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

2040 CANCER June 1, 2001 / Volume 91 / Number 11cells in mitosis and interphase indicated that the limitedactivity of estramustine and paclitaxel as singleagents could become synergistic against androgen independentprostate carcinoma cells. 14 When 96-hourinfusions of paclitaxel at 120 mg/m 2 every 21 dayswere given with continuous oral estramustine at 600mg/m 2 for 21 days in patients with hormone-refractoryprostate carcinoma, Hudes et al. 15 observed adecline in the level of serum prostate specific antigen(PSA) 50% in 53% of patients and measurable diseaseresponses in 44% of patients lasting a median of22 weeks. The spectrum of toxicity included 21% ofpatients with Grade 3 and 4 granulocytopenia andneuropathy attributed primarily to paclitaxel and 10%of patients with serious gastrointestinal and thromboticcomplications attributed primarily to estramustine.A similar spectrum of toxicity and response rateswere described by Petrylak et al. 7 with one infusion ofdocetaxel at 75 mg/m 2 and 5 days of estramustine at840 mg every 21 days.To improve on these regimens, it became a priorityto decrease toxicity and maintain or improve responserates. One approach was to modify the frequency,dose, and length of administration of eachdrug. Preclinical data 16 and clinical data 17,18 supportedthat weekly 1-hour infusions of paclitaxel 100 mg/m 2 could be as effective as higher doses atinducing tumor cell death and clinical response withsubstantially less side effects. New information concerningan intermittent schedule of estramustine becameavailable when the results of a Phase I study 19 of3 days of oral estramustine at 900 mg/m 2 or 1200mg/m 2 and 3-hour infusions of paclitaxel at 100mg/m 2 or higher every 21 days were analyzed. In thisstudy, gastrointestinal side effects were reduced,whereas clinical responses were observed in 4 of 15and in 6 of 14 heavily pretreated women with refractorybreast and ovarian carcinoma, respectively.These studies gave backing to a Phase I–II clinicaltrial to assess the maximum tolerated dose (MTD)safety and efficacy of weekly, 1-hour infusions of escalatingdoses of paclitaxel and a brief, intermittentschedule of oral estramustine in patients with hormonerefractory prostate carcinoma.MATERIALS AND METHODSStudy DesignTo determine the MTD, safety, and efficacy of paclitaxeland estramustine in this modified schedule, weused a Phase I–II design. The initial plan was to havea maximum of six cohorts of three patients. Eachcohort would be treated with an incremental dose ofpaclitaxel starting at 40 mg/m 2 . Oral estramustine initiallywas planned to be given at 600 mg/m 2 based onthe existing experience with this dose. However, soonafter the first cohort of patients had been enrolled, theresults of our Phase I study 19 became available, suggestingthat 900 mg/m 2 may be required for activity ofestramustine on a brief, intermittent schedule. Therefore,the protocol was amended to increase the dose ofestramustine to 900 mg/m 2 from Cohort II onward.Each cohort would receive a minimum of 12 consecutiveweeks of therapy with a break on Week 7. Thecohort would be expanded by three additional patientsat the same paclitaxel dose level if one patientdeveloped Grade 3 or 4 toxicity. The MTD would bereached if two patients in a given cohort experiencedGrade 3 or 4 toxicity. At this point, no further doseescalation would be allowed.Patient SelectionEligible patients had a histologic diagnosis of adenocarcinomaof the prostate with progressive systemicdisease despite at least two endocrine manipulations.One of the manipulations included either orchiectomy,a luteinizing hormone-releasing hormone(LHRH) analogue with or without antiandrogens,megesterol acetate, or diethylstilbestrol. For patientson an antiandrogen, discontinuation of the agent wasrequired as a second hormonal manipulation for aminimum of 4 weeks with evidence of subsequentrising PSA level or progressive, measurable disease.Patients were required to have a minimum life expectancyof 3 months and an Eastern Cooperative OncologyGroup performance score 2. Additional requirementswere adequate hepatic and renal function,granulocyte count 1500/L and platelet count 100,000/L. Patients were required to be at least 3weeks beyond surgery, recovered from infectious process,and have no significant active medical illnessthat would preclude protocol treatment or survival.Prior radiation to a symptomatic metastatic site thatwas not the only measurable or evaluable lesion wasallowed. Radiation therapy and corticosteroids had tobe completed at least 2 weeks before therapy. Hydronephrosiswith impaired renal function had to be adequatelydecompressed. Patients with central nervoussystem metastasis, unstable angina, uncontrolled congestiveheart failure, or arrhythmia were excluded. Allpatients were required to sign informed consent inaccordance with institutional, state, and federal guidelines.Evaluation CriteriaA complete history and physical examination withcomplete blood count, serum chemistry profile, andPSA level were performed at baseline, in Week 7, andin Week 13. Radionuclide bone scans and, computed

Weekly Paclitaxel/Estramustine in HRPC/Ferrari et al. 2041tomography (CT) scans of the abdomen and pelviswere required at baseline and at the end of the studyor as indicated by biochemical or clinical progression.Clinical evidence of toxicity and complete bloodcounts were assessed weekly.Treatment ProgramTherapy was administered in the outpatient setting.All patients continued on a LHRH agonist. Paclitaxelwas given as a weekly 1-hour intravenous infusion fortwo cycle of 6 weeks, with a break on Week 7. The doseescalations of paclitaxel planned for each cohort were40 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 90 mg/m 2 , 100 mg/m 2 ,and 110 mg/m 2 . Two days preceding the paclitaxelinfusion, patients began a 3-day course of oral estramustinegiven in three divided doses 1 hour before or2 hours after meals. The dose of estramustine was 600mg/m 2 per day for patients in Cohort I; however,starting with Cohort II, it was raised to 900 mg/m 2 perday in an attempt to decrease toxicity and maintainefficacy. One hour before paclitaxel infusion, patientsreceived intravenous diphenhydramine 50 mg, ranitidine50 mg, and dexamethasone 20 mg, which wasreduced subsequently to 8 mg if no reactions wereobserved. At the discretion of the treating physician,responding patients were offered an opportunity tocontinue on the same regimen after the study period.Toxicity and Response CriteriaToxicity was graded according to the revised NationalCancer Institute common toxicity criteria. Efficacy was20 –22assessed by changes in PSA levels, changes inmeasurable disease (assessed by CT scans of the abdomenand pelvis and chest X-rays), and changes inevaluable disease (assessed on bone scans). A completebiochemical response was defined as normalizationof PSA levels ( 4.0 ng/mL), a partial responsewas defined as a decline in PSA levels 50% frombaseline values, and disease progression was definedas rising PSA levels 50% above baseline values. Stabledisease was defined as PSA changes that did not meetthe criteria for partial response or disease progression.PSA responses required confirmation on a second determinationat least 2 weeks apart. Measurable diseasewas assessed in bidimensionally measurable lesionswith clearly defined margins by imaging X-rays andscans. A complete response was defined as the resolutionof all measurable masses and the absence ofany lesions or anomalies, a partial response was definedas a reduction 50%, and a minor response wasdefined as a reduction between 25% and 50% in themeasurable lesions.The duration of response 23 was calculated fromthe date of PSA decline 50% from the initiation ofTABLE 1Patient CharacteristicsCharacteristicNo. eligible patients 18No. evaluable 18RaceAfrican American 8Caucasian 8Others 2Median age in yrs (range) 69 (44–76)ECOG performance status0 171 12 0Sites of metastasesBone only 15Bone and soft tissue 3Median baseline PSA (range) 111 (38–2853)Median no. of hormonal therapies (range) 2 (2–4)Prior chemotherapy (%) 3 (16.7)Prior radiotherapy (%) 11 (61.1)ECOG: Eastern Cooperative Oncology Group; PSA: prostate specific antigen.treatment to the date of 50% increase above the nadirPSA value or an increase 25% in the smallest sum ofall tumor measurements obtained during the best response.Response was analyzed on an intent-to-treatbasis for all patients enrolled in the study and forthose in Cohorts II–IV who received the same highdose of estramustine.RESULTSPatient CharacteristicsThe pretreatment characteristics of the 18 patients arelisted in Table 1. The median age was 69 years (range,44 –76 years). There were eight African-American patients,eight Caucasian patients, and two Hispanic patients.Seventeen patients had a performance status of0, and only 1 had a performance status of 1. Themedian baseline PSA level was 111 ng/mL (range,38 –2853 ng/mL). Eighteen patients had bony metastasis,and 3 had pelvic lymph node enlargement. Nonehad parenchymal organ involvement. At study entry,all patients had evidence of disease progression byrising PSA levels after two hormonal manipulationsthat included antiandrogen withdrawal for 4 – 6 weeks.Three patients had received prior chemotherapy, and11 patients had received radiation to a metastatic site.Patient Distribution Among CohortsThe three patients in Cohort I were enrolled to receivepaclitaxel 40 mg/m 2 and estramustine 600 mg/m 2 . Allpatients completed two cycles of therapy. In Cohort II,three patients were enrolled to receive paclitaxel 60No.

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

Weekly Paclitaxel/Estramustine in HRPC/Ferrari et al. 2043TABLE 4Prostate Specific Antigen Response by CohortCohort Paclitaxel Estramustine No.Treatmentdiscontinued Progressed StablePSA decline> 50%Intent to treatresponse (%)I 40 600 3 0 3 0 0 0 of 3II 60 900 3 1 1 0 1 1 of 3IIII 75 900 6 1 0 1 4 4 of 6IV 90 900 6 2 0 0 4 4 of 6Total — — 18 4 4 1 9 9 of 18 (50)PSA: prostate specific antigen. 50%. Because the group of patients in Cohorts II–IVreceived a dose of estramustine 1.5 times greater thanCohort I, and this alone may have affected the PSAresponse irrespective of the dose of paclitaxel, we alsoanalyzed them as a group. The intent-to-treat analysisshowed that 9 of 15 patients (60%) had a PSA decline 50%; in 7 patients, the decline was 75%. Themedian duration of response (n 9 patients) was 16.7weeks, with a range from 3 weeks to 48.6 weeks.Fifteen of 18 patients (83%) had metastatic diseaselimited to bone, including 12 patients in Cohorts II–IV.Seven of these patients (58%) experienced PSA decline 50% from baseline. Stabilization with mild improvementwas reported in two patients. Three patients hadmeasurable disease to lymph nodes, one patient had ameasurable response with a PSA decline 75%, anotherpatient had no response with a PSA decline 50%, and one patient did not complete therapy.Bone scan abnormalities persisted in all patients.DISCUSSIONIn this report, we present the toxicity profile and responseof patients with hormone-refractory prostatecarcinoma to a new schedule and dose range of paclitaxeland oral estramustine. This regimen was basedon previous experience with other tumors suggestingthat more frequent 24,25 and lower doses of paclitaxel, 17,26as well as intermittent but higher doses of estramustine,19 could improve the toxicity profile of each drugwithout compromising their synergistic activity.Therefore, weekly 1-hour infusions of paclitaxel weregiven in escalating doses of 40 mg/m 2 , 60 mg/m 2 ,75mg/m 2 , and 90 mg/m 2 combined with 3 days of oralestramustine. The dose of estramustine, which wasestablished at 600 mg/m 2 in the original design andwas received by patients in Cohort I along with 40mg/m 2 of paclitaxel, was increased subsequently to900 mg/m 2 and fixed at that level for all subsequentpaclitaxel dose levels.The results of this trial indicate that the grade andspectrum of toxicity associated with taxanes in previousstudies of this combination 7,15 can be improvedmarkedly. Compared with the 20% and 53% incidencerates of Grade 3– 4 granulocytopenia, there was onlyone patient without febrile complications in our series.Similarly, there were no new incidents of anemiaor worsening of preexisting anemia compared with the18% and 59% incidence rates reported in the previousstudies, and there were no incidents of thrombocytopenia.Neurologic and musculoskeletal symptoms alsowere infrequent and predominantly were Grade 1.Hypersensitivity reactions, arrhythmia, or hypotensionwere not reported during the infusions. The incidenceof peripheral edema also was reduced markedly.Gastrointestinal complications commonly associatedwith oral estramustine 27 were ameliorated butnot eliminated with the brief and intermittent schedulethat was used. Despite the high dose of estramustine,the frequency and severity of nausea, emesis, anddiarrhea was low 7,28 and was limited to the days oftreatment. This may explain why, compared withother regimens using lower doses of estramustine forprolonged periods of time, 28 anorexia and weight losswere rare.This treatment schedule did not appear to preventthe development of thromboembolic events previouslyreported with regimens containing estramustine,27 as illustrated by the patient who developed apulmonary embolism in the second week of therapy.Given the proximity of the episode to the initiation oftherapy, the possibility cannot be excluded that it mayhave been related to the advanced stage of the diseaserather than the treatment. Also, because we did notobserve other patients with deep vein thrombosis, andrecent studies quote 8 –10% thromboembolic eventswith lower 28 and intermittent 7 dosing of estramustine,we do not have evidence that the higher dose used inthis trial played a role. In recognizing this risk, prophylaxisof thrombosis using low doses of warfarinand aspirin currently are included in the treatmentplan of new trials containing estramustine. Based on

2044 CANCER June 1, 2001 / Volume 91 / Number 11the fact that Cohort IV required expansion becausethere were two patients with Grade 3 and 4 toxicity, weconcluded that the MTD for this regimen had beenreached.A second objective of this study was to evaluatethe efficacy of the combination by PSA response and,whenever possible, by measurable disease parameters.The intent-to-treat analysis by PSA response criteriashowed an overall response rate of 50%, because9 of 18 patients enrolled in the study had a PSA decline 50% from baseline. When looking at PSA responserates by cohort, it appears that a dose of paclitaxelbetween 75 mg/m 2 and 90 mg/m 2 was required toachieve synergism with 900 mg/m 2 of estramustine.These PSA response rates are higher than the 23%rate reported with 24-hour infusions of paclitaxel at135–170 mg/m 2 every 3 weeks 29 or weekly 1-hour infusionsof paclitaxel at 150 mg/m 2 . 30 They also aresuperior to the 14% rate observed with continuousestramustine at 560 – 840 mg daily. 31We took into consideration the facts that the 15patients enrolled in Cohorts II–IV had received a 1.5times larger dose of estramustine compared with patientsin Cohort I and that this alone may have influencedtheir response independent of the dose of paclitaxel.The 60% response rate observed in the intentto-treatanalysis reflects the fact that the 9 responderswere among the 15 patients in this group. It is noteworthythat seven of these responders had a PSA decline 75% from baseline and that the drop in PSAlevels for eight of these patients occurred within theinitial 6 weeks of treatment, which may have affectedthe median PSA response duration determination 23 of16.7 weeks, because, at the time of first evaluation ofresponse, PSA levels had decreased beyond 50%.Although they were limited because of the natureof the study, the PSA response rates observed in theintent-to-treat analysis were within the 53% and 63%response rates reported previously with either paclitaxelor docetaxel every 3 weeks and continuous orintermittent lower doses of estramustine. 7,28 The timeto response and duration of response also were withinthe 8 weeks and 20 –22 weeks observed, respectively,in those studies.We also evaluated whether there was any evidenceof response in bone metastasis or measurabledisease. Like what is seen frequently with metastaticbone disease in patients with hormone-refractoryprostate carcinoma, we observed decreased intensityof bony lesions in two patients, but no decrease in thenumber of bone lesions was observed. We did observea partial response in one patient with measurabledisease to the lymph nodes, whereas the PSA level haddeclined more than 75%. These preliminary observationssuggest that measurable responses also may beexpected with this schedule after a decline in the PSAlevel 50%. 15This study supports the finding that the MTD ofpaclitaxel in a weekly 1-hour infusion schedule is 90mg/m 2 with intermittent estramustine at 900 mg/m 2for 3 days. The current schedule had markedly improvedhematologic and neurotoxicity profile andmilder gastrointestinal side effects compared withhigher doses of paclitaxel at 3-week intervals and continuousestramustine in patients with hormone-refractoryprostate carcinoma. 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