No abstract

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 received prior chemotherapy. Dose levels ranged from 100 mg/m2 to 230 mg/m2, with a total of 122 budotitane infusions administered. Neither leuko- nor 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 < or = 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, Cmax was 2.9 +/- 1.2 microg/ml, t1/2 78.7 +/- 24.4 h, Cltot 25.3 +/- 4.6 ml/min and AUC 203 +/- 71.5 h x microg/ml. At 230 mg/m2, Cmax was 2.2 +/- 0.8 microg/ml, t1/2 59.3 +/- 12.1 h, Cltot 44.9 +/- 23.6 ml/min and AUC was 183 +/- 90.4 h x microg/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.

Long-term results of both pretreated and previously untreated patients (pts) with hairy cell leukemia (HCL) using uniformly a single 7-day course of 2-chlorodeoxyadenosine (2-CdA) by continuous infusion are reported. In addition, the probability of obtaining another response with this drug in pts who relapsed after 2-CdA treatment will be addressed. A total of 44 consecutive pts (34 males, 10 females) with a median age of 57 years (range 33-77) at the time of initiation of 2-CdA treatment were analyzed. In all, 11 pts were pretreated with either splenectomy (n ¼ 6), interferon a (n ¼ 9) or deoxycoformycin (dCF) (n ¼ 3) or all procedures in sequence. Two pts treated with dCF did not respond to dCF, but only 2-CdA. The median time to the start of 2-CdA treatment of the 11 pretreated pts was 47 months (mo) (10-160). Out of 44, 43 (98%) achieved complete response (CR) (13 pts with residual disease-RD), one pt reached a good partial response with a single cycle of 2-CdA. Out of 44 pts, 13 had no nonhematologic toxicities at all. Toxicities (WHO grade I-IV) were mainly of grade I and II, in one pt grade IV infectious complication. Bone marrow biopsies were performed at the time of recovery of hematopoiesis, thereafter at 2-3 mo intervals, thereafter at 6 mo, and finally annually in 35 pts. The median follow-up is 8.5 years (0.1-12.2). Disease-free survival from the start of 2-CdA treatment is 36% at 12 years (median 8.4 years), 17/44 pts relapsed. Nine of these pts were treated with 2-CdA again, eight achieved a second CR (median 2.5 yrs), one pt did not respond. Eight of our cohort had a second malignancy before receiving 2-CdA. Six pts died in CR due to the second malignancy. The overall survival at 12 years after the start of 2-CdA treatment is 79%. 2-CdA is a safe and effective treatment of HCL inducing complete remissions in the majority of pts with only a single cycle of 2-CdA, and a paucity of toxicities. Responses are durable and long-lasting. Pts who relapsed following treatment with 2-CdA responded to subsequent retreatment with 2-CdA.

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 x WHO grade IV, 1 x WHO grade III). Thrombocytopenia was noted in 3/5 patients (1 x WHO grade IV, 2 x 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 micrograms/ml at 40 mg/m2 DOXeq. The area under the plasma concentration time curve (AUC) ranged from 28.83-80.21 micrograms/ml*h with dose-dependent elimination half lives (t1/2 alpha: 0.02-0.87 h; t1/2 beta: 2.69-11.58 h; t1/2 gamma: 41.44-136.58 h).(ABSTRACT TRUNCATED AT 250 WORDS)

The occurrence of second malignancies (SM) is an important late event following the treatment of Hodgkin's disease (HD). We sought to determine the incidence, the risk factors, and the prognosis of SM in our population of patients with HD. A total of 1120 patients diagnosed with HD were registered at six participating institutions in Munich (calendar period 1974-1994). The mean follow-up for the development of SM was 9.1 years. A cumulative treatment score was calculated for both radio- and chemotherapy. The relative and absolute risks of SM were established. All SM were investigated for response to treatment and outcome. We observed 85 SM [eight leukemias, 22 non-Hodgkin's lymphomas (NHL), two plasma cell neoplasias, and 53 solid tumors]. Five patients developed third malignancies. The relative risk of developing a second neoplasm was compared with that within the normal population and was 3.1-fold. The risk varied according to the category of SM. Higher relative risks (20.5 and 25.9-fold), but lower absolute risks were observed for leukemias and non-Hodgkin's lymphomas. Solid tumors had lower relative risks (1.8-fold). Splenectomy increased the risk of SM (relative risk 4.4-fold versus 2.7-fold). The risk of SM did not correlate with the initial treatment (radio- or chemotherapy) and did not decrease with prolonged follow-up. The cumulative intensity of radiotherapy, chemotherapy, or the two modalities combined correlated with the risk of SM. Since some cases occurred early after diagnosis, not all second neoplasms can be considered treatment-associated. After 15 years, an actuarial risk of 11.7% was calculated for all SM, of 1.0% for leukemias, of 3.0% for NHL, and of 7.7% for solid tumors. The prognosis of SM varied between good (thyroid cancer, melanoma: median survival 5+ years), average (breast cancer, NHL), and poor (acute myeloid leukemias, lung cancers: median survival 9 months). With the exception of NHL, second cancers often occurred in topographic relation to the field of previous radiotherapy. Taken together, in our patient population, we observed all three categories of SM (solid tumors, leukemias, NHL). The risk for second leukemias is lower than in previous studies, whereas the risk of second NHL is somewhat higher. We confirm that splenectomy is a possible risk factor for SM. Even after correction for the age-specific cancer incidence, treatment intensity is associated with the development of second malignant tumors. Continued follow-up is mandatory after treatment for HD. Since the prognosis of most SM is unfavorable, early recognition and prevention are of the utmost importance.