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Abstract

Thirty one patients with solid tumors were entered into a phase I trial with idarubicin, a new anthracycline antibiotic with oral antitumor activity in animals. The drug was scheduled to be given for 4 consecutive weeks at doses ranging from 10 to 20 mg/m2. Leukopenia was the dose-limiting toxicity. Thrombocytopenia was occasionally seen. Since several patients could not receive the third and fourth administrations of the drug at 17.5 and 20 mg/m2, higher doses were administered only for 2 consecutive weeks. With this schedule, the maximum tolerated dose was 25 mg/m2 and leukopenia was again the dose-limiting toxicity. With both schedules, myelosuppression was highly variable and could not be related to prior therapy, bone or liver metastases, or performance status. Other toxicities were mild to moderate and were dominated by nausea and vomiting which were observed in 29% of the patients. Alopecia and mucositis were unfrequent and cardiac toxicity was not observed. Starting doses of 15 mg/m2 for 4 consecutive weeks or 20 mg/m2 for 2 consecutive weeks could be proposed for oral phase II studies with idarubicin, under careful pharmacokinetic monitoring.

In conjunction with two phase I clinical trials, we have investigated the pharmacokinetics of marcellomycin (MCM), a new class II anthracycline antibiotic, in nine patients with normal renal and hepatic functions and no third-space fluid accumulation. MCM was infused IV over 15 min at a dosage of 27.5, 40, or 50 mg/m2. Plasma and urine samples were collected up to 72 h. MCM and metabolites were assayed by thin-layer chromatography and quantified by specific fluorescence. The disappearance of total MCM-derived fluorescence from plasma followed first-order kinetics and lacked the rebound in total fluorescence that has been described for the structurally similar agent, aclacinomycin A. After 40–50 mg/m2, the peak MCM concentration in plasma was 1.67±0.61 µM; MCM disappeared from plasma in a triexponential fashion and was undetectabel by 48 h after infusion. The area under the plasma concentration-time plot (AUC), including the infusion time, was 1.11±0.39 µMxh; plasma clearance of MCM was 1.50±0.88 l/min/m2. Five other fluorescent compounds were consistently observed in plasma. M2 was a contaminant present in the parent drug. P1 and P2 were conjugates of MCM and M2, respectively. G1 and G2 were aglycones. The peak concentrations of the metabolites were 25% or less or the peak concentration for MCM, but their persistence resulted in higher AUCs than that for MCM. For the dosage of 27.5 mg/m2, fewer data were available; but the pharmacokinetics of MCM and metabolites appeared to be similar to that at higher dosage. Urinary excretion of total fluorescence amounted to 8.0%±1.6% of the total dose at 40–50 mg/m2, and to 7.0%±2.3% at 27.5 mg/m2. No correlation was detected among the various pharmacokinetic parameters and toxicities encountered in these patients.

Lors d’une méningo-encéphalite, l’apparition d’un diabète insipide central est une complication endocrinienne classique, mais rare. Nous rapportons un cas en période néonatale. À 10jours de vie, une petite fille était hospitalisée en réanimation pour un état de choc septique. Elle était née à terme, eutrophe, sans critère d’infection materno-fœtale. Le diagnostic de méningo-encéphalite à Escherichia coliétait retenu. Au 5ejour, l’enfant présentait une polyurie hypo-osmotique associée à une déshydratation intracellulaire, réversible après administration intraveineuse de DDAVP : le diagnostic de diabète insipide central était retenu. L’IRM cérébrale et hypophysaire mettait en évidence des abcès au niveau de la région hypothalamique. Une antibiothérapie prolongée associée à un traitement par DDAVP intraveineux, puis oral ont permis une évolution favorable. À 3 mois d’évolution, la croissance staturopondérale et le tonus étaient normaux, le diabète insipide équilibré. Aucun déficit antéhypophysaire n’était retrouvé. L’IRM cérébrale révélait des zones de nécrose thalamocaudales bilatérales, mais de manière inattendue la présence d’un hypersignal en T1 de la posthypophyse. Le diabète insipide en période néonatale est le plus souvent néphrogénique, mais il faut être capable de l’évoquer devant des anomalies cérébrales constitutionnelles ou dans un contexte infectieux. D’après les données de la littérature, cette complication de la méningo-encéphalite est rare aussi bien en pédiatrie qu’à l’âge adulte. Il s’agit toujours d’une urgence diagnostique pour laquelle la mesure de copeptine pourrait aider. Au total, lors d’une infection cérébrale, il faut surveiller la diurèse pour diagnostiquer rapidement un diabète insipide associé quel que soit l’âge de l’enfant.

Le recrutement dans les essais en pédiatrie est souvent plus long et difficile comparé aux essais chez les adultes. Les méthodes séquentielles permettent de limiter la durée d’un essai randomisé et de conclure plus rapidement. Une des méthodes les plus utilisées est le test triangulaire (Whitehead et Stratton, 1983). Le test triangulaire tronqué est un cas particulier du test triangulaire permettant de conclure lorsque l’essai est arrêté prématurément. L’objectif de ce travail est d’illustrer l’utilisation de cette méthode dans l’analyse d’un essai pédiatrique (PREMILOC).

A total of 16 patients with histologically confirmed colorectal cancer were entered into this phase II trial, designed to evaluate the efficacy and safety of tallysomycin S10b. The compound was given i. v. weekly at a dose of 2.5 mg/m2by push injection. Pulmonary toxicity was the most significant side effect; it was observed in three patients and required treatment discontinuation in one. Skin lesions occurred in three patients. Other side effects were mild and their relationship to drug administration was ill-defined. No responses were observed in this group of patients, most of whom had received prior therapy.

Twenty evaluable patients with advanced measurable colorectal cancer received 3-week courses of a combination of IV dacarbazine 300 mg/m2/day from day 1 to day 5 and IV mitomycin 2 mg/m2/day from day 1 to day 5. Fourteen of these patients had had no prior chemotherapy and received two or more courses of this two-drug regimen. None of the patients achieved complete or partial response. Severe to life-threatening myelosuppression, was encountered in patients with prior radiotherapy and or prior chemotherapy, and/or in patients with a Karnofsky score =70. Hematologic toxicity was mild in the other patients. Nonhematologic toxic effects were generally mild to moderate and consisted essentially in nausea and vomiting. It is concluded that in our hands the regimen selected for this trial has no significant antitumor activity in advanced colorectal cancer.

Dasatinib (SPRYCEL®, formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity, leading to FDA approval in pts with CML-CP who are resistant to or intolerant of imatinib (im), the present phase II trial was designed to study previously untreated CML-CP pts treated with dasatinib. The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio =0.05% by qPCR) at 12 months (mo). All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily or a 100 mg-once-daily schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Blood counts were done weekly for the first 4 weeks (wks), every 4–6 wks for the first year, and then every 3–4 mo; bone marrow aspirates with cytogenetics were obtained at baseline and every 3–4 mo during the first year, and then every 6–12 mo; molecular monitoring of BCR-ABL transcript levels by qPCR was done at baseline, every 3-4 mo for the first year, and then every 6–12 mo. Of the first 24 pts enrolled between November 2005 and June 2006, pooled across dosing schedule, 54% were female; median age was 44 years (range 18–76). Nine (38%) of the pts were Sokal intermediate-risk and 1 (4%) was high-risk. Median baseline WBC count was 17.4 x109/L (range 3.7–300.0). At 3 mo, complete hematologic response (CHR) and major cytogenetic response (MCyR) was seen in 17 (89%) of 19 pts who had received at least 3 mo of therapy, and complete cytogenetic response (CCyR) was seen in 15 pts (79%). This compares favorably with a CCyR at 3 mo of 37% with im 400 mg/day and 61% with im 800 mg/day, in historical data of similar patients treated in studies at MD Anderson. qPCR at 3 months was <1% (ie, approximately 2-log reduction) in 5 (26%), and was <10% in 9 (47%) of these 19 pts. The most common non-hematologic adverse events (AE) included dyspnea (8 pts), fatigue (7 pts), muscle pain (6 pts), and headache (5 pts) and were predominantly grade (gr) 1–2. Pleural effusion occurred in 3 pts and was gr 1–2 in all. Hematologic toxicity included anemia in 8 pts (4 gr 3), pancytopenia in 4 pts (3 gr 3, 1 gr 4), and thrombocytopenia in 4 pts (2 gr 3, 2 gr 4). With a median duration of therapy of 5 mo, there were 10 pts who required interruption of treatment, 6 due to non-hematologic toxicities, 2 due to hematologic toxicities, and 2 due to both. Dose reductions occurred in 6 pts, 3 due to non-hematologic toxicity, 1 due to hematologic toxicity, and 2 due to both. Rapid, complete cytogenetic responses to dasatinib 100 mg/day have been observed in a high percentage of patients with previously untreated CML-CP. Accrual to this trial continues, and updated efficacy and safety data will be presented at the meeting.

Dasatinib (SPRYCEL®, formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity, leading to FDA approval in pts with CML-CP who are resistant to or intolerant of imatinib (im), the present phase II trial was designed to study previously untreated CML-CP pts treated with dasatinib. The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio ≤0.05% by qPCR) at 12 months (mo). All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily or a 100 mg-once-daily schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Blood counts were done weekly for the first 4 weeks (wks), every 4–6 wks for the first year, and then every 3–4 mo; bone marrow aspirates with cytogenetics were obtained at baseline and every 3–4 mo during the first year, and then every 6–12 mo; molecular monitoring of BCR-ABL transcript levels by qPCR was done at baseline, every 3-4 mo for the first year, and then every 6–12 mo. Of the first 24 pts enrolled between November 2005 and June 2006, pooled across dosing schedule, 54% were female; median age was 44 years (range 18–76). Nine (38%) of the pts were Sokal intermediate-risk and 1 (4%) was high-risk. Median baseline WBC count was 17.4 x109/L (range 3.7–300.0). At 3 mo, complete hematologic response (CHR) and major cytogenetic response (MCyR) was seen in 17 (89%) of 19 pts who had received at least 3 mo of therapy, and complete cytogenetic response (CCyR) was seen in 15 pts (79%). This compares favorably with a CCyR at 3 mo of 37% with im 400 mg/day and 61% with im 800 mg/day, in historical data of similar patients treated in studies at MD Anderson. qPCR at 3 months was <1% (ie, approximately 2-log reduction) in 5 (26%), and was <10% in 9 (47%) of these 19 pts. The most common non-hematologic adverse events (AE) included dyspnea (8 pts), fatigue (7 pts), muscle pain (6 pts), and headache (5 pts) and were predominantly grade (gr) 1–2. Pleural effusion occurred in 3 pts and was gr 1–2 in all. Hematologic toxicity included anemia in 8 pts (4 gr 3), pancytopenia in 4 pts (3 gr 3, 1 gr 4), and thrombocytopenia in 4 pts (2 gr 3, 2 gr 4). With a median duration of therapy of 5 mo, there were 10 pts who required interruption of treatment, 6 due to non-hematologic toxicities, 2 due to hematologic toxicities, and 2 due to both. Dose reductions occurred in 6 pts, 3 due to non-hematologic toxicity, 1 due to hematologic toxicity, and 2 due to both. Rapid, complete cytogenetic responses to dasatinib 100 mg/day have been observed in a high percentage of patients with previously untreated CML-CP. Accrual to this trial continues, and updated efficacy and safety data will be presented at the meeting.