A Phase I/II study of weekly paclitaxel and 3 days of high dose oral ...

2042 CANCER June 1, 2001 / Volume 91 / Number 11TABLE 2Distribution of Toxicity Events by Type and GradeToxicityGrade1 2 3 4Neuropathy 2 1 0 0Musculoskeletal 1 0 0 0Alopecia 3 2 0 0Neutropenia 0 0 1 0Phlebitis a 0 4 0 0Edema 0 0 1 0Thrombosis/embolism 0 0 0 1Nausea 3 3 1 0Emesis 2 0 0 0Diarrhea 0 0 1 0a Phlebitis refers to induration and erythema at the site of intravenous infusion.mg/m 2 with estramustine 900 mg/m 2 . One patient waslost to follow-up after 5 weeks of treatment. Two patientscompleted two cycles. For Cohort III, six patientswere enrolled to receive paclitaxel 75 mg/m 2with estramustine 900 mg/m 2 . The cohort was expanded,because one patient developed Grade 3 nauseaand diarrhea, requiring treatment interruption.Five patients completed two cycles. In Cohort IV, sixpatients were enrolled to receive paclitaxel 90 mg/m 2with estramustine 900 mg/m 2 . The cohort also wasexpanded, because 1 patient developed Grade 3edema with pulmonary embolism during the secondweek of the first cycle and was removed from protocol.One patient discontinued therapy after 4 weeks, andone patient developed Grade 3 neutropenia. Four patientscompleted two cycles.According to the MTD criteria, no further escalationswere made after Cohort IV. In summary, 14patients completed two cycles of therapy, and 4 patientsdid not complete the first cycle.Toxicity AssessmentToxicity could be evaluated in all patients enrolled inthe study, because the discontinuation of treatment infour patients occurred after they had started treatment.Overall, there were no therapy-related deaths. Adetailed account of the spectrum of toxicity and thenumber of patients for each grade of toxicity are listedin Table 2. Grade 1 and 2 paresthesias were observedin three patients, and Grade 1 musculoskeletal symptomswere documented in another patient. Partial lossof hair was seen in five patients. There was only onepatient with Grade 3 neutropenia without febrile complications.At the time of enrollment, 17 patients hadGrade 1 and 2 anemia secondary to prolonged androgenablation and chronic disease. There were no newTABLE 3Distribution of Grade 3 and 4 Toxicity Events among CohortsIII and IVToxicity Cohort III Cohort IVNeutropenia 0 1Edema 0 1Thrombosis/embolism 0 1Nausea 1 0Emesis 0 0Diarrhea 1 0patients with Grade 1 or 2 anemia or progression ofanemia during therapy. Four patients had superficialphlebitis with erythema at the site of intravenous injectionwithout evidence of deep vein thrombosis,which resolved with local therapy. One patient hadGrade 3 lower extremity edema and subsequently developeda pulmonary embolism with pleuritic chestpain and shortness of breath without hemodynamiccomplications. Symptoms improved rapidly with standardanticoagulation treatment with heparin and warfarin,and the patient was removed from study. Nauseawas the most common gastrointestinal symptomand was experienced by six of seven patients as Grade1–2 and by one patient as Grade 3. Grade 2 emesis wasseen in two patients, and Grade 3 diarrhea was experiencedby one patient.Overall, there were four events of Grade 3 toxicityand one event of Grade 4 toxicity. Table 3 summarizedthe number of Grade 3– 4 toxicity events by cohort.There was one patient with Grade 3 nausea and diarrheain Cohort III, and one patient with Grade 3 neutropeniaand one patient with edema and pulmonaryembolism in Cohort IV.PSA ResponseTable 4 summarizes the clinical responses for eachcohort according to PSA criteria and intent-to-treatanalysis results. Cohort I had one patient with stablePSA levels and two patients with PSA progression.Cohort II had one patient who was lost to follow upafter 5 weeks of treatment, one patient had PSA progression,and one had PSA decline 75%. In CohortIII, one patient was removed early, one patient hadstable PSA, one patient had PSA decline 50%, andthree patients had PSA decline 75%. In Cohort IV,two patients were removed early, one patient had PSAdecline 50%, and three patients had PSA decline 75%.The PSA response rate estimated on the basis ofthe intent-to-treat analysis showed that 9 of 18 patients(50%) enrolled in the study had a PSA decline