D o s e - E s c a l a t i n g S t u d y o f C a p e c i t a b i n e P l u s G e m c i t a b i n e
`C o m b i n a t i o n T h e r a p y i n P a t i e n t s W i t h A d v a n c e d C a n c e r
`
`By Richard L. Schilsky, Donna Bertucci, Nicholas J. Vogelzang, Hedy L. Kindler, and Mark J. Ratain
`
`Purpose: The goals of this phase I study were to
`determine the maximum-tolerated doses of capecitab-
`ine and gemcitabine in patients with advanced cancer
`and to describe the dose-limiting toxicities (DLT) and
`safety profile of this combination.
`Patients and Methods: Eligible patients had ad-
`vanced solid tumors that had failed to respond to stan-
`dard therapy or for which no standard therapy was
`available, measurable or assessable disease, Karnof-
`sky performance status > 70%, and acceptable organ
`function. Capecitabine was administered twice daily by
`mouth each day for 21 consecutive days followed by a
`1-week break. Gemcitabine was administered as a
`30-minute intravenous infusion weekly for 3 weeks
`followed by a 1-week break.
`Results: Forty patients were enrolled onto the study,
`and 33 are fully assessable for toxicity. The most com-
`mon toxicities during the first cycle of chemotherapy
`
`were neutropenia and mucositis. Only one patient
`treated at gemcitabine and capecitabine doses of 800
`and 2000 mg/m2, respectively, met protocol-specified
`DLT criteria; however, at these doses 65% of successive
`cycles required dose reduction or delay for toxicity. No
`episodes of DLT were observed at gemcitabine and
`capecitabine doses of 1,000 and 1,660 mg/m2, respec-
`tively, and 70% of cycles of therapy were delivered
`without dose reduction or delay. Therefore, these doses
`are recommended for further study. Tumor responses
`were observed in patients with metastatic colorectal
`and pancreatic cancer.
`Conclusion: Gemcitabine and capecitabine can be
`combined with acceptable toxicity at nearly full doses.
`Antitumor activity of the combination merits further
`investigation in phase II studies.
`J Clin Oncol 20:582-587. © 2002 by American
`Society of Clinical Oncology.
`
`CAPECITABINE IS AN orally administered, tumor-
`
`selective fluoropyrimidine that is converted to flu-
`orouracil (5-FU) in tissues by pyrimidine nucleoside phos-
`phorylase (PyNPase).1 Its tumor selectivity seems to be
`derived from selective overexpression of PyNPase, a pro-
`angiogenic molecule, in many tumors compared with nor-
`mal tissues.2-5 Capecitabine has demonstrated activity in
`treatment of patients with breast and colorectal cancer.6,7
`Gemcitabine is a pyrimidine nucleoside antimetabolite
`that, once converted to difluorodeoxycytidine triphosphate,
`inhibits DNA synthesis by inhibition of DNA polymerase
`and direct incorporation into DNA leading to premature
`termination of DNA chain elongation.8 The diphosphate
`intermediate of gemcitabine also inhibits ribonucleotide
`reductase and thereby depletes intracellular pools of de-
`oxyuridine monophosphate, resulting in enhanced binding
`
`From the Department of Medicine, Section of Hematology-Oncol-
`ogy, Cancer Research Center and Committee on Clinical Pharmacol-
`ogy, University of Chicago, Chicago, IL.
`Submitted April 5, 2001; accepted May 21, 2001.
`Supported in part by grant no. CA 14599 and by a grant from
`Hoffman-LaRoche, Inc, Nutley, NJ.
`Presented at the Thirty-Seventh Annual Meeting of the American
`Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.
`Address reprint requests to Richard L. Schilsky, MD, Biological
`Sciences Division, MC 1000, University of Chicago, 5841 S Maryland
`Ave, Chicago, IL 60637; email: rschilsk@medicine.bsd.uchicago.edu.
`© 2002 by American Society of Clinical Oncology.
`0732-183X/02/2002-582/$20.00
`
`of 5-fluorodeoxyuridine monophosphate, the active metab-
`olite of 5-FU, to thymidylate synthase.9,10 This biochemical
`interaction may explain the supra-additive effects of com-
`bining gemcitabine and capecitabine in MAXF401 and
`MX-1 human breast cancer xenograft models. In MX-1
`human breast cancer, treatment with gemcitabine also re-
`sulted in a dose-dependent 1.5- to 2.7-fold increase in
`expression of PyNPase and, presumably, an increase in
`intracellular release of 5-FU from capecitabine (H. Ishit-
`suka, personal communication, January, 2001). In vitro
`studies in colon cancer cells have also demonstrated syn-
`ergy when exposure to 5-FU precedes exposure to
`gemcitabine.11
`These preclinical studies provided the basis for a number
`of phase I clinical trials that examined combinations of
`5-FU and gemcitabine administered on several doses and
`schedules. At the University of Chicago, we conducted a
`phase I trial of continuous intravenous infusion of 5-FU
`with weekly 30-minute intravenous infusions of gemcitab-
`ine.12 The recommended phase II doses determined in this
`study were 5-FU 200 mg/m2/d for 21 days with gemcitabine
`450 mg/m2 weekly for 3 consecutive weeks or 5-FU 200
`mg/m2/d for 14 days with gemcitabine 1,800 mg/m2 weekly
`for 2 consecutive weeks. Dose-limiting toxicities (DLT)
`were mucositis, bone marrow suppression, and diarrhea.
`Tumor responses were observed in several tumor types,
`most notably renal cell carcinoma (RCC).
`A subsequent phase II trial of this combination was
`conducted in patients with metastatic RCC most of whom
`
`582
`
`Journal of Clinical Oncology, Vol 20, No 2 (January 15), 2002: pp 582-587
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`PHASE I TRIAL OF CAPECITABINE AND GEMCITABINE
`
`had already been treated with immunotherapy or chemo-
`therapy.13 5-FU was administered by continuous infusion at
`a dose of 150 mg/m2/d for 21 days with gemcitabine at 600
`mg/m2 weekly for 3 weeks. Cycles were repeated every 28
`days. Toxicities were primarily bone marrow suppression,
`mucositis, nausea, and fatigue. Partial responses were noted
`in 7 of 39 assessable patients (17%; 95% confidence
`interval, 8% to 34%). Median progression-free survival for
`patients in this study was 28.7 weeks, which was signifi-
`cantly better than that observed in similar patients with RCC
`treated on other phase II studies at our institution. Because
`daily oral capecitabine can mimic continuous infusion of
`5-FU and because upregulation of PyNPase by gemcitabine
`can enhance the intracellular activation of capecitabine, we
`undertook a phase I trial of these drugs in combination with
`the primary objectives to determine the maximum-tolerated
`doses (MTD) of capecitabine and gemcitabine in patients
`with advanced cancer and to describe the DLT and safety
`profile of this combination.
`
`PATIENTS AND METHODS
`
`Patient Selection
`
`Patients with histologically confirmed advanced solid tumors that
`had failed to respond to standard therapy or for which no standard
`therapy was available were eligible to participate in this study. Other
`eligibility criteria included measurable or assessable disease by com-
`puted tomography, magnetic resonance imaging, radiograph, or phys-
`ical examination; age at least 18 years; Karnofsky performance status
`of at least 70% (ambulatory and capable of self-care); life expectancy
`of at least 3 months; and adequate organ function defined as absolute
`least 1,500/␮L, platelet count of at
`neutrophil count of at
`least
`100,000/␮L, hemoglobin at least 9.0 g/dL, serum creatinine level ⬍ 1.6
`mg/dL, total bilirubin ⬍ 2.0 mg/dL, serum albumin ⬎ 2.5 g/dL,
`prothrombin time ⬍ 1.5 times control level, AST and ALT levels ⬍ 2.5
`times the upper limit of normal or ⬍ five times the upper limit of
`normal if liver metastases were present, and serum alkaline phospha-
`tase ⬍ 2.5 times the upper limit of normal or ⬍ five times the upper
`limit of normal if liver metastases were present or ⬍ 10 times the upper
`limit of normal if bone metastases were present. Patients must have
`been off previous anticancer therapy, including radiation therapy, for at
`least 4 weeks (6 weeks if the previous therapy included a nitrosourea or
`mitomycin) and must have recovered from the toxic effects of any
`previous therapy. Patients were excluded from the study if they had any
`unstable, pre-existing medical condition, prior unanticipated severe
`reaction to fluoropyrimidine therapy, organ allograft, evidence of CNS
`metastases, or history of significant gastric or small bowel resection,
`malabsorption syndrome, or other lack of integrity of the upper
`gastrointestinal tract that might compromise absorption of capecitab-
`ine. Pregnant and lactating women were also excluded from participa-
`tion, and all patients with reproductive potential were required to use an
`effective contraceptive method if they were sexually active. All patients
`gave written informed consent according to federal and institutional
`guidelines.
`
`583
`
`Study Design
`
`This was an open-label, single-center, nonrandomized, dose-escalat-
`ing phase I study. All laboratory tests required to assess eligibility had
`to be completed within 7 days before start of treatment. Capecitabine
`was administered twice daily by mouth each day for 21 consecutive
`days followed by a 1-week break. Gemcitabine was administered as a
`30-minute intravenous infusion weekly for 3 weeks followed by a
`1-week break. Initially, all patients received capecitabine at a dose of
`1,660 mg/m2/d. Cohorts of at
`least
`three patients each received
`escalating doses of gemcitabine until the MTD was determined or up to
`a maximum dose of 1,000 mg/m2. Once the MTD of gemcitabine given
`with capecitabine at 1,660 mg/m2/d was established, all subsequent
`patients enrolled onto the study received a gemcitabine dose at one
`dose level below the MTD, and cohorts of at least three new patients
`each received escalating doses of capecitabine until the MTD was
`established or up to a maximum dose of 2,500 mg/m2/d. Before entry
`of patients at a new dose level, all patients at the previous dose level
`must have been observed for at least 3 weeks. No intrapatient dosage
`escalation was permitted.
`
`Dose-Escalation and Definition of Study End Points
`
`The starting dose of gemcitabine was 400 mg/m2 given in combi-
`nation with capecitabine at 1,660 mg/m2/d. The starting doses were
`based on available clinical information about the tolerable doses of
`each drug used individually and about the MTD of gemcitabine used in
`combination with 5-FU. Gemcitabine doses were increased in incre-
`ments of 200 mg/m2/wk in cohorts of at least three new patients each
`until MTD was established or a maximum gemcitabine dose of 1,000
`mg/m2/wk was achieved. At that point, all new patients were treated
`with gemcitabine at one dose level below the MTD and escalating
`doses of capecitabine. Capecitabine dose levels studied were 1,660
`mg/m2/d, 2,000 mg/m2/d, and 2,500 mg/m2/d.
`Capecitabine was supplied by Roche Pharmaceuticals (Nutley, NJ)
`as Xeloda tablets in two dosage strengths, 150-mg and 500-mg tablets.
`The total daily dose was taken as two divided doses approximately 12
`hours apart within 30 minutes after the ingestion of food. The two doses
`were divided so as to allow the administration of whole tablets.
`Gemcitabine was commercially available as Gemzar (Eli Lilly,
`Indianapolis, IN) in 20-mg/mL vials, 10- and 50-mL sizes. The drug
`was prepared for administration according to directions in the package
`labeling.
`For purposes of determining the MTD, only DLTs occurring during
`the first cycle of therapy were considered. DLTs were defined as any of
`the following: grade 4 neutropenia lasting at least 3 days or grade 3 or
`4 neutropenia associated with fever ⱖ 38.1°C; grade 4 thrombocyto-
`penia lasting at least 3 days; grade 3 or 4 nonhematologic toxicity
`except alopecia, gastrointestinal toxicity, and palmar-plantar erythro-
`dysesthesia (hand-foot syndrome); grade 3 or 4 nausea, vomiting, or
`mucositis not reduced to grade 1 with maximal supportive therapy;
`grade 3 and 4 diarrhea or a second occurrence of grade 2 diarrhea;
`grade 2 or 3 hand-foot syndrome not reduced to grade 1 before the start
`of cycle 2; inability to administer two successive doses of gemcitabine
`within the first treatment cycle; or delay of ⱖ 14 days in initiating the
`second cycle of therapy because of persistent toxicity of grade 2 or
`higher. If one or more patients at a dose level experienced DLT, then
`three additional patients were treated at that dose level. The MTD was
`defined as the dose level at which no more than one of six patients
`experienced a DLT. Once this dose level was established, six additional
`patients were enrolled (maximum of 12) to gain additional experience
`with the combination. Patients who experienced DLT could be contin-
`
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`584
`
`SCHILSKY ET AL
`
`Appearance of Toxicity
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Table 1. Capecitabine Dose-Modification Schedule
`
`Schedule Modification According to Toxicity Grade
`
`First
`
`Second
`
`Third
`
`Fourth
`
`Interrupt treatment until resolved to grade 0-1,
`then continue at same dose
`
`Interrupt treatment until resolved
`to grade 0-1, then continue at
`75% of original dose
`
`Interrupt treatment until resolved to grade 0-1,
`then continue at 75% of original dose
`
`Interrupt treatment until resolved to grade 0-1,
`then continue at 50% of original dose
`Discontinue treatment permanently (off study)
`
`Interrupt treatment until resolved
`to grade 0-1, then continue at
`50% of original dose
`Discontinue treatment
`permanently (off study)
`
`Discontinue treatment unless
`investigator considers it to be in the
`best interests of the patient to
`continue at 50% of original dose,
`once toxicity has resolved to grade
`0-1 (after approval by the sponsor)
`
`ued on treatment at a modified dose at the discretion of the treating
`physician if they seemed to be benefiting from the therapy.
`
`Pretreatment and Follow-Up Studies
`
`Before initiation of therapy, all patients had a history and physical
`examination, assessment of Karnofsky performance status, chest radio-
`graph, 12-lead electrocardiogram, determination of tumor measure-
`ments, dipstick urinalysis, and routine laboratory studies that included
`a complete blood count with differential WBC count, electrolytes, urea,
`creatinine, glucose, total protein, albumin, calcium, phosphate, uric
`acid, alkaline phosphatase, total and direct bilirubin, and ALT and AST
`levels. History, physical examination, and laboratory tests were re-
`peated on day 1 of each cycle of therapy. Assessment of toxicity and
`hematology tests were performed weekly during each cycle of therapy.
`Tumor assessments were performed after every two cycles of therapy,
`and response was assessed using World Health Organization criteria. A
`complete response was defined as disappearance of all clinically
`detectable disease determined by two observations at least 4 weeks
`apart. Partial response was defined as ⱖ 50% decrease in total tumor
`size of all measured lesions lasting at least 4 weeks, no new lesions, and
`no progression of any lesion. Progressive disease was defined as a 25%
`or more increase of one or more measurable lesions or the appearance
`of new lesions. Time to progression was defined as the time from first
`day of treatment until documentation of disease progression.
`
`Dose Modifications
`
`The capecitabine dose was interrupted or modified based on ob-
`served toxicity according to the guidelines listed in Table 1. Patients
`were permitted to begin a new treatment cycle when the absolute
`neutrophil count exceeded 1,000/␮L and the platelet count was ⱖ
`100,000/␮L and other treatment-related toxicities had resolved to grade
`0 to 1. Gemcitabine dosing was interrupted whenever capecitabine was
`held because of toxicity. Doses of gemcitabine were not otherwise
`modified during the study.
`
`RESULTS
`
`The characteristics of the 40 patients enrolled onto this
`study are listed in Table 2. The median age was 65 years
`(range, 41 to 83 years) and the median Karnofsky perfor-
`
`mance status was 80% (range, 70% to 100%). All but two
`patients had previously received chemotherapy.
`Seven patients did not complete the first cycle of therapy
`and are, therefore, not assessable for toxicity. Three patients
`were noncompliant with the treatment protocol; one patient
`had rapid tumor progression and was withdrawn from the
`study, one patient developed sepsis from a pre-existing
`indwelling central venous catheter shortly after beginning
`treatment, one patient developed arm pain within 2 days of
`
`Table 2. Patient Characteristics
`
`Characteristic
`
`Patients enrolled
`Men
`Women
`Age, years
`Median
`Range
`Karnofsky performance status
`100
`90
`80
`70
`Prior therapy
`Chemotherapy only
`Chemotherapy and radiation
`None
`Diagnosis
`Colorectal
`Pancreatic
`Ovarian
`Prostate
`Breast
`Mesothelioma
`Melanoma
`Sarcoma
`Other
`
`65
`41-83
`
`No. of Patients
`
`40
`18
`22
`
`6
`11
`21
`2
`
`26
`12
`2
`
`21
`3
`3
`2
`2
`1
`1
`1
`6
`
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`PHASE I TRIAL OF CAPECITABINE AND GEMCITABINE
`
`585
`
`Table 3. Dose Levels
`
`Table 5. Nonhematologic Toxicity During Cycle 1
`
`No. of
`Patients
`
`Capecitabine
`(mg/m2/d)
`
`Gemcitabine
`(mg/m2)
`
`5
`3
`7
`12
`6
`
`1,660
`1,660
`1,660
`1,660
`2,000
`
`400
`600
`800
`1,000
`800
`
`No. of
`Cycles
`
`17
`10
`25
`44
`23
`
`Dose Level of
`Gem/Cape
`(mg/m2)
`
`400/1,660
`600/1,660
`800/1,660
`1,000/1,660
`800/2,000
`
`No. of
`Patients
`
`5
`3
`7
`12
`6
`
`No. of Patients With Grade of Toxicity
`
`Mucositis
`
`Diarrhea
`
`Fatigue
`
`HFS
`
`3
`
`4
`
`2
`
`3
`
`4
`
`DLT
`
`2
`
`3
`
`4
`
`3
`
`4
`
`2
`
`1
`1
`
`2
`
`2
`2
`
`1
`
`2 1
`
`1
`
`1
`
`initiating chemotherapy and withdrew from the study to
`undergo a cardiac evaluation, and one patient was deter-
`mined to be ineligible because of a prior bone marrow
`transplant. The dose levels evaluated in the 33 fully assess-
`able patients are listed in Table 3.
`The most common toxicities observed during the first
`cycle of chemotherapy are listed in Tables 4 and 5. The
`severity of neutropenia and mucositis increased with in-
`creasing doses of chemotherapy, although only one patient,
`treated at gemcitabine/capecitabine doses of 800/2,000 mg/
`m2, respectively, met protocol-specified criteria for DLT
`(grade 3 mucositis). Although no episodes of DLT were
`observed at gemcitabine/capecitabine doses of 1,000/1,660
`mg/m2, respectively, further escalation of the gemcitabine
`dose above the standard dose of 1,000 mg/m2 was prohib-
`ited by the protocol. Furthermore, our ability to administer
`successive cycles of chemotherapy without dose modifica-
`tion necessitated by toxicity became increasingly difficult at
`higher dosage levels. Table 6 lists the number of cycles of
`chemotherapy at each dosage level requiring protocol-
`specified dose reduction or delay because of severe or
`unresolved toxicity. At the gemcitabine/capecitabine dose
`level of 800/2,000 mg/m2, respectively, 15 (65%) of 23
`cycles of therapy (cycle 2 or higher) required dose reduction
`or delay for toxicity. In 10 of the 15 dose-modified cycles,
`dose reduction or delay was required because of grade 2 to
`3 neutropenia or thrombocytopenia that had occurred during
`the prior cycle of therapy. Despite the 3-week duration of
`dosing, few patients experienced clinically significant hand-
`foot syndrome (grade 2 or higher), and no patients experi-
`
`Table 4. Hematologic Toxicity During Cycle 1
`
`Dose Level of
`Gem/Cape
`(mg/m2)
`
`400/1,660
`600/1,660
`800/1,660
`1,000/1,660
`800/2,000
`
`Total No. of
`Patients
`
`5
`3
`7
`12
`6
`
`No. of Patients With Grade of Toxicity
`
`ANC
`
`Platelets
`
`Anemia
`
`2
`
`1
`1
`4
`3
`1
`
`3
`
`4
`
`2
`3
`3
`
`3
`
`4
`
`1
`
`2
`
`1
`
`2
`
`2
`
`1
`
`2
`4
`1
`
`3
`
`4
`
`DLT
`
`1
`
`Abbreviations: Gem, gemcitabine; Cape, capecitabine; ANC, absolute
`neutrophil count.
`
`Abbreviation: HFS, hand-foot syndrome.
`
`enced febrile neutropenia or required platelet transfusion.
`Based on the absence of DLT in cycle 1 and the ability to
`deliver 70% of successive cycles without dose modification
`or delay, we recommend doses of gemcitabine and capecit-
`abine of 1,000 mg/m2 and 1,660 mg/m2, respectively, for
`further evaluation in phase II studies.
`Although assessment of tumor response was not a pri-
`mary objective of this study, patients were evaluated for
`tumor response after every two cycles of treatment. Partial
`or significant minor responses occurred in four patients
`whose characteristics are listed in Table 7. The time to
`progression for these patients ranged from 24 to 32 weeks.
`The responses in the colon cancer patients are of particular
`note in that all had previously received fluoropyrimidine-
`based therapy. The median time to progression for all 33
`assessable patients was 12 weeks ranging from 4 to 32
`weeks and 16 patients had a time to progression of 16 weeks
`or longer.
`
`DISCUSSION
`A number of phase I and II trials have now been
`completed that evaluated various ways of combining 5-FU
`and gemcitabine.12-19 In most studies, DLTs of the combi-
`nation have included mucositis, fatigue, thrombocytopenia,
`and neutropenia. 5-FU has often been administered as a
`continuous intravenous infusion for 14 to 21 days, requiring
`that patients have central venous catheters and infusion
`pumps. Activity of the combination has been reported in
`patients with pancreatic cancer and RCC.13,16,19 At
`the
`University of Chicago, we have conducted phase I and II
`trials of infusional 5-FU and gemcitabine. In patients with
`RCC, partial responses were observed in seven of 39
`assessable patients (17%, 95% confidence interval, 8% to
`34%). Toxicities were primarily neutropenia, mucositis, and
`fatigue, and infectious complications included an episode of
`Staphylococcus aureus endocarditis and a central
`line
`infection.13
`Therefore, we sought to develop a combination of gem-
`citabine with capecitabine that would mimic the continuous
`
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`Table 6. Cycles Requiring Dose Reduction or Delay
`
`Dose Level of
`Gem/Cape
`(mg/m2)
`
`400/1,660
`600/1,660
`800/1,660
`1,000/1,660
`800/2,000
`
`Total No. of Cycles
`
`17
`10
`25
`44
`23
`
`Cycles With Dose
`Reduction or Delay
`
`No.
`
`0
`0
`8
`12
`15
`
`%
`
`–
`–
`32*
`31†
`65‡
`
`*In five of eight cycles, dose reduced for grade 3 ANC or platelets in prior
`cycle.
`†In nine of 12 cycles, dose reduced for grade 3 ANC in prior cycle.
`‡In 10 of 15 cycles, dose reduced for grade 2 to 3 ANC or platelets in prior
`cycle.
`
`intravenous infusion of 5-FU used in our prior studies without
`the complications related to indwelling venous catheters. In-
`deed, the 21-day regimen described here allows administration
`of gemcitabine at standard doses (1,000 mg/m2/wk) with
`capecitabine at doses that provide similar dose-intensity to the
`standard dose and schedule for this agent and the same total
`dose per cycle, ie, 1,660 mg/m2/d for 21 days is equivalent to
`2,500 mg/m2/d for 14 days. This regimen is generally well
`tolerated, with the major toxicity being neutropenia and anemia
`at the recommended phase II dose. Remarkably, little clinically
`significant hand-foot syndrome was observed despite the
`21-day schedule of capecitabine administration. Repetitive
`cycles could be administered without dose reduction or delay
`in 70% of cycles, and dose delays, when necessary, rarely
`required interruption of therapy for longer than 1 week. Indeed,
`15 of the 33 fully assessable patients received four or more
`cycles of therapy, with two patients receiving eight cycles. At
`the recommended gemcitabine and capecitabine doses of 1,000
`mg/m2 and 1,660 mg/m2, respectively, seven of 12 patients
`received four or more cycles of treatment, with four of these
`seven patients receiving all cycles of chemotherapy without
`dose reduction or delay.
`
`SCHILSKY ET AL
`
`We were encouraged to observe significant antitumor
`activity in this heavily pretreated patient population. Four
`patients had minor or partial responses with progression-
`free survival of 24 to 32 weeks. Disease stabilization was
`also observed in 12 patients who, therefore, received mul-
`tiple cycles of treatment. Phase II studies are now being
`planned for patients with pancreatic cancer and RCC to
`further define the antitumor activity and tolerability of this
`regimen.
`Pharmacologic studies were not performed as part of
`this clinical
`trial, but
`it
`is unlikely that such studies
`would have contributed much information at this point in
`the development of this regimen. Gemcitabine is metab-
`olized by deoxycytidine kinase to inactive compounds
`that are then eliminated primarily by renal excretion.
`Capecitabine undergoes a complex metabolic activation,
`but the final cytotoxic derivative, 5-FU, is then rapidly
`degraded by dihydropyrimidine dehydrogenase to biolog-
`ically inactive compounds.1 Given the substrate specific-
`ity of these metabolic pathways, it is unlikely that a
`pharmacokinetic interaction would occur between gem-
`citabine and capecitabine. Overexpression of PyNPase in
`tumor cells may be an important, although not the sole
`determinant of
`tumor
`response to fluoropyrimidines,
`particularly capecitabine. Cellular levels of thymidylate
`synthase
`and dihydropyrimidine dehydrogenase
`are
`likely to be important determinants of outcome as well.20
`Because tumor response was not a primary end point of
`our study, we did not evaluate tumor blocks for expres-
`sion of these enzymes. Such studies are likely to be more
`informative if performed in the context of phase II and III
`clinical trials where a more homogeneous population of
`patients is treated with uniform doses of chemotherapy
`with the goal of assessing antitumor activity and deter-
`mining the characteristics of those tumors most likely to
`respond to therapy with this regimen.
`
`Table 7. Characteristics of Responding Patients
`
`Dose Level of
`Gem/Cape
`(mg/m2)
`
`800/1,660
`1,000/1,660
`1,000/1,660
`800/2,000
`
`Response
`
`PR*
`MR†
`PR
`PR
`
`Time to
`Progression
`(weeks)
`
`32
`24
`32
`32
`
`Diagnosis
`
`Pancreatic
`Colon
`Colon
`Colon
`
`Karnofsky Performance
`Status
`
`100
`90
`90
`80
`
`Prior Therapy
`
`5-FU plus radiation
`5-FU/LV, Fudr, CPT-11, CVI 5-FU, RF ablation
`5-FU/LV, CPT-11
`5-FU/LV, radiation, flavopiridol, CPT-11
`
`Abbreviations: PR, partial response; MR, minor response; Fudr, fluorodeoxyuridine; RF, radiofrequency; CPT-11, irinotecan; LV, leucovorin; CVI, continuous
`venous infusion.
`*71% reduction but confirmatory scan 4 weeks later not performed.
`†46% reduction from baseline.
`
`NOVARTIS EXHIBIT 2220
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`

`
`PHASE I TRIAL OF CAPECITABINE AND GEMCITABINE
`
`587
`
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