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

More documents

Recommendations

Info

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.
Page 4 and 5: 2042 CANCER June 1, 2001 / Volume 9
Page 6 and 7: 2044 CANCER June 1, 2001 / Volume 9

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

Create successful ePaper yourself

Delete template?

Save as template?