934
`
`A Phase II Trial of Gemcitabine for Metastatic
`Neuroendocrine Tumors
`
`Matthew H. Kulke, M.D.1
`Haesook Kim, Ph.D.2
`Jeffrey W. Clark, M.D.3
`Peter C. Enzinger, M.D.1
`Thomas J. Lynch, M.D.2
`Jeffrey A. Morgan, M.D.1
`Michele Vincitore, B.S.1
`Ann Michelini, R.N., M.S.N.1
`Charles S. Fuchs, M.D., M.P.H.1,4
`
`1 Department of Medical Oncology, Dana-Farber
`Cancer Institute, Boston, Massachusetts.
`
`2 Department of Biostatistics, Dana-Farber Cancer
`Institute, Boston, Massachusetts.
`
`3 Division of Hematology/Oncology, Massachusetts
`General Hospital, Boston, Massachusetts.
`
`4 Channing Laboratory, Brigham and Women’s
`Hospital, Boston, Massachusetts.
`
`Supported by the Eli Lilly Corporation (Indianapolis, IN).
`
`Address for reprints: Matthew H. Kulke, M.D., De-
`partment of Adult Oncology, Dana-Farber Cancer
`Institute, 44 Binney Street, Boston, MA 02115;
`Fax:
`(617) 632-5370; E-mail: matthew_kulke@
`dfci.harvard.edu
`
`revision received
`Received January 26, 2004;
`June 1, 2004; accepted June 1, 2004.
`
`BACKGROUND. Treatment with traditional cytotoxic chemotherapy regimens con-
`taining streptozocin or dacarbazine has resulted in only marginal benefit for
`patients with metastatic neuroendocrine tumors. The use of these regimens has
`been further limited by their potential toxicity. Gemcitabine is generally well
`tolerated and possesses demonstrated activity against a wide range of malignan-
`cies. The authors assessed the efficacy of gemcitabine in the treatment of patients
`with metastatic neuroendocrine tumors.
`METHODS. Eighteen patients with metastatic neuroendocrine tumors were treated
`with gemcitabine administered on a standard weekly schedule. Patients were
`followed for evidence of toxicity, response, and survival.
`RESULTS. Gemcitabine was well tolerated. However, no radiologic or biochemical
`responses were observed. Although the majority of patients (65%) experienced
`disease stabilization as their best response to therapy, the overall median survival
`duration was only 11.5 months.
`CONCLUSIONS. The minimal activity of gemcitabine highlighted the need for
`novel treatment approaches. Cancer 2004;101:934 –9.
`© 2004 American Cancer Society.
`
`KEYWORDS: neuroendocrine tumors, carcinoid, pancreatic islet cell, gemcitabine.
`
`Neuroendocrine tumors often pursue an indolent clinical course.
`
`As they progress, however, patients may become symptomatic as
`a result of either hormonal hypersecretion or tumor bulk. Somatosta-
`tin analogs and, to a lesser extent, interferon alpha have proven
`successful in treating symptoms of the carcinoid syndrome and other
`symptoms related to hormonal hypersecretion.1,2 These agents only
`rarely, however, result in tumor regression.3 Furthermore, over time,
`many tumors may become refractory to such therapy, requiring pa-
`tients to pursue other forms of treatment.
`The role of cytotoxic chemotherapy in the treatment of patients
`with metastatic neuroendocrine tumors remains controversial. Com-
`binations including streptozocin, 5-fluorouracil (5-FU), or doxorubi-
`cin have yielded only modest response rates, and have been associ-
`ated with significant toxicity in patients with carcinoid and pancreatic
`islet cell tumors.4 – 6 Similarly, whereas dacarbazine (DTIC) also pos-
`sesses some degree of activity in such tumors, toxicity concerns have
`precluded its widespread use.7,8 Patients with pheochromocytoma, a
`less common neuroendocrine tumor, have been treated with strep-
`tozocin and DTIC-based chemotherapy regimens, also with only lim-
`ited success.9,10 Recent attempts to develop novel treatment regimens
`with less associated toxicity have been relatively unsuccessful. Phase
`II studies of paclitaxel and docetaxel, for example, have shown little
`activity against neuroendocrine tumors.11,12
`
`© 2004 American Cancer Society
`DOI 10.1002/cncr.20466
`Published online 16 July 2004 in Wiley InterScience (www.interscience.wiley.com).
`
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`Gemcitabine is a nucleoside analog with struc-
`tural similarities to cytarabine. Currently, on the basis
`of data from a randomized Phase III study, it is widely
`used in the treatment of patients with advanced pan-
`creatic adenocarcinoma. That Phase III study reported
`improvements in survival and clinical benefits such as
`reduced pain intensity, decreased analgesic use, and
`improved performance status (PS).13 The mild toxicity
`profile of gemcitabine, in addition to its antitumor
`activity in other malignancies, led us to evaluate its
`worth as a potential therapeutic agent for patients
`with metastatic neuroendocrine tumors. To our
`knowledge, the current clinical trial is the first to eval-
`uate gemcitabine in this setting.
`In the current multicenter Phase II study, 18 pa-
`tients with metastatic neuroendocrine tumors were
`treated with systemic gemcitabine administered on a
`standard weekly schedule. Patients were followed for
`response, toxicity, and survival.
`
`MATERIALS AND METHODS
`Study Population
`The study population consisted of patients with his-
`tologically confirmed, locally unresectable or meta-
`static neuroendocrine tumors (excluding small cell
`carcinoma). Previous treatment with chemotherapy
`was allowed. Patients may also have received previous
`treatment with chemoembolization or cryotherapy,
`provided that the areas of disease used for tumor
`measurements were not affected by these treatments.
`Further inclusion criteria included Eastern Coopera-
`tive Oncology Group (ECOG) PS ⱕ 2, life expectancy
`ⱖ 12 weeks, absolute neutrophil count (ANC) ⬎ 1500/
`mm3, and platelet count ⬎ 100,000/mm3. Adequate
`renal (serum creatinine level ⬍ 2.0 mg/dL and hepatic
`functioning (bilirubin level ⬍ 2.0 mg/dL and aspartate
`aminotransferase level ⬍ 5 times the upper limit of
`normal) were also required. Patients with either clin-
`ically apparent central nervous system metastases or
`carcinomatous meningitis who had experienced a
`myocardial infarction in the past 6 months or who
`were pregnant or lactating were excluded from receiv-
`ing protocol treatment. Patients at the Dana-Farber
`Cancer Institute (Boston, MA), Massachusetts General
`Hospital (Boston, MA), and the Brigham and Women’s
`Hospital (Boston, MA) were eligible for enrollment.
`Informed consent was obtained from all patients as
`required by the institutional review boards of the par-
`ticipating institutions.
`
`Treatment Program
`Pretreatment evaluation included acquisition of a
`medical history, physical examination, hematologic
`and biochemical analysis, and confirmation of the
`
`Gemcitabine in Neuroendocrine Tumors/Kulke et al.
`
`935
`
`histologic diagnosis by a pathologist at one of the
`treating institutions. Baseline radiologic tumor mea-
`surements were obtained by chest X-ray and by ab-
`dominal computed tomographic (CT) scanning.
`Each treatment cycle consisted of gemcitabine
`administered weekly for 3 weeks followed by a
`1-week rest period. Gemcitabine was delivered as a
`30-minute intravenous infusion, with a starting dose
`of 1000 mg/m2. Dose adjustments were made on the
`basis of platelet counts, leukocyte counts, and ANC
`as measured before the administration of each dose
`of gemcitabine. Patients with an ANC of 500 –999/
`mm3 or a platelet count of 50,000 –99,999/mm3 re-
`ceived a 25% dose reduction. Treatment doses re-
`mained the same for patients who had an ANC
`⬍ 500/mm3 or a platelet count ⬍ 50,000/mm3.
`Doses that were withheld due to toxicity or that
`were missed were not administered at a later time.
`Patients who did not recover after a 3-week delay
`were withdrawn from the study. All adverse events
`were documented and graded according to the Na-
`tional Cancer Institute Common Toxicity Criteria,
`Version 2.0.
`Radiologic tumor assessments were performed af-
`ter every two cycles of treatment. Patients with evi-
`dence of response (i.e., a complete response [CR] or a
`partial response [PR]) to treatment or stable disease
`(SD) remained in the study until there was evidence of
`disease progression or unacceptable toxicity, or until
`the patient chose to have therapy discontinued. Ra-
`diologic response was classified according to the
`World Health Organization (WHO) criteria. A CR re-
`quired total resolution of all detectable disease for ⱖ 4
`weeks. A PR was defined as a decrease of ⬎ 50% in the
`sum of the products of the largest perpendicular di-
`ameters of all measurable lesions persisting for ⱖ 4
`weeks without progression at any unmeasurable site
`and without the appearance of new sites of disease.
`SD was defined as a decrease of ⬍ 50% or an increase
`of ⱕ 25% in the sum of the products of the largest
`perpendicular diameters of all measurable lesions.
`Progressive disease (PD) was defined as an increase of
`ⱖ 25% in the product of the largest perpendicular
`diameters of 1 or more measurable lesions, the devel-
`opment of new lesions, or progression at an unmea-
`surable but evaluable site of disease.
`
`Statistical Considerations
`The current Phase II study was originally designed
`with the primary endpoint of response rate for the 30
`patients with advanced carcinoid tumors. A Simon
`two-stage design was used to test the null hypothesis
`that the true objective response rate was ⬍ 20%.14 As
`predefined by the protocol, the study was terminated
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`CANCER September 1, 2004 / Volume 101 / Number 5
`
`TABLE 1
`Baseline Patient Characteristics
`
`Characteristic
`
`Median age (range)
`Median time from original diagnosis (yrs)
`Gender
`Male
`Female
`ECOG PS
`0
`1
`2
`Tumor type
`Carcinoid (total)
`Ileal primary
`Unknown primary
`Pancreatic endocrine
`Pheochromoctyoma
`Tumor grade
`Well differentiated
`Poorly differentiated (atypical)
`Previous treatment
`No
`Yes treatmenta
`Median time from previous treatment (mos)
`Liver function
`Total bilirubin (mg/dL)
`Alkaline phosphatase (U/L)
`Aspartate aminotransferase (U/L)
`
`No. of patients (%)
`
`59 yrs (range, 22–76 yrs)
`1.8 (range, 1 mo–8 yrs)
`
`9 (50)
`9 (50)
`
`8 (44)
`9 (50)
`1 (6)
`
`9 (50)
`6 (33)
`3 (17)
`7 (39)
`2 (11)
`
`16 (89)
`2 (11)
`
`9 (50)
`9 (50)
`3.5 (range, 1–7)
`
`0.7 (range, 0.2–1.2)
`158 (range, 61–578)
`34 (range, 19–162)
`
`ECOG PS: Eastern Cooperative Oncology Group performance status; U: units.
`a Previous agents: streptozocin (5 patients); doxorubicin (5 patients); docetaxel (3 patients); carboplatin
`(2 patients); etoposide (2 patients); cisplatin (1 patient); interferon (1 patient); irinotecan (1 patient);
`vincristine (1 patient); cyclophosphamide (1 patient).
`
`early, after the accrual of 18 patients, due to the ab-
`sence of a radiologic response in any of these patients.
`Progression-free survival (PFS) was calculated from
`the start of therapy to the time of disease progression
`or death due to any cause (whichever occurred first).
`Overall survival (OS) was calculated from the start of
`therapy to the date of death. For survival calculations,
`patients were censored at the date of last patient con-
`tact. The distributions of duration of PFS and survival
`were estimated using the Kaplan–Meier method.15
`
`RESULTS
`Patient Population
`Eighteen patients were enrolled between June 1999
`and September 2000. The baseline characteristics of
`the study cohort are summarized in Table 1. The me-
`dian age of the study population was 59 years, with
`equal numbers of men and women. Seventeen pa-
`tients had an ECOG PS of 0 or 1, and 1 patient had a PS
`of 2. Nine patients had carcinoid tumors (six ileal
`tumors and three tumors of unknown origin), six had
`pancreatic endocrine tumors, and two had pheochro-
`
`moctyomas. No patient had a family history or clinical
`presentation suggestive of multiple endocrine neopla-
`sic type 1 (MEN-1) or type 2 (MEN-2). Tumors were
`well differentiated in 16 patients, whereas 2 patients
`had poorly differentiated (atypical) neuroendocrine
`tumors. The median time from original diagnosis was
`1.8 years (range, 1 month– 8 years).
`Of the 18 patients in the study cohort, 9 had
`previously received chemotherapy, which most com-
`monly consisted of streptozocin and/or doxorubicin.
`Of these nine patients, only one had previously expe-
`rienced a response to chemotherapy; of the remaining
`patients, six had SD as their best response, and two
`had PD. The median time from completion of prior
`chemotherapy was 3.5 months. Nine patients in the
`current study had evidence of active tumor growth on
`the baseline CT scan performed before the initiation
`of study treatment. The rate of prior tumor progres-
`sion in the remaining nine patients could not be de-
`termined. Because the length of time since the pre-
`ceding reference CT scan may have been greater than
`the 2-month restaging interval used in the current
`study, it was not possible to formally assess disease
`progression before therapy according to the study cri-
`teria.
`
`Duration of Treatment
`Eighty-one 4-week treatment cycles of gemcitabine (3
`weekly infusions, followed by a 1-week break) were
`administered. A median of 3 treatment cycles were
`administered (range, 1–17 cycles), and the median
`time on study was 2.8 months. The majority of pa-
`tients (12 [75%]) had treatment discontinued due to
`disease progression, and 3 patients withdrew consent.
`Two patients had treatment discontinued for other
`reasons— one patient underwent elective surgery, and
`another developed progressive symptoms due to car-
`cinoid heart disease. One patient died during the
`study due to hepatic failure, which was likely to have
`been attributable to the progression of extensive he-
`patic metastases.
`
`Toxicity
`All 18 patients were assessable for toxicity. Gemcitab-
`ine was well tolerated in the current patient popula-
`tion. The most common toxicity was myelosuppres-
`sion: Grade 3 or 4 neutropenia occurred in 5 (28%)
`patients (Table 2). In addition, two patients developed
`febrile neutropenia. Other toxicities included Grade 3
`thrombocytopenia in one patient and Grade 3 dys-
`pnea in two patients.
`
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`TABLE 2
`Treatment-Related Toxicity
`
`Toxicity
`
`Anemia
`Thrombocytopenia
`Neutropenia
`Febrile neutropenia
`Fever w/o neutropenia
`Fatigue
`Anorexia
`Nausea
`Dyspnea
`
`1
`
`4 (22)
`4 (22)
`2 (11)
`—
`5 (28)
`7 (39)
`5 (28)
`9 (44)
`0
`
`TABLE 3
`Best Response to Therapy
`
`Maximum toxicity grade (%)
`
`2
`
`4 (22)
`3 (18)
`0
`—
`1 (6)
`1 (6)
`5 (28)
`2 (11)
`1 (6)
`
`3
`
`0
`1 (6)
`4 (22)
`2 (12)
`0
`0
`0
`0
`2 (11)
`
`4
`
`0
`0
`1 (6)
`0
`0
`0
`0
`0
`0
`
`Response
`
`No. of patients (%)
`
`Stable disease
`Progressive disease
`
`11 (65)
`7 (35)
`
`FIGURE 1. Progression-free survival among patients with metastatic neu-
`roendocrine tumors treated with gemcitabine.
`
`Efficacy
`Of the 18 patients treated with gemcitabine, none had
`radiologic evidence of either a PR or CR to therapy.
`Eleven patients (65%) had SD as their best response to
`therapy (Table 33;0). The median PFS duration was 8.3
`months (95% confidence interval [CI], 2.3– 6 months;
`Fig. 1), and the median OS duration was 11.5 months
`(95% CI, 8.0 –16.6 months; Fig. 2). Patients were also
`followed via serial 24-hour urine collection for the
`assessment of 5-hydroxyindolacetic acid (5-HIAA)
`and/or serum chromogranin A (CGA) levels. Six pa-
`tients had elevated 5-HIAA levels at baseline, and nine
`patients had elevated CGA levels. Of these patients,
`
`Gemcitabine in Neuroendocrine Tumors/Kulke et al.
`
`937
`
`FIGURE 2. Overall survival among patients with metastatic neuroendocrine
`tumors treated with gemcitabine.
`
`none experienced a decrease of ⬎ 50% relative to
`baseline as a result of therapy. One patient with gas-
`trinoma was followed with serial gastrin levels and
`also did not exhibit evidence of a response to therapy.
`
`DISCUSSION
`Although treatment with gemcitabine was well toler-
`ated in patients with metastatic neuroendocrine tu-
`mors, the current study demonstrated little evidence
`of efficacy. No radiologic or biochemical responses
`were observed among 18 patients, and the median
`survival duration was ⬍ 1 year. Although the time to
`tumor progression was 8.5 months and the SD rate
`was substantial (65%), the relevance of these observa-
`tions in patients with neuroendocrine tumors is un-
`certain, given the often indolent course of this disease.
`In fact, a nearly identical percentage (66%) of patients
`who had received systemic chemotherapy before en-
`rollment in the current study had experienced disease
`stabilization in response to their previous chemother-
`apy regimen.
`A number of chemotherapeutic regimens have
`been used in the treatment of patients with metastatic
`neuroendocrine tumors. Although several of these reg-
`imens appear to have some activity, their widespread
`use has been limited due to concerns regarding their
`relative toxicity. In an initial study performed by
`ECOG, patients with metastatic carcinoid tumors were
`randomized to receive streptozocin in combination
`with either 5-FU or cyclophosphamide.4 Tumor re-
`sponses, defined as either radiologic regression or de-
`creases in biochemical markers, occurred in 33% of
`patients treated with streptozocin/5-FU and in 26% of
`patients treated with streptozocin/cyclophosphamide.
`Unfortunately, the toxicity associated with streptozo-
`cin/5-FU was prohibitive, prompting a second trial in
`
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`CANCER September 1, 2004 / Volume 101 / Number 5
`
`which the dosing interval between cycles was length-
`ened. In this second randomized trial, the response
`rate associated with the streptozocin/5-FU combina-
`tion decreased to 22%, compared with 21% for pa-
`tients treated with doxorubicin alone.5 The median
`survival durations were 14 and 11 months, respec-
`tively, and this difference was not statistically signifi-
`cant.
`Pancreatic endocrine tumors are perceived as be-
`ing more responsive to cytotoxic chemotherapy than
`are carcinoid tumors. Few randomized trials involving
`patients with this disease have been performed. In one
`such trial, 105 patients with pancreatic islet cell tu-
`mors were randomized to receive either streptozocin/
`doxorubicin, streptozocin/5-FU, or chlorozotocin.6
`Compared with the streptozocin/5-FU combination,
`patients who received streptozocin/doxorubicin had a
`superior response rate (69% vs. 45%), improved time
`to tumor progression (20 months vs. 6.9 months), and
`a longer median OS (2.2 years vs. 1.4 years). A second,
`smaller study evaluating a combination of streptozo-
`cin, doxorubicin, and 5-FU in 11 patients also re-
`ported significant activity, with objective responses
`observed in 6 patients (54%).16 Retrospective analyses,
`however, have failed to confirm these encouraging
`results. In one such study, performed at Memorial-
`Sloan Kettering Cancer Center (New York, NY), only 1
`of 16 patients with pancreatic islet cells treated with
`streptozocin/doxorubicin experienced a confirmed ra-
`diologic response according to standard WHO crite-
`ria.17 A similar series of 16 patients treated at Dana-
`Farber Cancer Institute also reported only 1 confirmed
`response.18
`DTIC has been evaluated as a potential alternative
`to streptozocin-based therapy for both carcinoid and
`pancreatic endocrine tumors. In a Southwest Oncol-
`ogy Group study, 56 patients with metastatic carcinoid
`tumors were treated with DTIC, which was adminis-
`tered at a dose of 650 – 850 mg/m2 monthly.7 Nine
`patients (16%) had objective radiologic responses.
`Toxicity was moderate, with 88% of patients experi-
`encing nausea, emesis, or anorexia. The ECOG per-
`formed a Phase II study of DTIC administered at a
`dose of 850 mg/m2 monthly to 42 patients with ad-
`vanced pancreatic islet cell carcinoma.8 DTIC was
`clearly active in this setting. Objective responses were
`observed in 33% of patients. However, toxicity was
`again a concern, with two fatal complications re-
`ported. The addition of 5-FU and epirubicin to DTIC
`does not appear to further enhance antitumor activity
`beyond what is achieved with DTIC alone; this modi-
`fication was associated with an objective response rate
`of 25% in a heterogeneous group of patients with
`advanced neuroendocrine tumors.19
`
`Similar regimens have been used to treat patients
`with malignant pheochromocytoma, also without
`overwhelming success. A combination of DTIC, vin-
`cristine, and cyclophosphamide resulted in biochem-
`ical responses and was associated with anticipated
`hematologic, neurologic, and gastrointestinal side ef-
`fects.10 The role of streptozocin in the treatment of
`pheochromocytoma is controversial, with only anec-
`dotal responses reported.9
`Newer chemotherapeutic agents have, to date,
`proved relatively inactive in neuroendocrine tumors.
`High-dose paclitaxel, administered with granulocyte–
`colony-stimulating factor, was evaluated in 24 patients
`with metastatic carcinoid or islet cell tumors.12 Signif-
`icant hematologic toxicity was observed, and re-
`sponses were noted in only 8% of patients. Docetaxel
`was associated with biochemical responses but did
`not result in any radiologic responses in a recent
`Phase II trial involving 21 patients with carcinoid tu-
`mors.11 It is noteworthy that the median OS periods
`for patients treated with paclitaxel and patients
`treated with docetaxel in these trials were 20 months
`and 24 months, respectively.
`The median survival duration of 11.5 months for
`patients treated with gemcitabine in the current study
`compares unfavorably with these earlier studies. This
`finding may be partially attributable to the fact that
`many patients enrolled in the study already had rela-
`tively advanced disease—the median time from diag-
`nosis to study enrollment for patients in the current
`study was 1.8 years. Even taking this finding into ac-
`count, however, the short median survival duration
`observed in the current study lends support to the
`hypothesis that gemcitabine is relatively inactive
`against neuroendocrine tumors.
`Chemotherapeutic options for patients with met-
`astatic neuroendocrine tumors remain limited. Al-
`though regimens containing streptozocin or DTIC
`have been associated with modest activity, the poten-
`tial side effects of these regimens, as well as the fre-
`quently indolent natural history of these tumors, have
`prevented their widespread use in this setting. To
`date, none of the newer and potentially less toxic
`chemotherapeutic agents have proven to be effective
`against neuroendocrine tumors. The current study
`adds gemcitabine to this list of inactive agents and
`highlights the need for novel approaches in the treat-
`ment of such tumors.
`
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`NOVARTIS EXHIBIT 2014
`Par v. Novartis, IPR 2016-01479
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