American Journal of Therapeutics 3, 750—754 (1996)
`
`PHASE II TRIAL OF PACLITAXEL IN PATIENTS
`
`WITH ADVANCED COLON CANCER PREVIOUSLY
`
`UNTREATED WITH CYTOTOXIC CHEMOTHERAPY:
`
`AN EASTERN COOPERATIVE ONCOLOGY
`
`GROUP TRIAL (PA286)
`
`AVi I. Einzig,” Donna Neuberg,2 Peter H. Wiernik,3 Louise B. Grochow,4 Guillermo Ramirez,5
`Peter]. O’Dwyer,6 Nicholas J. Petrelli7
`
`Paclitaxel was administered as a 24-h continuous infusion at 250 mg/m2 in this Phase II trial in
`patients with adenocarcinoma of the colon or rectum. Nineteen patients were evaluated for toxicity
`and 15 were assessable for response. There were no complete or partial responses, and toxicity
`present was primarily neutropenia. This study found that paclitaxel as a single agent does not have
`activity in adenocarcinoma of the colon or rectum.
`
`Key words: paclitaxel (Taxol), colon cancer
`
`Clinical investigators are facing an apparent therapeu-
`tic impasse in advanced colorectal cancer. Moertel
`described the evaluation of 40 inactive drugs studied
`in the past 20 years [1]. The sole agent with reproduc-
`ible activity was 5—fluorouraci1 (5-FU), which yields
`response rates of 15% to 20% in large studies using
`traditional bolus schedules. Studies in the early 19705
`with 5-FU/ Methyl CCNU or 5-FU/Methy1 CCNU/
`Vincristine showed response rates of 30—40% [2—4].
`These results were not uniformly confirmed, however,
`and the bulk of subsequent studies reported response
`
`7Albert Einstein College of Medicine, Department of Medicine,
`Bronx, NY.
`
`2 Dana Farber Cancer Institute, Division of Biostatics, Boston,
`MA.
`
`3 Montefiore Medical Center, Department of Oncology, Bronx, NY.
`4 john Hopkins University, Baltimore, MD.
`5 University of Wisconsin Hospital, Madison, WI.
`6 Fox Chase Cancer Center, Philadelphia, PA.
`7 Roswell Park Cancer Center, Buffalo, NY.
`* Address for correspondence: Department of Medicine, Albert
`Einstein College of Medicine, 1825 Eastchester Road, Bronx, NY
`10461, USA.
`
`1075—2765 © 1996 Chapman 8 Hall
`
`rates similar to those of S-FU alone [5—7]. Another
`
`approach to improving the selective toxicity of S—FU
`for tumor cells involves the biochemical modulation of
`
`its intracellular action [8]. Results from Phase III trials
`
`comparing S-FU with 5-FU and leucovorin for the
`treatment of advanced, previously untreated colorectal
`carcinoma have demonstrated partial response rates
`resulting from the combination ranging from 16% to
`45%, while those obtained with S-FU alone were 5% to
`
`18% [9—16]. A metaanalysis of all 5—FU/leucovorin
`studies suggested that this improvement in response
`rate was not associated with improved survival [17].
`While the use of other modulatory agents in combina-
`tion with 5-FU has provided encouraging results in
`Phase II studies [18 19], results from Phase III studies
`in advanced colorectal cancer have not shown clear
`
`superiority for one modulatory agent over another
`with respect to survival. The treatment of metastatic
`colorectal carcinoma presents a difficult challenge to
`the oncologist, and the most likely strategy for improv-
`ing results is the identification of new agents which are
`active in this disease.
`
`Paclitaxel, isolated from the stem bark of the western
`
`yew Taxus brevifolia, shows activity in many solid
`
`Genentech 2071
`
`Hospira v. Genentech
`|PR2017-00737
`
`Genentech 2071
`Hospira v. Genentech
`IPR2017-00737
`
`

`

`PACLITAXEL /N TREATMENT OF COLON CANCER
`
`751
`
`tumors include ovarian, breast, melanoma, lung, head
`and neck, and others [20]. This Phase II study was
`conducted by the Eastern Cooperative Oncology Group
`(ECOG) to evaluate the antitumor activity of paclitaxel
`when administered as a 24-h continuous infusion to
`
`patients with advanced large-bowel cancer. The dose
`and schedule of administration was based on Phase I
`
`clinical data [21].
`
`PATIENTS AND METHODS
`
`Eligibility criteria
`
`To be eligible, patients were required to have measur—
`able, histologically-confirmed metastatic, residual, or
`recurrent adenocarinoma of the colon or rectum not
`
`potentially curable by surgery, with an ECOG perfor-
`mance status of (O or 1). Patients were required to have
`adequate bone-marrow function (white bloood count
`24,000 cells/mm3 and a hemoglobin count of at least
`10 gm/ 100 ml), normal liver function (bilirubin 51.5
`mg%) and normal renal function (serum creatinine
`51.5 mg%). Patients must not have received prior
`chemotherapy.
`Patients were informed of the Phase II investiga—
`tional nature of the treatment and the toxicities that
`
`might be anticipated from such treatment. All patients
`provided written informed consent. The study was
`approved by the institutional review boards of each of
`the participating centers.
`
`Drug formulation and preparation
`
`Paclitaxel was supplied by the National Cancer Insti-
`tute (Bethesda, MD) as a concentrated sterile solution 6
`mg / ml in a 5—ml ampule (30 mg ampule) in polyoxeth-
`ylated castor oil from Cremaphor EL (50%) and dehy-
`drated alcohol USP (50%). The drug was diluted in
`1000 ml of 0.9% sodium chloride injection USP or 5%
`dextrose injection before administration. In-line filtra-
`tion with a 0.2 mm filter was used.
`Paclitaxel was administered as a continuous intrave-
`
`nous (IV) infusion during a 24-h period for a total dose
`of 250 mg/mz. The dose was reduced in subsequent
`courses to 200 mg / m2 for patients experiencing grades
`3—4 neutropenia or thrombocytopenia. Hematopoietic
`colony-stimulating factors were not recommended in
`this study. Because of the known toxicity of paclitaxel
`and / or the Cremaphor vehicle, precautions before
`treatment for the possibility of an acute hypersensitiv—
`ity reaction were taken. All patients were premedi-
`cated with dexamethasone, diphenhydramine and
`cimetidine as previously reported [22]. Patients who
`developed severe anaphylaxis despite these precau-
`
`tions were removed from study. For other toxicity
`grades 3—4,
`treatment was withheld until patients
`receovered at least grade 1 status.
`
`Study parameters
`
`Before therapy, all patients had a complete history,
`physical examination, blood cell and platelet count,
`serum biochemical and electrolyte profile, urine analy-
`sis, ECG, and chest x-ray. Computed tomographic (CT)
`scans and x-rays used to document indicator lesions
`for measurable disease were taken up to 2 weeks
`before the initiation of treatment. Anti-tumor response
`was assessed every 12 weeks if a CT scan was required
`to document measurable disease or after every cycle if
`physical examination provided adequate assessment
`of measurable disease. Toxicity was evaluated accord-
`ing to the ECOG grading system [23]. Complete
`response (CR) was defined as the total disappearance
`of all detectable malignant disease for at least 4 weeks.
`Partial response (PR) was defined as a 50% or greater
`decrease in the product of the longest perpendicular
`diameters of all measurable lesions for at least 4 weeks
`
`without an increase in size of any area of known
`malignant disease or the appearance of new lesions.
`Stable disease (SD) was defined as a decrease of less
`than 50% or an increase of less than 25% over original
`measurements of all known malignant disease with no
`appearance of new areas of malignant involvement
`over 8 weeks or more. Progression was defined as the
`occurrence of new lesions or an increase of 25% or
`
`greater in the sum of the areas of original measure-
`ments.
`
`Statistical analysis
`
`This pilot Phase II study of the efficacy of paclitaxel in
`patients with advanced large—bowel cancer was de-
`signed to detect a regimen with a response rate of at
`least 20%. Therefore, if responses were observed among
`the first 14 patients, at least 25 additional patients
`would need to be entered in order to obtain an
`
`estimate of the response rate with :10% standard
`deviation.
`
`Clinical protocol management
`
`Patients were hospitalized for each treatment course.
`Weekly blood cell and platelet counts were monitored
`after discharge from the hospital. Cardiac monitoring
`was not required. Courses of paclitaxel were adminis-
`tered every 3 weeks if there was no evidence of tumor
`progression or abnormal blood cell counts. Patients
`received at least two cycles to evaluate response, and
`measurable disease was evaluated by CT scans or
`physical exam prior to each cycle.
`
`American journal of Therapeutics (1996) 3( 11)
`
`

`

`752
`
`RESULTS
`
`Twenty patients were entered, in this Phase II study;
`demographic characteristics are listed in Table 1. Two
`patients were considered ineligible for the protocol
`due to a minor protocol violation (initial hemoglobins
`of 9.7 and 9.6 with the protocol requiring a hemoglobin
`of 10), but their data are analyzed and included in the
`toxicity and response evaluations. Four patients were
`not assessable for response, three patients developed a
`hypersensitivity reaction during the first course of
`treatment, and one patient discontinued therapy after
`an initial course due to peripheral neuropathy. No
`patient had received prior adjuvant therapy.
`
`Toxicity
`
`Table 2 summarizes the toxicity data from this study.
`The principle hematologic toxicity was, as expected,
`neutropenia. Fourteen of the 16 patients who were
`assessable for hematologic toxicity had grade 4 neutro-
`penia during the initial course of treatment. Five
`patients received only 1 course of treatment; 11 pa-
`tients received subsequent courses of treatment at 200
`mg / m2. Nine of the 16 patients who developed grade 4
`
`Table 1. Patient characteristics.
`
`n
`Male/Female
`Patients assessable for toxicity
`Patients assessable for response
`ECOG performance status
`0
`1
`
`Age, y
`Median
`
`Range
`Courses
`Median
`
`Range
`Site of Primary Disease
`Right Colon
`Sigmoid
`Cecum
`Left Colon
`Rectum
`
`Multiple
`Unknown
`Sites of Metastatic Disease
`Liver
`
`Multiple Sites
`(Liver, lung, bone, ovaries,
`abdominal lymph nodes)
`Local recurrence
`
`American journal of Therapeutics (1996) 3(11)
`
`20
`11/9
`19
`15
`
`9
`10
`
`60
`
`39—74
`
`2
`
`1—8
`
`4
`3
`2
`3
`4
`
`2
`1
`
`14
`
`8
`
`8
`1
`
`AI EINZIG et al.
`
`Table 2. Toxic effects (n = 19)*.
`
`Grade (ECOG toxicity scale)’
`
`Toxicity
`
`Neutropenia
`Thrombocytopenia
`Anemia
`Fever/Infection
`Nausea
`Vomiting
`Diarrhea
`Stomatitis
`
`Allergy
`Alopecia
`Neuro-Sensory
`Neuro-Motor
`
`0
`
`1
`13
`4
`5
`11
`13
`13
`12
`
`15
`3
`7
`12
`
`1
`
`0
`1
`4
`2
`3
`2
`2
`2
`
`1
`2
`5
`2
`
`2
`
`1
`2
`7
`8
`2
`1
`1
`1
`
`1
`11
`3
`2
`
`3
`
`0
`0
`1
`1
`0
`0
`0
`1
`
`0
`—
`1
`0
`
`4
`
`14
`0
`0
`0
`0
`0
`0
`0
`
`2
`—
`0
`0
`
`initial dose due to a
`*Three patients did not receive the full
`hypersensitivity reaction. n = 19. tECOG Toxicity Scale.
`
`neutropenia required hospitalization for fever; fortu-
`nately, there were no neutropenia-associated deaths.
`Thrombocytopenia and anemia presented as minor
`toxicities.
`
`Total alopecia was observed in the majority of
`patients. There were rare episodes of nausea, vomiting,
`diarrhea and stomatitis which were not clinically
`significant.
`Peripheral neuropathy was mild (five patients with
`grade 1 and three patients with grade 2). One patient
`developed grade 3 peripheral neuropathy after an
`initial course of treatment and refused further treat—
`ment.
`
`Three patients developed hypersensitivity reactions
`during the initial course of treatment despite premedi-
`cation, resulting in discontinuation of treatment. These
`patients were not rechallenged.
`Although clinically insignificant cardiac arrhyth-
`mias have been reported with paclitaxel [24], continu-
`ous cardiac monitoring was not performed in this
`study. There were no new EKG changes noted on serial
`studies performed before each course of treatment.
`
`Responses
`
`There were no complete or partial responses in 15
`assessable patients (Table 3). One patient had stable
`disease (lung metastases and mesenteric lymph nodes)
`through five courses of treatment and then decided to
`discontinue treatment. One patient had stable liver
`metastases after two courses and then discontinued
`
`treatment. The two patients who were considered
`ineligible due to pre-existing anemia each received two
`courses of treatment and progressed.
`
`

`

`PACLITAXEL IN TREATMENT OF COLON CANCER
`
`753
`
`Table 3. Response to treatment.
`
`Condition
`
`Stable
`
`Progression
`Not assessable
`
`n
`
`1
`
`1
`
`13
`4
`
`Comment
`
`Lung, mesenteric lymph nodes
`stable for 4 months.
`Liver stable for 2 months.
`
`—
`3 patients with hypersensitivity
`reaction during initial course,
`1 patient with peripheral neu-
`ropathy after initial course.
`
`DISCUSSION
`
`Identifying new active agents for patients with ad-
`vanced adenocarcinoma of the large bowel remains a
`great challenge. This trial was carried out in an optimal
`population of chemotherapy-naive patients with mea-
`surable disease. The dose of 250 mg / m2 resulted in
`grade 4 neutropenia in 88% of patients, confirming that
`treatment was delivered at the MTD. The optimal dose
`and schedule of paclitaxel administration is still being
`investigated in other solid tumors, but without a
`response in this trial in which patients received at least
`200 mg/ m2 as a 24-h continuous infusion, further trials
`of paclitaxel in adenocarcinoma of the large bowel are
`not warranted.
`
`ACKNOWLEDGEMENT
`
`This study was conducted by the Eastern Cooperative
`Oncology Group and supported in part by Public
`Health Service grants CA14958, CA23318, CA16116,
`CA21076, CA18281, CA12296, and CA21115 from the
`National Cancer Institute and the Department of Health
`and Human Services. The contents of this article are
`
`solely the responsibility of the authors and do not
`necessarily represent the official views of the National
`Cancer Institute.
`
`REFERENCES
`
`1. Moertel CG: Chemotherapy of gastrointestinal cancer.
`N Engl] Med 1978;299:1049—1052.
`2. Posey LE, Morgan LR: Methyl CCNU versus Methyl
`CCNU and 5-Fluorouracil in Carcinoma of the Large
`Bowel. Cancer Treat Rep 1977;61:1453—1458.
`3. Baker LH, Talley RW, Matter R, et (11.: Phase III compari-
`son of the treatment of advanced gastrointestinal cancer
`with bolus weekly S-FU versus methyl CCNU plus bolus
`weekly S-FU: A Southwest Oncology Group Study. Can—
`cer 1976;38:1-7.
`
`Falkson E, Falkson HC: Fluorouracil, Methyl CCNU and
`Vincristine in cancer of the colon. Cancer 1976;38:1468—
`1470.
`
`Engstrom P, Macintyre I, Douglass H Ir, et al.: Combina-
`tion chemotherapy of advanced bowel cancer. Proc
`AACR/ASC01978;19:384.
`
`. Lokich I], Skarin AT, Mayer R], et £11.: Lack of effectiveness
`of combined 5-fluorouracil and Methyl-CCNU therapy
`in advanced colorectal cancer. Cancer 1977;40:2792—2796.
`
`Kemeny N, Yagoda A, Golbey R: Randomized study of
`two different schedules of Methyl-CCNU, 5-Fluorouracil
`and Vincristine for metastatic colorectal adenocarci-
`noma. Proc ACCR/ASCO 1977;18:279.
`
`Leyland-Jones BR, O'Dwyer P]: Biochemical modula-
`tion: Application of laboratory models to the clinic.
`Cancer Treat Rep 1986;70:219—229.
`. Erlichman C, Fine S, Wong A, et al.: A randomized trial of
`5-Fluorouracil and folinic acid in patients with metastatic
`colorectal carcinoma. J Clin Oncol 1988;6469—6475.
`Buroker TR, O’Connell M], Wieand HS, et al.: Random-
`ized comparison of two schedules of fluorouracil and
`leucovorin in the treatment of advanced colorectal can—
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`cer. J Clin Oncol 1994;12:14—28.
`Arbuck SG: Overview of clinical trials using S-FU and
`leucovorin for the treatment of colorectal cancer. Cancer
`1988;63:1036—1044.
`Petrelli N, Herrera L, Rustum Y, et (11.: A prospective
`randomized trial of S—Fluorouracil versus S-Fluorouracil
`
`and methotrexate in previously untreated patients with
`advanced colorectal cancer. J Clin Oncol 1987521599—
`1565.
`
`Petrelli N, Douglass HO Jr, Herrera L, et al.: The modula-
`tion of fluorouracil with leucovorin in metastatic colorec-
`
`tal carcinoma: A prospective randomized phase III trial,
`Gastrointestinal Tumor Study Group. J Clin Oncol 1989;
`7(10):1419—1426.
`Nobile MT, Rosso R, Sertoli MR, et al.: Randomized
`
`comparison of weekly bolus S-Fluorouracil with or
`without leucovorin in metastatic colorectal carcinoma.
`
`Eur] Cancer 1992;28A(11):1823—1827.
`Valone FH, Friedman MA, Wittlinger PS, et 111.: Treatment
`of patients with advanced colorectal carcinomas with
`fluorouracil alone, high-dose leucovorin plus fluoroura-
`cil or sequential methotrexate, fluorouracil, and leucovo-
`rin: a randomized trial of the Northern California Oncol-
`
`ogy Group. J Clin Oncol 1989;7(10):1427—1436.
`Doroshow IH, Multhauf P, Leong L, et (11.: Prospective
`randomized comparison of fluorourcil versus fluoroura-
`cil and high-dose continuous infusion leucovorin cal-
`cium for the treatment of advanced measurable colorec-
`
`in patients previously unexposed to
`tal cancer
`chemotherapy. I Clin Oncol 1990;8(3):491-501.
`Piedbois P, Buyse M: What can we learn from a metaanal-
`ysis of trials testing the modulation of S-FU by leucovo-
`rin? Advanced Colorectal Meta-analysis Project. Ann
`Oncol 1993;4(2):51519.
`Wadler S, Wiemik PH: Clinical update on the role of
`
`American journal of Therapeutics (1996) 3(11)
`
`

`

`754
`
`Al EINZIG et al.
`
`fluorouracil and recombinant interferon Alta-20a in the
`
`treatment of colorectal carcinoma. Semin Oncol 1990;(1):
`16—21.
`
`19. Wadler S, Lembersky B, Atkins M, et al.: Phase II Trial of
`Fluorouracil and Recombinant Interferon Alfa-2a in Pa-
`tients with Advanced Colorectal Carcinoma: An Eastern
`
`Cooperative Oncology Group Study. J Clin Oncol 1991;92
`1806—1810.
`
`20. McGuire WP, Rowinsky EK (eds.): Paclitaxel in Cancer
`Treatment, Marcel Dekker, New York, 1995, pp. 1—337.
`21. Wiemik PH, Schwartz EL, Straumann I], et al.: Phase I
`
`22.
`
`23.
`
`24.
`
`Clinical and Pharmacokinetic study of Taxol. Cancer Res
`1987;47:2486—2493.
`
`Weiss R, Donehower RC, Wiernik PH, et a1.: Hypersensi-
`tivity reactions from Taxol. J Clin Oncol 1990;821263—
`1268.
`
`Oken MM, Creech RH, Tormey DC, et (11.: Toxicity and
`response criteria of the Eastern Cooperative Oncology
`Group. Am] Clin Oncol 1982;53:649—655.
`Rowinsky EK, McGuire WP, Guamier T, et (11.: Cardiac
`disturbances during the administration of Taxol. J Clin
`Oncol 1991;921709—1712.
`
`American journal of Therapeutics (1996) 3(11)
`
`