Review
`
`Monthly Focus: Oncologic
`
`Recent developments in the
`pharmacological treatment of
`advanced pancreatic cancer
`Matthew H Kulke
`Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston,
`MA 02115, USA
`
`Metastatic pancreatic cancer is one of the leading causes of cancer-related
`death in North America and Europe. The high mortality rate associated with
`pancreatic cancer is related to the fact that the vast majority of patients
`develop incurable, metastatic disease. Such patients have, in the past, had
`few treatment options. In recent years, however, the systemic administration
`of gemcitabine has been accepted as a standard first-line treatment for
`patients with advanced pancreatic cancer. While treatment with gemcitabine
`has been shown to result in both clinical benefit and in prolongation of sur-
`vival, objective tumour responses following therapy with gemcitabine are rel-
`atively uncommon and median survival times remain short. Current efforts
`have, therefore, focused on evaluating chemotherapy regimens in which
`gemcitabine is combined with a second cytotoxic agent. Several such combi-
`nations appear to be associated with higher objective response rates than
`single-agent gemcitabine and have been well-tolerated in early clinical trials.
`Ongoing, prospectively randomised clinical trials will help better define the
`efficacy of these new combinations and will determine if they result in a sig-
`nificant benefit when compared to gemcitabine monotherapy. A number of
`novel chemotherapeutic and biological agents also appear promising and are
`likely to play a future role in the treatment of patients with advanced
`pancreatic cancer.
`
`Keywords: chemotherapy, gemcitabine, pancreatic cancer, systemic therapy
`
`Expert Opin. Investig. Drugs (2003) 12(6):983-992
`
`1. Introduction
`
`An estimated 28,000 new cases of pancreatic cancer occur in the US each year.
`Although pancreatic cancer is only the ninth most common cancer in the US, it is
`the fourth leading cause of cancer-related death. The high mortality rate associated
`with pancreatic cancer is attributable to the fact that the majority of patients with
`pancreatic cancer present with advanced stage disease. Less than 20% of patients
`with pancreatic cancer are diagnosed at a time when the tumour is still confined to
`the pancreas and can be surgically removed. Uncertainty about the efficacy of sys-
`temic therapy and a high incidence of patient comorbidities have further led to the
`perception of pancreatic cancer as a largely untreatable disease.
`The systemic administration of 5-fluorouracil (5-FU) has historically been one of
`the only treatments available to patients with metastatic pancreatic cancer. Unfortu-
`nately, the response rates associated with 5-FU are low and attempts to combine
`5-FU with other chemotherapeutic agents have shown little additional benefit. In
`the mid-1990s, gemcitabine became available for the treatment of pancreatic cancer.
`Based on evidence of improvements in median survival and clinical benefit,
`
`2003 © Ashley Publications Ltd ISSN 1354-3784
`
`983
`
`1. Introduction
`
`2. 5-Fluorouracil
`
`3. 5-Fluorouracil-based
`chemotherapy combinations
`
`4. Gemcitabine
`
`5. Gemcitabine-based
`chemotherapy combinations
`
`6. Novel agents in advanced
`pancreatic cancer
`
`7. Expert opinion and conclusion
`
`For reprint orders, please
`contact:
`reprints@ashley-pub.com
`
`Ashley Publications
`www.ashley-pub.com
`
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`Recent developments in the pharmacological treatment of advanced pancreatic cancer
`
`gemcitabine has now become the standard first-line therapy
`for patients with metastatic pancreatic cancer.
`While single-agent gemcitabine is now a broadly accepted
`treatment regimen for pancreatic cancer, it is still associated
`with an objective tumour response rate of < 10%. Further-
`more, the median survival time for patients with metastatic
`pancreatic cancer is < 6 months [1]. In an effort to improve
`upon these statistics, several investigators are exploring the
`use of gemcitabine-based combination chemotherapy regi-
`mens. Ongoing clinical trials should help determine which of
`these combinations may be the most promising and which
`may offer patients improved overall survival and quality of
`life when compared to gemcitabine monotherapy. Several
`promising novel agents are also being investigated and may
`play a role in the future treatment of patients with advanced
`pancreatic cancer.
`
`2. 5-Fluorouracil
`
`5-FU has historically been a mainstay of treatment for
`patients with metastatic pancreatic cancer. Enthusiasm for the
`use of 5-FU in metastatic pancreatic cancer has been tem-
`pered by the fact that the response rates associated with its use
`are low. Response rates in the 20% range have been reported
`in older trials; however, the response rates associated with
`5-FU given in combination with leucovorin in two more
`recent Phase II studies were < 10% [2,3].
`Newer, oral 5-FU analogues have also demonstrated only
`modest activity in pancreatic cancer. Capecitabine, an oral
`precursor of 5-FU, is converted to 5-FU by an enzyme (thy-
`midine phosphorylase) that is preferentially expressed in
`malignant cells [4]. A recent study involving 42 patients with
`advanced pancreatic cancer showed that treatment with
`capecitabine was associated with an overall response rate of
`9.5% [5]. In another study, investigators from the Southwest
`Oncology Group treated 116 patients with eniluracil, an
`irreversible inactivator of dihydropyrimidine dehydroge-
`nase, given in combination with oral 5-FU [6]. Responses
`were observed in only 8% of chemotherapy-naive patients
`and in 2% of pretreated patients. The median survival time
`for patients in this trial was only 3.6 months, leading the
`investigators to conclude that other treatment strategies are
`likely to hold more promise in the treatment of advanced
`pancreatic cancer.
`
`3. 5-Fluorouracil-based chemotherapy
`combinations
`
`Combination regimens based on 5-FU have failed to demon-
`strate significant survival benefits when compared to 5-FU
`monotherapy. A five-drug combination of 5-FU, cytoxan,
`methotrexate, vincristine and mitomycin C (the Mallinson regi-
`men) was not associated with a significant survival advantage
`when compared in a randomised fashion to single-agent 5-FU
`[7]. Combinations of 5-FU, doxorubicin and mitomycin C
`
`(FAM) and 5-FU, doxorubicin and cisplatin (FAP) have also
`failed to demonstrate superiority to monotherapy with 5-FU in
`randomised trials [7,8]. In a recent, multi-centre European trial,
`> 200 patients with advanced pancreatic cancer were ran-
`domised to receive 5-FU with or without cisplatin. The 5-FU/
`cisplatin combination was associated with a response rate of
`12%, as compared to a 0% response rate for single-agent 5-FU
`[9]. Despite the difference in response rates, no significant differ-
`ences in survival were noted between the two arms. The use of
`protracted infusion 5-FU with or without mitomycin C has also
`been evaluated in a randomised trial of > 200 patients. The
`response rate associated with infusional 5-FU and mitomycin C
`was 20%, as compared to 8.3% for infusional 5-FU alone.
`Again, no significant differences in median survival were noted
`between the two arms (6.5 versus 5.1 months, p = 0.42) [10].
`
`4. Gemcitabine
`
`Recent years have witnessed the development of several new
`drugs for the treatment of pancreatic cancer, the most success-
`ful of which has been gemcitabine. Gemcitabine is a nucleo-
`side analogue with structural similarities to cytarabine. Two
`initial Phase II studies demonstrated that gemcitabine was
`associated with modest activity in pancreatic cancer [11,12]. In
`a follow-up Phase II study, 74 patients with metastatic pancre-
`atic cancer who were refractory to therapy with 5-FU were
`treated with gemcitabine [13]. Patients were followed not only
`for evidence of radiological response but also for evidence of
`clinical benefit, defined as reduction in pain intensity,
`decrease in analgesic use or improvement in performance sta-
`tus. In this trial, 27% of patients achieved a clinical benefit
`response, suggesting that a systematic assessment of subjective
`outcomes could be used to evaluate the impact of gemcitabine
`in patients with pancreatic cancer.
`in which
`These studies
`led to a randomised trial,
`126 patients with metastatic pancreatic cancer were ran-
`domised to receive either gemcitabine or 5-FU [1]. The primary
`end point in this trial was clinical benefit, as defined in the ear-
`lier Phase II study. Patients randomised to receive gemcitabine
`were treated using a regimen of gemcitabine 1000 mg/m2 given
`over 30 min weekly for 7 weeks, followed by a 1-week rest
`period. Subsequently patients received gemcitabine weekly for
`3 out of every 4 weeks. Patients randomised to the 5-FU arm
`received 5-FU 600 mg/m2 weekly. This trial demonstrated that
`23.8% of those patients receiving gemcitabine derived clinical
`benefit, as compared to only 4.8% of those who received 5-FU.
`The trial further demonstrated that treatment with gemcitabine
`was associated with improvements in both 1 year (18 versus
`2%) and median survival times (5.65 versus 4.41 months).
`Based on the results of this trial, gemcitabine was approved as a
`standard first-line therapy for patients with metastatic pancre-
`atic cancer in the US.
`Subsequent studies with gemcitabine have focused on opti-
`mising its efficacy through modifications of both dose and infu-
`sion schedule. Gemcitabine is metabolised by deoxycytidine
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`kinase to several active metabolites that inhibit both DNA rep-
`lication and repair. The rate of formation of these active metab-
`olites is known to be dependent on dose rate. A recent
`randomised Phase II trial compared high-dose gemcitabine
`(2200 mg/m2 given over the standard 30-min infusion) to
`fixed-dose rate infusion gemcitabine (1500 mg/m2 given at a
`rate of 10 mg/m2/min over 150 min) [14]. Patients in the fixed-
`dose rate infusion arm of this trial had superior objective
`response rates and superior 1- and 2-year survival rates com-
`pared to patients receiving high-dose gemcitabine, suggesting
`an advantage for the fixed-dose rate schedule.
`
`5. Gemcitabine-based chemotherapy
`combinations
`
`5.1 Gemcitabine/fluoropyrimidine combinations
`The relatively mild toxicity profile of gemcitabine has allowed
`for the development of gemcitabine-based combination
`chemotherapy regimens, many of which have now been stud-
`ied in patients with advanced pancreatic cancer. The activity
`of 5-FU in pancreatic cancer, albeit modest, led to early inter-
`est in gemcitabine/5-FU combinations. In one large, prospec-
`tively randomised trial performed by the Eastern Cooperative
`Oncology Group (ECOG), 327 patients with advanced pan-
`creatic cancer received gemcitabine with or without weekly
`bolus 5-FU [15]. Patients in the single-agent arm of this trial
`received gemcitabine 1000 mg/m2 weekly, administered for
`3 out of every 4 weeks, whereas patients in the experimental
`arm received the same dose and schedule of gemcitabine
`together with 5-FU 600 mg/m2. Patients receiving the gem-
`citabine/5-FU combination had a slightly longer median sur-
`vival time than those receiving single-agent gemcitabine
`(6.7 versus 5.4 months); however, this difference was not sta-
`tistically significant.
`In an attempt to enhance the efficacy of the gemcitabine/
`5-FU combination, other investigators have combined weekly
`gemcitabine therapy with 5-FU administered as a prolonged
`intravenous infusion. In an initially encouraging Phase I/II
`study, 26 patients with metastatic pancreatic cancer received
`weekly gemcitabine in combination with infusional 5-FU
`administered at a dose of 200 mg/m2/day [16]. The objective
`response rate in this trial was 19, and 42% of patients exhib-
`ited stabilisation of their disease. However, in a subsequent
`randomised Phase II study of 92 patients, weekly gemcitabine
`was compared to a regimen of weekly gemcitabine in combi-
`nation with infusional 5-FU administered at a dose of
`200 mg/m2 for 6 of 8 weeks, followed by 3 of 4 weeks. The
`combination regimen was associated with an overall response
`rate of only 11%, as compared to 8% for gemcitabine mono-
`therapy; and there was no difference in median survival time
`between the two arms [17]. These results again suggest that
`there is little, if any, advantage to adding 5-FU to gemcitabine
`in patients with advanced pancreatic cancer.
`Combinations of capecitabine and gemcitabine also appear
`similar in efficacy to gemcitabine monotherapy, although data
`
`Kulke
`
`remain preliminary. In a Phase I/II trial, gemcitabine was
`given at a fixed dose of 1000 mg/m2 on days 1 and 8 of a
`21-day cycle and capecitabine was given in increasing doses
`for 14 days followed by a 1-week rest [18]. Objective radiologi-
`cal responses were noted in 5/27 (18.5%) patients treated
`with this regimen. Gemcitabine/capecitabine combination
`therapy has subsequently been compared to gemcitabine
`monotherapy in a randomised Phase II trial. A total of
`83 patients with metastatic pancreatic cancer received either
`monotherapy with gemcitabine or a regimen of biweekly
`gemcitabine (2200 mg/m2) in combination with capecitabine
`(2500 mg/m2 given on days 1 – 7) [19]. The objective response
`rates observed with the two regimens were similar, with
`responses noted in 17% of the patients receiving combination
`therapy and 14% of patients receiving monotherapy. Phase III
`trials comparing gemcitabine monotherapy with gemcitabine/
`capecitabine combinations should better define the potential
`differences between these regimens.
`
`5.2 Gemcitabine and cisplatin
`Preclinical studies have suggested that gemcitabine may be
`synergistic with cisplatin as an inhibitor of DNA repair. This
`observation has led to several Phase II studies evaluating gem-
`citabine together with cisplatin in patients with metastatic
`pancreatic cancer (Table 1). In a German study, 41 patients
`with metastatic pancreatic cancer were treated with gemcitab-
`ine 1000 mg/m2 (days 1, 8 and 15) in combination with cis-
`platin 50 mg/m2 (days 1 and 15) [20]. In 35 evaluable patients,
`one complete response and three partial responses were
`observed, for an overall response rate of 11%. In a similar,
`42-patient US study, 26% had complete or partial responses
`[21]. The most common toxicities in both studies were neutro-
`penia and thrombocytopenia.
`Using a slightly different dosing regimen, an Austrian
`group treated 16 patients with a combination of gemcitab-
`ine 1000 mg/m2 and cisplatin 35 mg/m2 given weekly for
`3 out of every 4 weeks [19]. Objective responses were noted
`in 5/16 (31%) patients; however this regimen was associated
`with significant myelosuppression. To decrease the toxicities
`associated with this regimen, an Italian group modified the
`schedule and administered cisplatin 35 mg/m2 in combina-
`tion with gemcitabine 1000 mg/m2 on days 1 and 8 of a
`21-day schedule [22]. While this modified schedule was bet-
`ter tolerated, the results were disappointing, with objective
`responses noted in only 5/45 (9%) patients.
`The most encouraging results with gemcitabine/cisplatin
`combinations have come from another Italian study, in which
`107 patients with metastatic pancreatic cancer were ran-
`domised to receive either standard-dose gemcitabine or a
`combination of gemcitabine 1000 mg/m2 and cisplatin
`25 mg/m2 administered 3 out of every 4 weeks [23]. The com-
`bination regimen was associated with an overall response rate
`of 26%, as compared to 0% among patients receiving single-
`agent gemcitabine. The median time to disease progression
`was also significantly
`longer in the patients receiving
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`Recent developments in the pharmacological treatment of advanced pancreatic cancer
`
`Table 1. Phase II studies of gemcitabine ‘doublet’
`combination chemotherapy in advanced pancreatic cancer.
`
`No.
`patients
`
`Response
`rate (%)
`
`Median
`survival
`
`Ref.
`
`Gemcitabine/cisplatin
`45
`9
`42
`26
`41
`11.5
`16
`31
`
`Gemcitabine/irinotecan
`60
`25
`45
`24
`
`Gemcitabine/docetaxel
`34
`8
`29
`29
`54
`13
`15
`27
`43
`19
`33
`9.4
`14
`7.1
`24
`17
`
`5.6 months
`7.1 months
`8.2 months
`9.6 months
`
`Cascinu et al. [22]
`Philip et al. [21]
`Heinemann et al. [20]
`Brodowicz et al. [19]
`
`7 months
`5.7 months
`
`Stathopoulos et al. [26]
`Rocha-Lima et al. [27]
`
`8.9 months
`10.5 months
`26 weeks
`NA
`9 months
`4.7 months
`6.1 months
`6 months
`
`Ryan et al. [58]
`Jacobs et al. [32]
`Stathopoulos et al. [59]
`Sherman et al. [60]
`Ridwelski et al. [61]
`ECOG [62]
`Petrovic et al. [63]
`Gonzalez et al. [54]
`
`Louvet et al. [34]
`
`Gemcitabine/oxaliplatin
`30 (Stage II/
`31
`11.5 months
`III patients)
`34 (Stage
`IV patients)
`ECOG: Eastern Cooperative Oncology Group; NA: Not available.
`
`30.3
`
`8.7 months
`
`Louvet et al. [34]
`
`on day 8. Objective responses were noted in 25% of patients
`and the median survival time was 7 months [26]. One drawback
`to this regimen was a high incidence of neutropenia and the
`consequent requirement for growth factor support. In a second
`Phase II study, 45 patients with advanced pancreatic cancer
`were treated with a combination of gemcitabine 1000 mg/m2
`and irinotecan 100 mg/m2 [27]. A total of 11 (24%) patients
`experienced partial radiological responses and 22 (50%) experi-
`enced declines in CA19-9 levels of > 50%. This regimen
`appeared to be well-tolerated: only 2% of patients experienced
`grade 4 neutropenia, 2% experienced grade 4 vomiting and 7%
`experienced grade 4 diarrhoea. Based on the promising results
`of this trial, this combination of irinotecan and gemcitabine is
`being compared to single-agent gemcitabine in a multi-centre
`Phase III randomised trial.
`
`5.4 Gemcitabine and docetaxel
`Docetaxel is a semisynthetic taxane that has been shown to
`have single-agent activity both in pancreatic cancer and in
`other malignancies. Phase II studies of single-agent docetaxel in
`patients with advanced pancreatic cancer have demonstrated
`overall response rates in the range of 0 – 20% [28-31]. Numerous
`Phase II studies of docetaxel in combination with gemcitabine
`have now been completed in patients with metastatic pancre-
`atic cancer (Table 1). In one of the largest of these studies,
`54 patients were treated with gemcitabine 1000 mg/m2 (days 1
`and 8) and docetaxel 100 mg/m2 (day 8) on a 21-day schedule.
`Despite the use of prophylactic growth factor support, 11% of
`patients treated on this study developed febrile neutropenia,
`preventing the further development of this regimen. In a sec-
`ond study, patients were treated with gemcitabine 800 mg/m2
`(days 1, 8 and 15) and docetaxel 7 5mg/m2 (day 1) on a 28-day
`schedule [32]. This dose schedule was also associated with exces-
`sive haematological toxicity and was subsequently changed to
`gemcitabine 1000 mg/m2 and docetaxel 40 mg/m2 adminis-
`tered on days 1 and 8 of a 21-day schedule, which was signifi-
`cantly better tolerated. Overall, 10/34 (29%) of patients had
`objective partial responses, supporting the further investigation
`of this gemcitabine/docetaxel regimen.
`
`5.5 Gemcitabine and oxaliplatin
`Oxaliplatin, a platinum analogue with structural similarities to
`cisplatin, differs from cisplatin in that it is not associated with
`significant renal toxicity. Oxaliplatin has also demonstrated
`promising activity in patients with metastatic colorectal cancer
`and was recently approved in the US for this indication. Evi-
`dence of possible synergism between oxaliplatin and gemcitab-
`ine has led investigators to explore gemcitabine/oxaliplatin
`combinations in patients with advanced pancreatic cancer.
`The North Central Cancer Treatment Group (NCCTG) per-
`formed a Phase I dose escalation study of gemcitabine in com-
`bination with oxaliplatin in patients with advanced pancreatic
`cancer, in which they identified a maximum tolerated dose of
`oxaliplatin 100 mg/m2 administered on day 1 and gemcitab-
`ine 1000 mg/m2 administered on days 1 and 8 of a 21-day
`
`combination therapy (20 versus 8 weeks, p = 0.048). While
`no statistically significant survival differences were noted, the
`relatively small size of the study precluded a meaningful sur-
`vival analysis. The superior response rate and time to disease
`progression associated with the gemcitabine/cisplatin combi-
`nation in this study clearly warrant further confirmatory ran-
`domised studies.
`
`5.3 Gemcitabine and irinotecan
`Irinotecan is a topoisomerase inhibitor with demonstrated
`activity in several gastrointestinal malignancies. An initial Jap-
`anese trial of 35 patients demonstrated that single-agent iri-
`notecan was associated with a response rate of 11% in patients
`with metastatic pancreatic cancer [24]. A subsequent Phase II
`trial confirmed these findings, demonstrating an overall
`response rate of 9% in 34 patients [25]. This evidence of activ-
`ity, together with preclinical data suggesting synergism
`between irinotecan and gemcitabine, led to the investigation
`of combination regimens of gemcitabine and irinotecan.
`In an initial study, the Greek Cooperative Group for Pancre-
`atic Cancer treated 60 patients with gemcitabine 1000 mg/m2
`on days 1 and 8, in combination with irinotecan 300 mg/m2
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`cycle [33]. In this trial, 3/18 (16%) patients demonstrated
`objective responses. In a recent Phase II study, 64 patients
`(34 with metastatic and 30 with locally advanced disease) were
`treated with gemcitabine 1000 mg/m2 on day 1 and oxalipla-
`tin 100 mg/m2 on day 2 every other week [34]. The response
`rates associated with this combination were 31% for patients
`with locally advanced disease and 30% for patients with meta-
`static disease, and the median survival times were 11.5 months
`and 8.7 months, respectively.
`
`5.6 Multi-drug gemcitabine-based combination
`regimens
`The role of multi-drug gemcitabine-based combination regi-
`mens in the treatment of pancreatic cancer remains controver-
`sial. A three-drug combination of gemcitabine, cisplatin and
`infusional 5-FU, was associated with an objective response
`rate of 13% and a median survival time of 8.4 months [35].
`Another regimen, utilising gemcitabine, 5-FU, leucovorin and
`cisplatin (G-FLIP) was associated with an objective response
`rate of 24% and median survival time of 3.9 months in
`patients refractory to first-line therapy [36]. Similar results
`were seen with a regimen utilising a combination of gemcitab-
`ine, oxaliplatin, leucovorin and infusional 5-FU [37]. While
`this regimen was associated with an encouraging overall
`response rate of 29%, grade 3 or 4 neutropenia occurred in
`28% of cycles and febrile neutropenia developed during 5%
`of the treatment cycles.
`In one of the most aggressive studies performed to date, an
`Italian group evaluated a four-drug combination of cisplatin,
`epirubicin, 5-FU and gemcitabine in 49 patients with unre-
`sectable pancreatic cancer [38]. Patients in this study were
`treated with 40 mg/m2 each of cisplatin and epirubicin on
`day 1, gemcitabine 600 mg/m2 on days 1 and 8 every 4 weeks
`and fluorouracil 200 mg/m2/day as a protracted intravenous
`infusion. The regimen was associated with an impressive
`objective response rate of 58% and a median survival time of
`11 months. Like many of the other multi-drug combinations,
`however, it was also associated with relatively high rates of
`neutropenia and thrombocytopenia. The toxicity associated
`with these multi-drug regimens, together with the often mar-
`ginal performance status of patients with advanced pancreatic
`cancer, may preclude their widespread acceptance.
`
`5.7 Future studies with gemcitabine-based
`combination therapy
`The relatively small size of the many Phase II studies evaluat-
`ing gemcitabine-based combinations makes it virtually impos-
`sible to assess which combination may be more promising
`than another and which, if any, may prove to be superior to
`gemcitabine monotherapy. Indeed, the superior response rates
`and encouraging median survival times observed in these
`studies may be explained simply by differences in patient
`selection. Several ongoing, randomised studies, in which these
`regimens are being compared both to each other and to gem-
`citabine monotherapy, should help resolve some of these ques-
`
`Kulke
`
`tions. One such study, being performed by the Cancer and
`Leukaemia Group B (CALGB), randomises patients to receive
`either gemcitabine, administered at a fixed dose rate of
`10 mg/m2/min over 150 min or gemcitabine in combination
`with irinotecan, cisplatin or docetaxel (Figure 1). A second
`study, being performed by the ECOG, will randomise
`patients to receive standard dose gemcitabine, fixed dose rate
`gemcitabine or a combination of gemcitabine and oxaliplatin.
`The results of these studies, together with other large, pro-
`spectively randomised trials, are likely to define what future
`role gemcitabine-based combination therapy may play in the
`treatment of metastatic pancreatic cancer.
`
`6. Novel agents in advanced pancreatic cancer
`
`The development of novel agents provides additional hope for
`the future treatment of pancreatic cancer. The mechanisms of
`many of these new drugs differ significantly from standard
`cytotoxic agents, allowing them to be safely combined with
`more traditional regimens. Many, in fact, have already been
`evaluated in early clinical trials. While the results of some of
`these trials have been disappointing, other agents appear to be
`active in pancreatic cancer, both alone and in combination
`with more traditional agents.
`
`6.1 Metalloproteinase inhibitors
`Metalloproteinase inhibitors represent a class of proteolytic
`enzymes that are important in maintaining the extracellular
`matrix. It is thought that excess metalloproteinase activity
`may lead to breakdown of the extracellular matrix, tumour
`invasion and the development of metastases. One of the best
`studied of the metalloproteinase inhibitors is marimistat. A
`Phase III study performed in > 400 patients with metastatic
`pancreatic cancer compared marimistat, given at three differ-
`ent dose levels, to single-agent therapy with gemcitabine [39].
`Gemcitabine was associated with an objective response rate of
`26%, compared to only 3% for all three marimistat arms.
`Patients treated with gemcitabine also had a longer progres-
`sion-free survival time than patients treated with marimistat,
`although no statistically significant differences in overall sur-
`vival were observed. Given these negative results, it is unclear
`what role marimistat will play in the future treatment of pan-
`creatic cancer.
`
`6.2 Farnesyl transferase inhibitors
`One of the most potentially attractive targets in the treatment
`of pancreatic cancer is the ras oncogene, which is mutated in
`> 90% of pancreatic carcinomas. Farnesyl transferase inhibi-
`tors (FTIs), prevent activation of the mutant Ras protein by
`blocking a key step in protein processing. While FTIs have
`shown promising activity in laboratory models, clinical trials
`of FTIs have, to date, been disappointing. In a Phase II study
`of the FTI R115777, involving 20 patients with metastatic
`pancreatic cancer, none responded to treatment [40]. Further-
`more, a Phase III trial in which patients were randomised to
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`Recent developments in the pharmacological treatment of advanced pancreatic cancer
`
`Randomised
`(240 patients)
`
`22
`REST
`REST
`
`22
`REST
`
`Arm A: Gemcitabine/cisplatin
`
`Day
`Gemcitabine 1000 mg/m2
`Cisplatin 50 mg/m2
`
`1
`X
`X
`
`8
`X
`REST
`
`Arm B: Gemcitabine fixed dose rate infusion
`
`Day
`Gemcitabine 1500 mg/m2
`(10 mg/m2/min)
`
`1
`X
`
`Arm C: Gemcitabine/docetaxel
`
`Day
`Gemcitabine 1000 mg/m2
`Docetaxel 40 mg/m2
`
`1
`X
`X
`
`Arm D: Gemcitabine/irinotecan
`
`Day
`Gemcitabine 1000 mg/m2
`Irinotecan 100 mg/m2
`
`1
`X
`X
`
`8
`X
`
`8
`X
`X
`
`8
`X
`X
`
`15
`X
`X
`
`15
`X
`
`15
`REST
`REST
`
`15
`REST
`REST
`
`Figure 1. Schema for the Cancer and Leukaemia Group B Trial in patients with metastatic pancreatic cancer (CALGB 89904).
`
`receive gemcitabine alone or gemcitabine in combination
`with R115777, showed no differences in survival between the
`two treatment arms [41]. Whether other FTIs will prove more
`promising remains uncertain.
`
`6.3 Proteasome inhibitors
`The ubiquitin proteasome pathway is an intracellular pathway
`for the degradation of proteins, including several proteins that
`play key roles in the regulation of the cell cycle. The proteas-
`ome therefore represents another potential target for novel
`anticancer agents. PS-341, a dipeptidyl boronic acid inhibitor,
`has been shown in preclinical studies to have activity against
`the proteasome and is one of the first proteasome inhibitors to
`be tested in clinical trials. In an initial Phase I study of PS-341
`in combination with gemcitabine, two patients with pancre-
`atic cancer appeared to have stabilisation of their disease [42].
`Phase II studies of gemcitabine in combination with PS-341
`are currently underway.
`
`6.4 Pemetrexed
`Pemetrexed is a multitargeted antifolate that inhibits several
`key folate-dependent enzymes, including thymidylate syn-
`thase and dihydrofolate reductase [43]. Treatment with peme-
`trexed was initially found to result in partial responses in two
`patients with pancreatic cancer treated on a Phase I trial [44].
`
`In a subsequent Phase II trial, an overall response rate of 5.7%
`was observed in 35 evaluable patients with pancreatic cancer
`[45]. Based on preclinical evidence of synergism between gem-
`citabine and pemetrexed, a Phase II trial was undertaken with
`gemcitabine 1250 mg/m2 administered on day 1 and 8 of a
`21-day cycle, in combination with pemetrexed administered
`at a dose of 500 mg/m2 on day 8 [46]. Objective responses
`were noted in 6/42 (15%) patients and the median survival
`time was 6.5 months. A 520-patient, multi-centre Phase III
`trial comparing the combination of gemcitabine and peme-
`trexed to gemcitabine monotherapy should establish whether
`the pemetrexed combination will play a further role in the
`treatment of metastatic pancreatic cancer.
`
`6.5 Irofulven
`Irofulven (MGI-114) is a semisynthetic sesquiterpen, derived
`from the cytotoxic mushroom metabolite illudin S. In pre-
`clinical models, irofulven has been shown to be cytotoxic to
`human pancreatic cancer cells [47]. Irofulven has been admin-
`istered to > 400 patients in Phase I and II trials using a vari-
`ety of dose schedules and has shown activity in patients with
`advanced pancreatic cancer [48]. In one such study, irofulven
`was administered as a 5-min infusion, once every 2 weeks,
`with a dose-limiting toxicity of nausea and vomiting. Three
`patients with pancreatic cancer receiving this regimen had
`
`988
`
`Expert Opin. Investig. Drugs (2003) 12(6)
`
`NOVARTIS EXHIBIT 2059
`Par v. Novartis, IPR 2016-01479
`Page 6 of 10
`
`

`

`Kulke
`
`Table 2. Phase II studies of gemcitabine in combination with mAbs in advanced pancreatic cancer.
`
`Regimen
`
`% Patients expressing
`antibody
`
`No. patients treated
`
`Response rate
`
`Ref.
`
`Gemcitabine/trastuzumab
`Gemcitabine/IMC-C225
`
`21
`89
`
`21
`41
`
`22%
`12%
`
`Safran et al. [47]
`Abbruzzese et al. [53]
`
`disease stabilisation, leading to interest in further studies
`with this regimen in patients with gemcitabine-refractory
`disease [49].
`
`6.6 Rubitecan
`Rubitecan (9-aminocamptothecin), an oral camptothecin
`analogue, has modest activity in pancreatic cancer. In patients
`refractory to standard systemic chemotherapy, the administra-
`tion of rubitecan resulted in objective responses in 3/36 (9%)
`of patients [50]. Phase I studies of rubitecan in combination
`with gemcitabine have also been reported and may lead to fur-
`ther studies of this agent in patients with advanced disease [51].
`
`6.7 Receptor tyrosine kinase inhibitors
`The rapid development of receptor tyrosine kinase inhibitors
`in recent years represents a unique opportunity to enhance the
`treatment of patients with advanced pancreatic cancer. In con-
`trast to more conventional cytotoxic agents, receptor tyrosine
`kinases specifically target growth factor receptors thought to
`be critical for tumour growth. Trastuzumab, a mAb that tar-
`gets the Her-2 receptor tyrosine kinase, was one of the first of
`these drugs to be developed. Trastuzumab has been exten-
`sively studied in patients with metastatic breast cancer and has
`demonstrated clear efficacy in this setting. More recently, tras-
`tuzumab has also been evaluated in patients with other malig-
`nancies. A Phase II trial of gemcitabine and trastuzumab in
`patients with advanced pancreatic cancer demonstrated that
`this combination was associated with a response rate of 22%
`(Table 2) [52]. Unfortunat