Phase I/pharmacokinetic trial of the novel thioxanthone SR233377 (WIN33377) on a 5-day schedule.

PURPOSE: SR233377 (WIN33377) is a novel 4-aminomethyl thioxanthone derivative with promising preclinical activity against solid tumors at doses substantially below the MTD. We performed a phase I trial to determine a suitable phase II dose of SR233377 when administered as a 2-h intravenous infusion for five consecutive days. METHODS: A group of 25 patients with a range of solid tumor diagnoses and good performance status received SR233377 at eight dose levels ranging from 4.8 mg/m2 per day to 74.7 mg/m2 per day. Cycles were repeated every 35 days and patients were evaluated for response following two cycles of treatment. Doses were escalated in cohorts of three using a modified Fibonacci scheme. Pharmacokinetic sampling was performed during the first cycle in all patients. RESULTS: Toxicities of SR233377 on this schedule included neutropenia, fever, nausea, and dyspnea but all were mild and not dose-limiting. Asymptomatic prolongation of the corrected QT (QTc) interval during infusion in all patients monitored at the 74.7 mg/m2 dose level prompted closure of the study. QT lengthening correlated with increasing plasma concentrations of SR233377. SR233377 Cmax values increased linearly with dose, but substantial interpatient variability in SR233377 AUC, clearance, and half-life was noted. There was no evidence of drug accumulation when day 1 and day 5 AUC and Cmax values were compared. Seven patients displayed tumor growth inhibition lasting for 4 months or more. CONCLUSIONS: We conclude that SR233377 administered on a 5-day schedule is associated with tolerable clinical symptoms and some activity against a range of solid tumors but dosing is limited by QTc prolongation, a condition that predisposes to ventricular arrhythmias. Phase II development on this schedule is not recommended based on the occurrence of this concentration-dependent effect. Further investigation of alternative schedules of administration and of SR233377 analogues is warranted.

Segmental spinal fixation of a thoracic vertebral fracture in an adult chimpanzee.

Accidental trauma associated with an epileptic convulsion in a 10-year-old, male chimpanzee (Pan troglodytes) resulted in incomplete paraplegia from fracture and subluxation of T4. Dorsal laminectomy and segmental spinal fixation were used in treatment. The segmental spinal fixation consisted of sublaminar wires attached to a contoured 316L stainless steel U-rod. The chimpanzee recovered sufficient function to allow reintroduction into the chimpanzee colony at a zoological park during the 12 months after surgery and continues to do well 24 months after surgery.

High-dose melphalan and granulocyte-macrophage colony-stimulating factor for refractory multiple myeloma.

High-dose melphalan has induced remissions in about 40% of patients with refractory myeloma, but the mortality has been high, at about 20%, due to complications of prolonged granulocytopenia. In an attempt to stimulate earlier granulocyte recovery, recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered subcutaneously to 23 patients with refractory myeloma who had been treated with melphalan at a high dose of 100 mg/m2. Thirty-nine percent of patients achieved marked tumor cytoreduction by at least 75%, 2 died within 2 months from infectious complications during severe neutropenia; and median durations of relapse-free and overall survival were 7 and 10+ months, respectively. The nine patients presenting with both advanced age over 50 years and a long history of prior therapy of over 1 year required significantly longer median times of 31 days for granulocytes and of 63 days for platelets to reach safe levels of at least 500/microL and 50,000/microL, respectively, than the 14 remaining patients who had none or only one of these adverse features (21 and 26 days, respectively). In a historic control of 43 patients treated previously with high-dose melphalan but without GM-CSF, hematologic recovery to the aforementioned levels of granulocytes and platelets proceeded over almost 5 weeks, regardless of age and prior treatment exposure. Thus GM-CSF seems to hasten marrow recovery, especially in patients with adequate normal marrow stem-cell reserve as defined by younger age or less prior therapy. While not shortening the duration of neutropenia, GM-CSF dose increments (from 0.25 to 0.5 to 0.75 mg/m2) increased the incidence of severe toxicity from 0% to almost 40%, especially among older patients. These results support the usefulness of low-dose GM-CSF (0.25 mg/m2) in stimulating marrow recovery in selected patients with adequate marrow reserve treated with high-dose melphalan for refractory multiple myeloma.

Familial polycythemia vera.

The occurrence of polycythemia vera in a father, mother, and two sons is reported. Thirteen kindreds with familial polycythemia vera in 31 members are reviewed. Comprehensive records were available for all four patients as well as other family members, since all were diagnosed and treated at the author's institution over a period of nearly 50 years. The mean age at diagnosis, sex predominance, symptoms, and incidence of chromosomal abnormalities, leukocytosis, thrombocytosis, and elevated leukocyte alkaline phosphatase levels were similar to those of nonfamilial cases. The mean RBC volume at diagnosis and the incidence of splenomegaly appear to be higher in familial than nonfamilial cases. The mode of inheritance is unclear, but genetic factors may be involved in the pathogenesis of this myeloproliferative disorder.

Phase II trial of sequential chemotherapy and low-dose radiotherapy in advanced gastric adenocarcinoma. A Southwest Oncology Group Pilot Study.

Thirty-four patients with metastatic gastric adenocarcinoma were treated with the combination of chemotherapy and radiation therapy in a Phase II trial. Induction chemotherapy consisted of one cycle of 5-fluorouracil (5-FU), adriamycin, and BCNU (FAB), followed in 4 weeks by a cycle of 5-FU, adriamycin and mitomycin-C (FAM). In responding and stable patients, consolidation radiotherapy to major sites of disease, followed by maintenance FAM, was administered. Twelve of 30 (40%) patients with measurable disease responded (3 complete responses and 9 partial responses), with a median response duration of 6.0 months. Toxicity was moderate and consisted of nausea, vomiting, and myelosuppression. No additive effects for this combined modality approach could be demonstrated.

Magnetic resonance with marked T2-weighted images: improved demonstration of brain lesions, tumor, and edema.

The object of this study was to determine the sensitivity of magnetic resonance (MR) for imaging intracranial lesions with heavily T2-weighted images compared with that of computed tomographic (CT) and T1-weighted images. Fifty-five patients with known intracranial pathology consisting of primary neurogenic tumors, brain infarcts, demyelinating disease, and metastases were studied by MR and CT. Patients were studied with either 0.6 or 1.5 T systems with T1- and T2-weighted radiofrequency pulse sequences. The heavily T2-weighted images were found to be superior to the T1-weighted images in terms of sensitivity, with 168 lesions found versus 86 by CT and 104 by T1-weighted imaging.

Ocular and orbital toxicity following intracarotid injection of BCNU (carmustine) and cisplatinum for malignant gliomas.

Eleven patients treated with intracarotid BCNU, cisplatinum, or BCNU and cisplatinum in combination for recurrent malignant gliomas were followed with serial ophthalmologic examinations for 2 to 11 months. Eight patients developed significant visual loss ipsilateral to the side of infusion. Secondary glaucoma and internal ophthalmoplegia were new complications observed after BCNU treatment. An unusual pigmentary retinopathy, previously unreported, was seen in patients treated with cisplatinum. One patient also developed a cavernous sinus syndrome after the intracarotid administration of cisplatinum.

Aggressive doxorubicin-containing regimen (prednisone, methotrexate, 5-FU, doxorubicin, and cyclophosphamide; PM-FAC) in disseminated estrogen receptor-negative breast cancer.

Twenty-seven women with disseminated estrogen receptor-negative breast cancer received an aggressive chemotherapy program of prednisone, methotrexate, 5-FU, doxorubicin, and cyclophosphamide. Responses were achieved in 21 of 26 (81%) evaluable patients, eight (31%) of whom had complete responses. The median survival was 17 months. Despite the favorable overall response and a significant number of complete responses, all patients eventually relapsed. Although most patients relapsed systematically, two relapsed initially in the CNS.