Phase I/II Study of 72-Hour Infusional Paclitaxel and
`Doxorubicin With Granulocyte Colony-Stimulating
`Factor in Patients With Metastatic Breast Cancer
`
`By Jason S. Fisherman, Kenneth H. Cowan, Marianne Noone, Andrea Denicoff, Stacey Berg, David Poplack,
`Frank Balis, David Venzon, Mary McCaloe, Barry Goldspiel, Catherine Chow, Frederick P. Ognibene,
`and Joyce O’Shaughnessy
`
`Purpose: We conducted a phase I/II trial of concur-
`rently administered 72-hour infusional paclitaxel and
`doxorubicin in combination with granulocyte colony—
`stimulating factor (G-CSF) in patients with previously un-
`treated metastatic breast cancer and bidimensionally
`measurable disease.
`Patients and Methods: We defined the maximum-tol-
`
`erated dose (MTD) of concurrent paclitaxel and doxoru-
`bicin administration and then studied potential pharma-
`cokinetic interactions between the two drugs. Forty-two
`patients who had not received prior chemotherapy for
`metastatic breast cancer received 296 total cycles of
`paclitaxel and doxorubicin with G-CSF.
`Results: The MTD was determined to be paclitaxel
`180 mglm2 and doxorubicin 60 mg/m2 each by 72-hour
`infusion with G-CSF. Diarrhea was the dose-limiting tox-
`icity (DLT) of this combination, with three of three patients
`developing abdominal computed tomographic (CT) scan
`evidence of typhlitis (cecal thickening) at the dose level
`above the MTD. All patients developed grade 4 neutro-
`penia (absolute neutrophil count [ANC] < 500/ML), gen-
`erally less than 5 days in duration. This combination was
`
`ACLITAXEL is an active new agent in the treatment
`of metastatic breast cancer, with response rates of
`56% to 62% in minimally pretreated patients."2 Treatment
`with single—agent doxorubicin is also associated with high
`response rates, especime when administered in high doses.3
`There has been considerable interest in combining paclitaxel
`and doxorubicin in an attempt to increase the antitumor effects
`of single agents. The cytotoxic effects of paclitaxel are sched-
`ule—dependent, and maximal cytotoxicity occurs on dividing
`cells in the G2/M phase of the cell cycle.“‘5 In vitro studies
`in MCF—7 human breast carcinoma cell lines have shown
`
`that the inhibitory concentration 50 (ICSO) of paclitaxel is 2
`logs lower when cells are exposed to paclitaxel over 72 hours
`(1 nmol/L) compared with a 3—hour exposure (110 nmol/L)
`
`
`
`From the Medicine Branch, Pediatric Branch, Biostatistics and
`Data Management Section, Cancer Therapy Evaluation Program,
`National Cancer Institute; and Pharmacy, Radiology, and Critical
`Care Medicine Departments, Clinical Center, National Institutes of
`Health, Bethesda, MD.
`Submitted April 4, 1995; accepted October 4, 1995.
`Address reprint requests to Joyce O’Shaughnessy, MD, National
`Cancer Institute, 9000 Rockville Pike, Building 10, Room 12N226,
`Bethesda, MD 20892.
`This is a US government work. There are no restrictions on its use.
`0732—I83X/96/I403-0012$0.00/0
`
`generally safely administered at dose levels at or below
`the MTD. The overall response rate was 72% (28 of 39
`patients; 95% confidence interval [CI], 55% to 85%), with
`8% complete responses (CR5) (three of 39; 95% Cl, 2% to
`21%) and a median response duration of 9 months. The
`median overall survival time for all patients is 23 months,
`with a median follow-up duration of 28 months. Pharma-
`cokinetic studies showed that administration of pacli-
`taxel and doxorubicin together by 72-hour infusion did
`not affect the steady-state concentrations of either drug.
`Conclusion: Concurrent 72-hour infusional paclitaxel
`and doxorubicin can be administered safely, but is asso-
`ciated with significant toxicity. The overall response rate
`of this combination in untreated metastatic breast cancer
`patients is similar to that achieved with other doxorubi-
`cin-based combination regimens. The modest complete
`response rate achieved suggests that this schedule of
`paclitaxel and doxorubicin administration does not pro-
`duce significant additive or synergistic cytotoxicity
`against breast cancer.
`J Clin Oncol 14:774-782, 1996. This is a U5 govern-
`ment work. There are no restrictions on its use.
`
`(Dr Susan Bates, personal communication, January 1995].
`Other studies have shown that a concentration of 20 to 30
`
`nmol/L of paclitaxel is associated with maximal cytotoxicity
`against MCF-7 human breast carcinoma cell lines over a 24-
`hour exposure, but that prolonging the duration of exposure
`to paclitaxel up to 72 hours at this threshold does result
`in additional cell kill.6 These studies suggest that additional
`cytotoxicity may result from prolonging the duration of the
`paclitaxel infusion. A recent study reported by Wilson et al7
`showed a 48% response rate with 96-hour infusional pacli-
`taxel 140 mg/m2 in doxorubicin— or mitoxantrone—resistant
`metastatic breast cancer.7
`
`Paclitaxel is an excellent substrate for P—glycoprotein
`(ng), the cytoplasmic membrane-associated, energy-de-
`pendent drug efflux pump associated with pleiotropic
`drug resistances'9 The work of several investigators has
`suggested that ng is a low—affinity efflux pump, and that
`its substrates are removed more efficiently from cells that
`express this protein when administered in high doses by
`bolus rather than by low-dose continuous infusion.‘°'11
`This provides additional rationale for administering pacli-
`taxel as a prolonged infusion to decrease cell efflux of
`paclitaxel by ng.
`In this study, doxorubicin was also administered by
`72—hour continuous infusion in an attempt to avoid any
`potential overlapping cardiac toxicities between the two
`
`774
`
`Journal of Clinical Oncology, Vol 14, No 3 (March), l996.: pp 774-782
`Celltrlon v. Genentech
`
`IPR2017-01122
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28
`.
`.
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved. Genentech Exhlblt
`
`

`

`PACLITAXEL AND DOXORUBICIN FOR BREAST CANCER
`
`775
`
`drugs by decreasing peak plasma concentrations of doxo-
`rubicin. Granulocyte colony-stimulating factor (G-CSF)
`was used to ameliorate neutropenia and to escalate the
`paclitaxel and doxorubicin dose—intensities as much as
`possible, since previous studies had suggested dose—re-
`sponse relationships for both paclitaxel and doxoru-
`bicin.3'12'13
`
`The objectives of this phase I/II trial were to determine
`the maximum—tolerated doses (MTD) of paclitaxel given
`by 72—hour continuous infusion concurrently with 72-
`hour infusional doxorubicin with recombinant G—CSF,
`
`to investigate the therapeutic activity of paclitaxel and
`doxorubicin in patients with previously untreated meta—
`static breast cancer, and to study the pharmacokinetics of
`combined paclitaxel and doxorubicin.
`
`PATIENTS AND METHODS
`
`Eligibility
`All patients gave informed consent according to National Institutes
`of Health (NIH) guidelines. All patients had histologically proven
`adenocarcinoma of the breast with evidence of metastatic disease.
`Bidimensionally measurable disease was required for entry and pa—
`tients must have received no prior chemotherapy for metastatic dis-
`ease. N0 patient had been previously treated with paclitaxel or doxo-
`rubicin in the adjuvant setting. Patients who developed metastatic
`disease within 12 months of their initial diagnosis were eligible
`for study, as were patients with longer disease-free intervals. Prior
`hormonal therapy or radiotherapy did not exclude patients from entry
`provided the radiation did not exceed 25% of the total bone marrow.
`Other requirements were Kamofsky performance status greater than
`70%, WBC count greater than 3,500/uL and platelet count 2
`lO0,000/,uL, hepatic transaminase and bilirubin levels no greater
`than two times normal unless there was evidence of metastatic liver
`disease, serum creatinine concentration 5 1.5 mg/dL or creatinine
`clearance greater than 50 mL/min, no prior history of cardiac disease
`including arrhythmias or conduction system abnormalities, and a
`baseline gated blood pool scan (MUGA) and ECG that were normal
`for age. Concurrent chemotherapy, radiotherapy, or immunotherapy
`was prohibited.
`
`Study Design and Conduct
`All chemotherapy infusions were given to patients while they
`were hospitalized at the NIH Warren G. Magnuson Clinical Center,
`because this trial represented the first time that paclitaxel and doxoru-
`bicin had been administered in combination. The first cycle of che-
`motherapy for each patient was administered with continuous cardiac
`monitoring in the medical intensive care unit. Premedications in—
`cluded the following: (1) dexamethasone 20 mg orally or intrave-
`nously 14 and 7 hours before the start of the paclitaxel infusion
`followed by 10 mg orally or intravenously daily during the infusion
`(given ~ 16 hours after the start of paclitaxel and then every 24
`hours thereafter); (2) diphenhydramine 25 mg orally or intravenously
`30 minutes before paclitaxel then every 6 hours during the infusion;
`and (3) cimetidine 300 mg orally or intravenously 30 minutes before
`paclitaxel then every 8 hours during the infusion.
`Patients were evaluated with a history and physical examination
`before the start of each cycle, and all toxicities were graded ac-
`cording to National Cancer Institute (NCI) common toxicity criteria.
`
`A complete blood cell count with differential was obtained three
`times per week to document the duration of the neutrophil nadir.
`Electrolytes, blood urea nitrogen, creatinine, liver function tests, and
`an ECG were obtained once per cycle. Repeat cardiac MUGA scans
`were obtained when patients had been treated with z 350 mg/m2
`of doxorubicin and every cycle thereafter. Patients’ MUGA scans
`had to demonstrate a left ventricnlar ejection fraction (LVEF) greater
`than 40% to receive additional doxorubicin.
`Both paclitaxel (provided by The Division of Cancer Treatment,
`NCI, Bethesda, MD) and doxorubicin (Adriamycin; Adria Labs,
`Columbus, OH) were administered over 72 hours by continuous
`infusion through separate lumens of a centrally placed intravenous
`catheter. Subcutaneous single-lumen catheters were not used due to
`uncertainties regarding drug compatibility. Paclitaxel was prepared
`in polyolefin solution containers and administered through non-
`DEitp plasticized tubing. A 0.22pm filter was used for in-line filtra—
`tion distal to the infusion pump. Paclitaxel and doxorubicin infusions
`were prepared by diluting the total daily (ie, 24-hour) supply in 250
`mL of 5% dextrose injection or 0.9% sodium chloride injection.
`Cycles of paclitaxel and doxorubicin were administered every 21
`days.
`Recombinant human G-CSF (Filgrastim', provided by Amgen,
`Thousand Oaks, CA, and The Division of Cancer Treatment, NCI)
`lO rig/kg was administered subcutaneously daily starting approxi—
`mately 24 hours following completion of the chemotherapy infu-
`sions. G-CSF was terminated when the absolute neutrophil count
`(ANC) was greater than LOGO/ML on two successive determinations
`after the nadir. The next cycle was administered when the ANC was
`2 1,500/liL, platelet count 2 100,000/HL, and all grade 2 or greater
`nonhematologic toxicity had resolved. Dose modifications were per—
`mitted beginning with cycle 2 and consisted of a one dose—level
`reduction for grade 4 thrombocytopenia (platelet count < 20,000/
`ML) or grade 4 neutropenia (ANC < 500/uL) that lasted longer than
`5 days in duration, and a two dose-level reduction for grade 3 or 4
`nonhematologic toxicity. Intrapatient dose escalation was not per-
`mitted.
`
`Dose-limiting toxicity (DLT) was defined as any grade 3 or 4
`nonhematologic toxicity, excluding nausea or vomiting controlled
`with antiemetics. Hematologic DLT was considered to be an ANC
`less than 500/,LLL for greater than 5 days, a single platelet count less
`than 20,000/uL, or failure of the blood counts to recover by day 22.
`Three patients were entered at each dose level and dose escalations
`proceeded until one of three patients experienced DLT; that cohort
`of patients was then expanded to six patients. The MTD was defined
`as the dose level at which no more than two of six patients developed
`DLT on cycle 1. Initially, the paclitaxel dose was fixed at 160
`mg/m2, doxorubicin was escalated to a maximum of 75 mg/m2 in
`successive cohorts of patients, and then the paclitaxel dose was
`escalated. Having defined the MTD of paclitaxel with 75 mg/m2 of
`doxorubicin, the doxorubicin dose was fixed at 60 mg/m2 to deter-
`mine the MTD of paclitaxel with this conventional dose of doxorubi-
`cin. Twelve additional patients were treated at this second MTD to
`study potential pharmacokinetic interactions between paclitaxel and
`doxorubicin.
`
`Response Criteria
`Extent of disease was documented by physical examination every
`cycle with appropriate radiologic studies performed at baseline (in-
`cluding chest roentgenogram, chest and abdominal computed tomog-
`raphy [CT], and bone scan). The clinically relevant imaging studies
`were repeated every three cycles, at which time a full assessment
`of antitumor response was undertaken. A complete response (CR)
`
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`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`

`

`776
`
`FISHERMAN ET AL
`
`was defined as the disappearance of all physical and radiologic find-
`ings of cancer for at least 4 weeks. A partial response (PR) required
`at least a 50% reduction in the sum of the products of the longest
`perpendicular diameters of all bidimensionally measurable lesions
`for at least 4 weeks, during which time no new lesions appeared. A
`minor response required at least a 25% reduction in the same parame—
`ters. Due to the initial significant limitations in paclitaxel drug sup—
`ply, all patients were required to have a minor response to continue
`on study beyond three cycles. Patients were treated with three addi—
`tional cycles of doxorubicin and paclitaxel beyond their best clinical
`response.
`
`Supportive Care
`Patients were hospitalized and treated with broad~spectrum antibi—
`otics for a temperature 2 100,5°F with an ANC less than SOO/uL.
`Prophylactic platelet transfusions were administered for a platelet
`count 5 20,000/,uL and red blood cells were transfused for a hemo-
`globin level 5 8 g/dL.
`
`Pharmacokinetic Studies
`
`Twelve patients were divided into four groups of three patients
`for the purpose of pharmacokinetic studies during cycles 1 and 2 at
`the recommended phase II dose of paclitaxel 180 mg/m2 with 60 mg/
`m2 of doxorubicin. Patients received either paclitaxel or doxorubicin
`alone (three patients each) or paclitaxel and doxorubicin together
`(six patients) for cycle 1. Patients who received paclitaxel or doxoru—
`bicin alone in cycle 1 received the combination in cycle 2, and those
`who received the combination in cycle 1 received either paclitaxel
`(three patients) or doxorubicin (three patients) alone in cycle 2.
`
`Statistical Analysis
`Paclitaxel, doxorubicin, and doxorubicinol plasma concentrations
`were measured as previously described.”15 The steady—state concen-
`trations (CSS) for each patient were calculated from the mean of the
`48-, 70—, 71-, and 72-hour samples. The clearance was calculated
`from the following formula: clearance = infusion rate/C5,. The Wil-
`coxon signed—rank test was used to compare the paired mean C5,.
`Response rates were compared using Fisher’s exact test. Response
`duration, time to progression, and survival time were estimated by
`the Kaplan-Meier method.
`
`RESULTS
`
`Forty-two patients were treated with 296 cycles of
`paclitaxel, doxorubicin, and G-CSF in six dose-level co—
`horts between March 1991 and December 1992. Patient
`
`characteristics are listed in Table l. The median age was
`49, with a range of 29 to 73 years. Twelve patients had
`received prior adjuvant chemotherapy (none including
`doxorubicin). Twenty—four patients had no prior radio-
`therapy; 15 patients had local radiotherapy and three had
`radiotherapy for distant metastases. No patient had been
`treated with chemotherapy for metastatic disease. Sixteen
`patients had received prior hormonal therapy in the adju-
`vant and/or metastatic setting.
`The median disease-free interval from time of diagno~
`sis of primary breast cancer to the time of documentation
`of metastatic disease was 26 months, with a range of 0.7
`
`Table 1. Patient Characteristics
`
`No. of patients
`Age, years
`Median
`Range
`No. with prior adiuvant chemotherapy
`No. with prior hormonal therapy
`No. with prior radiotherapy
`No. with estrogen receptor status
`Positive
`Negative
`Unknown
`
`No. with progesterone receptor status
`Positive
`Negative
`Unknown
`
`Median disease-Free interval (from primary
`diagnosis to metastases, months)
`Patients with disease sites
`Liver
`%
`No.
`Lung
`%
`No.
`Bone
`%
`No.
`Soft-tissue
`%
`No.
`Patients with no. of disease sites
`1
`
`%
`No.
`
`2
`
`42
`
`49
`29-73
`12
`16
`18
`
`18
`20
`4
`
`20
`16
`6
`
`26
`
`48
`20/42
`
`55
`23/42
`
`48
`20/42
`
`1 4
`7/42
`
`31
`13/42
`
`%
`No.
`2 3
`36
`%
`
`No. 15/42
`
`33
`14/42
`
`to 155 months. The median interval between the diagnosis
`of primary breast cancer and entry on study was 32
`months, with a range of 0.7 to 262 months. One half of
`patients had their on-study date as the date of diagnosis
`of metastatic disease. The median number of metastatic
`
`disease sites for all patients was two, with a range of one
`to four. Six patients had soft tissue disease as the only
`site of metastatic disease. The median number of cycles
`administered per patient was eight and ranged from one
`to 13; only three patients received more than nine cycles
`of paclitaxel and doxorubicin. All cycles were assessable
`for toxicity. The overall incidence and severity of clinical
`and laboratory toxicities are listed in Table 2.
`
`Gastrointestinal Toxicity
`
`Gastrointestinal toxicity was the DLT of this combina-
`tion regimen. The DLT of paclitaxel 180 mg/m2 with 75
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`

`

`PACLITAXEL AND DOXORUBICIN FOR BREAST CANCER
`
`777
`
`Table 2. Overall Clinical and Laboratory Toxicities (N = 42)
`Grade
`
`Toxicity
`
`Abdominal pain
`Alopecia
`Cardiac arrhythmias
`Diarrhea
`Fatigue
`Fever
`HSRS
`Mucositis
`
`Myalgia/artl'iralgia
`Nail changes
`Nausea
`
`Neuropathy
`Thrombosis
`Anemia
`
`Leukopenia
`Neutropenia
`Thrombocytopenia
`Hypomagnesemia
`Hypokalemia
`
`1
`
`2
`O
`5
`7
`1
`3
`0
`3
`
`7
`15
`8
`
`l7
`0
`2
`
`0
`O
`5
`1 O
`20
`
`2
`
`1
`41
`0
`14
`33
`38
`1
`26
`
`l7
`6
`13
`
`8
`0
`5
`
`0
`0
`5
`7
`4
`
`3
`
`3
`O
`3
`12
`7
`1
`0
`9
`
`2
`0
`6
`
`1
`O
`27
`
`l
`O
`1 2
`O
`l
`
`4
`
`0
`0
`1
`0
`o
`0
`0
`0
`
`0
`0
`0
`
`0
`1
`8
`
`41
`42
`1 8
`O
`0
`
`mg/m2 of doxorubicin was reversible grade 3 diarrhea
`with abdominal pain. Significant thickening of the cecum
`consistent with typhlitis was documented by CT scan in
`three of three patients at this dose level. All three patients
`recovered fully Without surgical intervention, and no re-
`currences were observed on re-treatment with paclitaxel
`and doxorubicin at a two dose-level reduction. The MTD
`
`of paclitaxel was 160 mg/m2 in combination with doxoru-
`bicin 75 mg/m2 (Table 3). We then fixed the dose of
`doxorubicin at 60 mg/m2 and continued to escalate pacli-
`taxel. At the dose level of paclitaxel 200 mg/m2 with 60
`mg/m2 of doxorubicin, three of six patients developed
`dose-limiting reversible grade 3 diarrhea (two patients)
`or grade 3 abdominal pain (one patient). No cecal thick-
`ening was seen on CT scans in these patients. The MTD
`of paclitaxel was 180 mg/m2 when given in combination
`with doxorubicin at 60 mg/m2 (Table 3).
`Diarrhea was both an acute and cumulative toxicity of
`this regimen, with 29% (12 of 42) of patients requiring
`
`Dose
`Level
`
`Doxorubicin
`(mg/m2)
`
`Table 3. Dose-Limiting Toxicity
`Total No. of
`Patients Willi
`DLT
`
`Paclitaxel
`(mg/m2]
`
`1
`
`2
`3
`A
`5
`6
`
`45
`
`60
`75
`75
`60
`60
`
`160
`
`1 60
`1 60
`180
`180
`200
`
`1/6
`
`0/3
`0/6
`3/3
`1/18
`3/6
`
`Abbreviation: N/A, not applicable.
`
`DLT
`
`Grade 4 Ieukopenia
`> 5 days
`N/A
`N/A
`Typhlitis
`Thrombosis
`Diarrhea
`
`dose reductions for grade 3 diarrhea and an additional 14
`patients (33%) developing grade 2 toxicity at some time
`during the course of therapy. The majority of patients
`treated at the MTD (paclitaxel 180 mg/m2 and doxorubi-
`cin 60 mg/m2) developed grade 2 or 3 diarrhea at some
`time in the course of therapy, as well as grade 2 mucositis.
`Electrolyte losses resulted in grade 2 or greater hypoka—
`lemia or hypomagnesemia in 29% of patients (12 of 42).
`Fifty-five percent of patients required replacement ther-
`apy for hypokalemia and 36% for hypomagnesemia at
`some time in the course of therapy. One patient developed
`ventricular fibrillation and reversible cardiac arrest as a
`
`consequence of diarrhea—induced hypokalemia. One pa-
`tient died on study due to diarrhea and Pseudomonas
`aeruginosa sepsis, having failed to seek medical attention
`for fever and neutropenia. Moderate (grade 1 to 2) muco—
`sitis was common, but rarely interfered with adequate
`nutrition and hydration. Nausea and vomiting Were gener-
`ally well controlled with standard antiemetics that did not
`include serotonin antagonists.
`
`Hematologic Toxicity
`
`Grade 4 neutropenia (ANC < SOD/ML) occurred in all
`patients. The median cycle day the ANC fell below 500/
`ML was 8 (range, 7 to 9) for all cycles. The median
`number of days for all cycles during which the ANC was
`less than SOO/tiL was 4 days (range, 3 to 6) and did not
`change between cycles 1 and 9. Forty-three percent of
`patients (18 of 42) developed grade 4 thrombocytopenia
`at some time during therapy; however, no clinically sig-
`nificant bleeding episodes occurred during this study.
`Thirty—eight percent of cycles (112 of 296) required RBC
`and 8% (23 of 296) platelet transfusions. Hospitalization
`for fever and neutropenia occurred in 93% of patients (39
`of 42) during one or more cycles of therapy. For all 42
`patients, 49% of cycles (144 of 296) required hospitaliza-
`tion for fever and neutropenia. Thirteen percent of cycles
`(37 of 296) were associated with documented infections.
`
`Neurologic Toxicity
`
`Neurologic toxicity with this regimen was generally
`mild; however, two patients developed significant func-
`tional impairment (walking and buttoning) from periph-
`eral neuropathy. Eight patients had transient dysesthesias,
`numbness, or burning, and seven had distal extremity
`peripheral neuropathy that persisted for several cycles.
`The peripheral neuropathy associated with infusional
`paclitaxel and doxorubicin was cumulative and was gen-
`erally slowly reversible after treatment was stopped.
`
`Cardiac Toxicity
`
`All patients underwent continuous cardiac monitoring
`during cycle 1 of therapy. Five patients were noted to
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`

`

`778
`
`Response Criteria
`
`Overall response rate
`Complete response
`Partial response
`Minor response
`Stable disease
`Progressive disease
`Not assessable
`
`Table 4. Clinical Responses
`
`No.
`
`28/39
`3/39
`25/39
`7/39
`3/39
`1 /39
`3/42
`
`%
`
`72
`8
`64
`18
`8
`2
`
`95% Cl (96)
`
`55-85
`2-21
`
`have asymptomatic bradycardia with pulse rates of 50 to
`60, and one patient developed asymptomatic first-degree
`atrioventricular block during cycle 1. This patient devel—
`oped symptomatic second-degree heart block with the
`second cycle and was removed from study. Two patients
`developed bradycardia with transient dizziness, which re-
`solved on stopping the infusion and on treatment with
`vagolytic agents. Three patients were noted to have tran-
`sient T-wave inversions in their precordial ECG leads
`during the paclitaxel and doxorubicin infusions without
`symptoms or serial elevations in myocardial enzymes. No
`patient developed congestive heart failure on this study.
`The median cumulative delivered dose of doxorubicin
`
`was 435 mg/m2 for all patients (range, 60 to 600 mg/mz),
`with nine patients receiving greater than 480 mg/mz. One
`patient developed substemal chest pain and flushing asso-
`ciated with inverted T waves 1 minute after she started
`
`the second cycle of paclitaxel and doxorubicin. The infu-
`sion was stopped and the T waves normalized after sev-
`eral hours without myocardial enzyme or ECG evolution.
`The patient subsequently received the intended doses of
`chemotherapy in the intensive care unit without recur-
`rence of this hypersensitivity reaction (HSR).
`All patients developed alopecia, which was generally
`complete by the end of the second cycle. Mild to moderate
`myalgias, arthralgias, or bone pain were common, and,
`in some patients, were temporally related to G—CSF ad-
`ministration. One patient who was treated at the MTD
`(paclitaxel 180 mg/m2 and doxorubicin 60 mg/m2) devel—
`oped a sudden superior mesenteric vein thrombosis during
`the cycle 1 hematologic nadir and required an emergency
`colectomy. This 36-year—old patient had no history of a
`coagulopathy or prior thrombotic events.
`
`Responses
`
`Thirty-nine of 42 patients were assessable for antitumor
`response. One patient died of sepsis during cycle 1; one
`patient was not able to comply with the treatment regimen
`during cycle 1 and was removed from study; and one
`patient’s pulmonary disease was not considered measur-
`able on final analysis. Response rates are listed in Table
`4. The overall response rate was 72% (28 of 39; 95%
`
`FISHERMAN ET AL
`
`confidence interval [CI], 55% to 85%), With three (8%)
`CR3 (95% CI, 2% to 21%). The response rate in patients
`who had received prior adjuvant chemotherapy was 58%
`(seven of 12) and was 78% in those who had not received
`prior adjuvant therapy (P = .39). Prior hormonal therapy
`also had no significant influence on the likelihood of
`achieving an antitumor response.
`The three patients with CRs were treated at dose levels
`of 160 mg/m2 of paclitaxel and 75 mg/m2 of doxorubicin
`(one patient) and 200 mg/m2 of paclitaxel and 60 mg/m2
`of doxorubicin (two patients). The three CRs occurred in
`patients with stwo sites of disease (one with lung, one
`with a supraclavicular node, and one with mediastinal
`nodes and a single site of bone disease). There were
`no significant differences in the overall response rates
`between subgroups of patients analyzed by the presence
`or absence of specific organ involvement. Of six patients
`who had only soft tissue disease, there were 2 CRs, 3
`PRs, and one minor response for an overall response rate
`of 83% (five of six). There was no evidence in this study
`of a dose-response relationship for infiisional paclitaxel
`and doxorubicin; no differences in response rates were
`seen in the patient cohorts treated with increasing doses
`of paclitaxel and doxorubicin. However, the three CRs
`were observed at or above the MTDs of paclitaxel and
`doxorubicin. Six of seven patients (86%) who were
`treated with 60 mg/m2 of doxorubicin and 200 mg/m2 of
`paclitaxel achieved an objective response, two of which
`were CRs. The average delivered dose-intensity over all
`296 cycles was 16 mg/mZ/wk of doxorubicin and 49 mg/
`m2/wk of paclitaxel.
`The median duration of response (from date of best
`response to progression) was 9 months for the 27 patients
`who achieved an objective response. The median time to
`progression was 12 months for all patients. There was
`no significant difference in time to progression based on
`estrogen or progesterone receptor status. With a median
`follow—up time of 28 months, there have been 24 deaths,
`and the median survival time for all patients is 23 months.
`The estimated survival probability at 24 months is 46%
`(95% CI, 32% to 61%). Kaplan—Meier plots of time to
`progression and overall survival are shown in Figs 1
`and 2.
`
`Pharmacokinetics
`
`We have previously reported the results of the pharma-
`cokinetic studies of paclitaxel and doxorubicin.16 The
`mean (:SD) clearance of paclitaxel was 480 (t 170)
`mL/min/m2 in the single-agent arm and 470 (i 120) mL/
`min/m2 in the combination arm (P = .75). The clearance
`of doxorubicin was 630 (t 150) mL/min/m2 in the single-
`agent arm, and 580 (i 280) mL/min/m2 in the combina-
`tion arm (P = .46).
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`

`

`PACLITAXEL AND DOXORUBICIN FOR BREAST CANCER
`
`779
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`
`0
`
`
`
`PercentProgression-Free
`
`6
`
`
`l—‘ |
`'—l—‘
`'—l—_ _I
`12
`18
`24
`30
`42
`Months Since Entry on Study
`
`Fig I. Kaplan-Meier plot of progression-free survival for all pa-
`tients treated with 72-hour infusional paclitaxel and doxorubicin.
`
`Administration of paclitaxel and doxorubicin together
`did not affect the Css of either drug. However, the Css
`of doxorubicinol, the primary circulating metabolite of
`doxorubicin which has a moderate degree of cytotoxic
`activity, was statistically significantly elevated with the
`combination regimen.15 The CSS of 72-hour infusional
`paclitaxel was 0.12 umol/L (range, 0.07-0.21 umol/L) at
`the lSO-mg/m2 dose level.
`
`DISCUSSION
`
`In this phase I study, the MTD of 72—hour infusional
`paclitaxel administered simultaneously with 75 mg/m2 of
`72-hour infusional doxorubicin was 160 mg/m2 in combi—
`nation with G-CSF. The MTD of paclitaxel was 180 mg/
`m2 when the doxorubicin dose was decreased to 60 mg/
`m2. The latter doses of paclitaxel and doxorubicin were
`chosen for pharmacokinetics study and further evaluation
`of antitumor activity because there was less gastrointesti-
`nal toxicity observed in the patients treated with 60 mg/
`
`1 00
`90
`80
`7O
`60
`50
`4O
`30
`20
`1 0
`0
`
`
`
`PercentSurviving
`
`6
`
`30
`24
`18
`12
`Months Since Entry on Study
`
`36
`
`42
`
`Fig 2. Kaplan-Meier plot of overall survival for all patients treated
`with 72-hour infusional paclitaxel and doxorubicin.
`
`m2 of infusional doxorubicin compared with 75 mg/m2.
`Although none of the 18 patients treated with 180 mg/
`m2 of paclitaxel and 60 mg/m2 of doxorubicin developed
`cycle 1 dose-limiting gastrointestinal toxicity, it is possi—
`ble that significant gastrointestinal toxicity could be ob-
`served in larger studies given the occurrence of typhlitis
`at the next highest dose level.
`The observation that three of three patients treated with
`the highest dose level (paclitaxel 180 mg/m2 and doxorubicin
`75 mg/m2) developed clinical evidence of typhlitis is notable,
`because this complication has not been reported with the
`administration of either drug alone regardless of infusion
`length.17 Rather, upper gastrointestinal toxicity (mucositis and
`stomatitis) has been dose—limiting in a number of studies
`that have evaluated infusional paclitaxel or doxorubicin as
`monotherapy.7’18’20 Although the duration of grade 4 neutro-
`penia in the patients who developed typhlitis was only 4 to
`6 days, the hematologic nadirs occurred precipitously, with
`absolute granulocyte counts typically decreasing from greater
`than LOGO/ML to less than 100/,uL within a 24-hour period.
`Hruban et al21 described gastrointestinal epithelial necrosis
`on pathologic examination of colon biopsies obtained on two
`patients treated with 250 mg/m2 of 24-hour infusional pacli-
`taxel. We hypothesize that the clinical typhlitis that developed
`in our three patients was the result of precipitous and severe
`neutropenia in the setting of direct mucosal toxicity from
`infusional paclitaxel and doxorubicin. The pathogenesis of
`the one superior mesenteric vein thrombosis is unknown. We
`have not observed this toxicity in any of our other studies
`using 72- or 96-hour paclitaxel.
`Other studies of combined paclitaxel and doxorubicin
`have also described dose-limiting gastrointestinal toxic-
`ity.22’23 However, it appears that the likelihood of devel-
`oping gastrointestinal toxicity, as well as the site at which
`it occurs, are dependent on the sequence and schedule of
`paclitaxel and doxorubicin administration. Holmes and
`Valero22 described unexpected severe mucositis with 125
`mg/m2 of paclitaxel given over 24 hours followed by 60
`mg/m2 of doxorubicin over 48 hours. The MTD of this
`sequence in previously untreated metastatic breast cancer
`patients was paclitaxel 125 mg/m2 and doxorubicin 48
`mg/m2. Of interest, reversing the sequence of paclitaxel
`and doxorubicin administration (doxorubicin first over 48
`hours followed by paclitaxel over 24 hours) was associ-
`ated with less toxicity; the MTD of this sequence was
`paclitaxel 150 mg/m2 and doxorubicin 60 mg/m2. The
`DLT with this latter schedule was neutropenia with fever;
`dose-limiting mucositis did not occur when doxorubicin
`preceded paclitaxel.
`Preliminary results from ongoing pharmacokinetic
`studies at MD. Anderson suggest that the area under the
`curve (AUC) and maximum plasma concentration (Cum)
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28
`Copyright © 1996 American Society of Clinical Oncology. All rights reserved.
`
`

`

`780
`
`FISHERMAN ET AL
`