean area under the concentration time curve at 31.5 mg/m² was 2,768 ng•h/mL. Conclusion: A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m² may be a tolerable dose of TTI-237.     

Assessment of N-methylformamide (NMF) administered orally on a three times weekly schedule: a phase I study

Summary This phase I study was conducted to reevaluate the dose-limiting toxicities, maximum tolerated (MTD) and recommended phase II doses of oral NMF administered on a three times weekly schedule for 4 out of every 6 weeks. This schedule was based on the observation that prolonged administration of NMF was associated with the most efficacious antitumor activity in preclinical studies. Phase II trials that employed a starting dose of 800 mg/m², determined in a previous phase I trial, were suspended because of frequent and severe toxicities. In the current study, a symptom complex characterized by nausea, vomiting, and malaise was the dose-limiting toxicity of oral NMF administered on this schedule. Other toxicities included hepatic enzyme elevations, mild myelosuppression, and worsening of preexistent toxic peripheral neuropathies. Of interest, three patients who were asymptomatic prior to treatment, rapidly developed symptoms of increased intracranial pressure after starting NMF; and, computerized tomographic brain scans revealed metastatic tumors with significant peritumoral edema. NMF was well tolerated at 600 mg/m², however, an abrupt increase in toxicity resulted when the dose was increased to 700 mg/m². Although NMF peak plasma concentrations (C_max) and areas under the plasma disappearance curves (AUC) differed between the 600 and 700 mg/m² dose levels, these differences were not striking, and similar NMF plasma concentrations and exposures were well tolerated during intravenous trials. Based on this study, the recommended phase II dose for oral NMF administered three times weekly for 4 of 6 weeks was 600 mg/m². C_maxs and AUCs at this dose were significantly lower than those that were demonstrated to induce cytotoxicity, and differentiating, chemosensitizing, and radiosensitizing effects in preclinical studies suggesting that further clinical evaluations of NMF may not be warranted.     

A Phase I trial of spirogermanium administered on a continuous infusion schedule

We have evaluated the toxicity of the antitumor agent spirogermanium on a schedule of continuous intravenous administration for periods up to five days. The doses tested were between 100 mg/m²/day and 500 mg/m²/day. Peripheral vein phlebitis occurred at all dose levels and was not relieved by addition of hydrocortisone or heparin to the infusion. No phlebitis occurred when the drug was administered through a central vein. The dose limiting toxicity of spirogermanium was neurologic, notably tremors and mental confusion. These problems became progressively more severe at doses above 250 mg/m²/day. There was no discernible bone marrow, renal or hepatic toxicity. One patient developed reversible interstitial pneumonitis. The recommended Phase II dose of spirogermanium is 200 mg/m²/day for five days, with the possibility of escalation in selected patients. Because spirogermanium is more toxic to tumor cells with prolonged exposure than with intermittent exposure, this schedule could be considered for Phase II trials, particularly in diseases thought to be especially sensitive such as ovarian and prostatic carcinoma or lymphomas.     

Phase Ι trial of weekly Docetaxel and daily Temozolomide in patients with metastatic disease

Summary  Docetaxel is second generation taxoid that has shown activity against a variety of cancers and has been approved for use in cancers of the breast, lung, head and neck, ovaries and prostate. Temozolomide is an alkylating agent which crosses the blood brain barrier and has demonstrated antitumor activity against a broad range of tumor types, including malignant glioma, melanoma, non small cell lung cancer and carcinoma of the ovary and colon. A Phase I trial was conducted to determine the toxicity of this combination in refractory solid tumor patients. Methods: Twenty five patients with metastatic cancers were enrolled in a Phase I dose escalation trial. Docetaxel was administered weekly in 5 escalating doses of 25 to 35 mg/ m² as a one-hour bolus intravenous infusion for 3 consecutive weeks. Temozolamide was administered orally daily for 3 weeks (escalating doses of 75 to 100 mg/m²). Cycles were repeated at 4 week intervals. Results: The maximum tolerated dose (MTD) was not determined in this study. The most commonly reported adverse events were mild to moderate nausea, vomiting and fatigue. Thrombocytopenia was the most commonly observed grade 3 and 4 hematological toxicity. Eight patients had dose interruptions for adverse events and only one patient had a dose reduction while receiving 30 mg/ m² of docetaxel and 90 mg/ m² of temozolomide due to grade 3 thrombocytopenia. Two patients achieved partial responses and 88% of the patients are deceased. The median survival is 8.4 months. Conclusions: The combination of docetaxel and temozolomide was well tolerated and these agents can be safely combined. For phase II trials, docetaxel 35 mg/ m² IV day 1, 8 and 15, and daily temozolomide at 100 mg/ m² day 1–21 are recommended. Supported by grants from Schering Plough and Sanofi-Aventis     

A phase I trial of the oral platinum analogue JM216 with concomitant radiotherapy in advanced malignancies of the chest

JM216 is an orally administered platinumanalogue. We undertook this study todetermine the maximally tolerated dose(MTD) of JM216 when administered withconcomitant radiotherapy to the chest(200 cGy daily, 5×/week) in patients withlocoregionally advanced non-small cell lung(NSCLC) or esophageal cancer. Patientswere excluded for inadequate bone marrowreserve, prior radiotherapy to the primarytumor or previous treatment with platinumdrugs. A dose-limiting toxicity (DLT) wasdefined using the National Cancer Institute(NCI) Common Toxicity Criteria (CTC) andconsisted of grade 2 renal, hepatic,cardiac, or pulmonary toxicity or grade 3hematologic, neurological, orgastrointestinal toxicity. A total of 23patients were registered; two neverreceived treatment and are excluded fromanalyses. Six patients were treated at adose of 30 mg/m²/day for 5 days withtwo grade 2 DLT's: cough (1 pt) andelevated trans-aminases (1 pt). Sevenevaluable patients were treated at60 mg/m²/day and seven experiencedgrade 3 or 4 toxicity, five related tomyelosuppression. The dose was thenreduced to 45 mg/m²/d. Eight patientswere evaluable for toxicity, of which 5experienced DLT: myelosuppression (3 pts),esophagitis (2 pts), dyspnea (1 pt), andelevated creatinine (1 pt). Fourteenpatients were evaluable for efficacy, ofwhich 6 had an objective response,including one complete response. Therecommended phase II dose of JM216 withconcurrent radiation therapy is30 mg/m²/d for 5 days. The major DLTis myelosuppression with only limitedincreased toxicity within the field ofradiation. This conceivably may limit theuse of JM216 as a radiation sensitizer.     

Clinical phase I and pharmacokinetic trial of vinorelbine administered as single intravenous bolus every 21 days in cancer patients

Summary We have performed a high-dose clinical and pharmacokinetic trial with vinorelbine administered as a bolus injection every 21 days. The aim was to evaluate a schedule with longer treatment intervals than one week and to determine the toxicity pattern of such a schedule. A total of 13 patients (pts) with solid tumors (non-small-cell lung [3 pts], unknown primary [3 pts], mesothelioma [2 pts], colon/rectum, sarcoma, thyroid, head/neck and cervix [1 pt each]) were entered [9 male, 4 female, median age: 56 years (range: 37–69)]. Dose levels were 35, 40 and 45 mg/m² with a total of 26 cycles administered. At 40 mg/m², 2/6 pts developed grade 4 granulocytopenia. 1/1 pt at 45 mg/m² developed a grade 4 leuko- and granulocytopenia. Non-hematological toxicities were mild to moderate. Neurologic toxicity except for constipation was mild. Constipation occurred at 35 mg/m² in 1/6 pts WHO grade 4, at 40 mg/m² in 2/6 pts WHO grade 3 and at 45 mg/m² in 1/1 pt WHO grade 4 and was due to neurotoxicity. No objective antitumor response was observed. Vinorelbine pharmacokinetics were analysed in whole blood and plasma and were similar to previously published studies using 30 mg/m². Our results confirm a high affinity of vinorelbine to corpuscular blood elements. We conclude that the MTD of vinorelbine administered once every 21 days as bolus injection is 40 mg/m², the dose-limiting toxicities are constipation and granulocytopenia and the recommended dose for subsequent Phase II trials is 35 mg/m².     

Phase I study and clinical pharmacology of 6-diazo-5-oxo-L-norleucine (DON)

The toxicity of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) administered as a 24 hour infusion has been evaluated. Studies of the clinical pharmacology of the drug have also been performed in 3 patients. The limiting toxicity of the drug was acute nausea, vomiting and diarrhea that was dose dependent in its severity and duration. The maximum tolerated dose was 600 mg/m² over 24 hours. The other major toxicity was thrombocytopenia that was maximal 7–10 days after the completion of the infusion. The drug does not exhibit renal, hepatic or central nervous system toxicity. DON achieves steady state levels during these infusions and is eliminated by first order kinetics when the infusion is completed (t1/2 = 1.81 h). The principal route of excretion is renal. A starting dose of 400 mg/m² would be acceptable for Phase II studies of this drug administered on this schedule.     

A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors

Summary The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received ≤2 prior cytotoxic regimens for recurrent disease were treated with gemcitabine over 90 min on days 1 and 8 plus BMS-247550 over 3 h on day 8, every 21 days in a phase I study. Dose-limiting toxicity definitions were based on severe myelosuppression, or grade 3 or 4 treatment-related non-hematologic toxicity, or dose delay of greater than 2 weeks due to treatment toxicity observed in the first treatment cycle. Dose cohort 1 received gemcitabine 900 mg/m² and BMS-247550 20 mg/m². Grade 4 neutropenia lasting ≥7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m² plus BMS-247550 30 mg/m²) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m² plus BMS-247550 30 mg/m²), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m² plus BMS-247550 25 mg/m²), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicites included neutropenia, thrombocytopenia, neutropenic fever, hypophosphotemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m² over 90 min days 1 and 8 plus BMS-247550 20 mg/m² on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.     

A phase I study of gemcitabine, 5-fluorouracil and leucovorin in patients with advanced, recurrent, and/or metastatic solid tumors

Introduction: This was a dose escalation phase I trial designed to establish the MTD (maximum tolerated dose) and toxicity profile of the combination of gemcitabine, leucovorin and 5-fluorouracil (5-FU).Methods: Standard eligibility criteria were required for patients with advanced malignancy to enrol. Gemcitabine was escalated from an initial dose of 800 mg/m². Gemcitabine was administered prior to leucovorin (25 mg/m²) followed by bolus 5-FU (600 mg/m²) every week for 3 weeks followed by 1 week of rest.Results: Of 21 patients enrolled, 20 were eligible for MTD determination. Patients received a median of three 4-week cycles of chemotherapy (range: 1 to 8 cycles). Toxicity was predominantly hematologic or gastroenterologic. Four dose levels were studied. At a gemcitabine dose of 1,500 mg/m² systemic symptoms of fatigue accompanied hematologic toxicity and patients refused further therapy. At 1,250 mg/m², full dose intensity was not delivered during the first cycle in 7 of 8 patients treated. Therefore, 1,000 mg/m² was established as the recommended phase II dose for gemcitabine in this study. Antitumor activity was seen at all dose levels.Conclusions: The combination of gemcitabine, leucovorin and 5-FU was tolerable at full doses of all 3 drugs with an expected toxicity profile. Recommended phase II dose for gemcitabine was 1,000 mg/m². Initial evidence of clinical activity was seen in a variety of tumor types.     

Phase I trial of Adozelesin using the treatment schedule of daily × 5 every 3 weeks

Summary CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6–30 mcg/m²/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m²/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m²/day to be repeated every 4–6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.     

Phase I clinical study of didemnin B

Didemnin B (NSC-325319), a new depsipeptide isolated from a Caribbean tunicate, has been evaluated in a clinical phase I study. The drug was administered in a schedule of a 4 weekly intravenous injection in a six-weeks cycle. Fifty-three patients received 71 evaluable cycles in an escalated dose ranging from 0.4 mg/m²/week to 2.5 mg/m²/week. No hematological toxicity was demonstrated at any dose level. Without prophylactic antiemetics nausea and vomiting was dose limiting at 1.2 mg/m²/week. Due to the use of Cremophor EL as a solvent, hypersensitivity reactions occurred in 9 patients. These reactions occurred following prior exposure to the drug and were commonly seen at the 3rd dose. They were not dose related but became more frequent at 1.5 mg/m²/week necessitating prophylactic treatment with H₁ and H₂ receptor blocking agents. Non-hematological toxicities included mild diarrhea, mucositis, anorexia, headaches, and local phlebitis. The dose- limiting toxicity was generalized weakness which became severe and disabling in 3 of 6 patients treated at 2.5 mg/m²/week. No objective responses were documented in 39 patients with evaluable disease. The recommended dose for phase II studies was 2.3 mg/m²/week × 4 4 in a 6-weeks cycle given with prophylactic antiemetics and H₁ and H₂ receptor blocking agents.     

A phase I and pharmacokinetic study of liposomal vinorelbine in patients with advanced solid tumor

Purpose This phase I study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of an untargeted liposomal formulation of vinorelbine (NanoVNB?) and to characterize its plasma pharmacokinetics in patients with advanced solid tumors which were refractory to conventional treatment or without an effective treatment. Patients & methods The study incorporated an accelerated titration design. Twenty-two patients with various solid tumors were enrolled. NanoVNB^? was administered intravenously at doses of 2.2–23 mg/m² once every 14 days. Pharmacokinetic endpoints were evaluated in the first cycle. The safety profiles and anti-tumor effects of NanoVNB? were also determined. Results Skin rash was the DLT and the most common non-hematological toxicity. The MTD was 18.5 mg/m². Drug-related grade 3–4 hematological toxicities were infrequent. Compared with intravenous free vinorelbine, NanoVNB? showed a high C_max and low plasma clearance. Of the 11 patients completing at least 1 post-treatment tumor assessment, 5 had stable disease. No responders were noted. Conclusion NanoVNB? was well tolerated and exhibited more favorable pharmacokinetic profiles than free vinorelbine. Based on dose-limiting skin toxicity, further evaluation of NanoVNB? starting from 18.5 mg/m² as a single agent or in combination with other chemotherapeutic agents for vinorelbine-active malignancies is warranted.