- Email: [email protected]
O-141 Gemcitabine (GEM) and carboplatin (CARB) in patients (pts) with advanced non-small cell lung cancer (NSCLC): Update of a randomized phase II study
Oral Sessions/Cl~emotherapy
0 138 El
Tumour Necrosis Factor-alpha Cell Signalling Events in Human Bronchoepithelial Cells
William A. Swain, Kenneth J. O’Byrne.
University of L&ester,
Leicester, UK
Recent experimental evidence indicates that chronic immune activation, associated with angiogenesis, suppression of cell mediated immunity and inhibition of apoptosis, plays a central role in the development of malignant disease. In particular the interplay between cell death and survival/proliferation is crucial in the early stages of carcinogenesis. On a molecular level, the activation and integration of cell signalling pathways influence how this balance is set. Central to the instigation and propagation of a chronic immune response is the cytokine TNF-cc, which can exert a number of effects depending on cell type and context. The studies outlined here were designed to investigate if TNF-ol activates signalling pathways in a bronchoepithelial cell line (BEASPB) that could facilitate entry into the multistage carcinogenesis paradigm. In particular we have focused upon possible crosstalk with the EGFR/P13tVAkt pathway, which is integral in cell survival under conditions that would normally eliminate damaged cells. Furthermore, this pathway is known to be constitutively active in a variety of human tumours and as such represents a valid target for future pharmacological therapies. TNF-c( induces increased expression and tyrosine phosphorylation of EGFR over a range of time points, most notably at 8 hrs. In addition these conditions resulted in increased phosphorylation of Akt at SeP3, with the peak induction also at 8 hrs. Moreover, activation of Akt by TNF-CY was shown to be dependent upon oxidative stress as preincubation with N-ace@ cysteine attenuated this effect. In contrast, treatment with EGF or H202 resulted in transient activation of EGFR/Akt, which peaked at 15 mins. These results demonstrate for the first time that TNF-a can transactivate EGFR in this cell line. Furthermore, exposure to this cytokine activates AM in an oxidative stress dependent manner. Together, these events may contribute to cell survival under inflammatory conditions designed to eliminate cells in the early stages of carcinogenesis. Therefore, therapies designed to interfere with these processes may prove to be beneficial in the chemoprevention of lung cancer in the future.
0 139
EII
Expression and Modulation of c-kit and c-Met Receptor . Tyrosme Kinases and Downstream Effects On Topoisomerase-I activity in Small Cell Lung Cancer
Gautam Maulik’, Ajit Bharti’, Meghavi Rajgor’ , Simha Jagadeesh’ , Erik Schaefer’, Eshan Khan’, Patrick C. Ma’, Ravi Salgia’ ’ Dana Farber Cancer Institute, Boston, USA; a Biosource International, Hopkinton, USA Small cell lung cancer (SCLC) is an aggressive illness, for which cytotoxic chemotherapy appears to have reached its maximal efficacy. We have shown that SCLC is characterized by the overexpression of several receptor tyrosine kinases (RTKs), especially c-Kit, c-Met and Ret. These are key regulators of cell growth, differentiation, survival and motility. The ligands for c-Kit and cMet are stem cell factor (SCF), and hepatocyte growth factor (HGF) respectively. In SCLC, SCF and HGF can influence c-Kit and c-Met activation by autocrine or paracrine mechanisms. Utilizing 10 SCLC cell lines, there was cKit expression in 6/10 cell lines and c-Met expression in 7/i 0 cell lines. H526 SCLC cells overexpress c-Kit, and in stimulation of these cells with SCF (100 rig/ml, 30 min), tyrosines at position 703 (binding site of Grb2 and the activation of Ras-RatERK1&2 signaling pathway) and Y823 (a major autophosphorylation site) are phosphorylated as determined by unique phosphospecific antibodies. In a similar fashion, H69 SCLC cells overexpress c-Met, and in stimulation of these cells with HGF (40 rig/ml, 7.5 min), tyrosines at position 1003, 1230/1234/1235, 1313, 1349 and 1365 are phosphorylated. Since the inhibition of topoisomerase-I (topo-I) is one approach used to treat SCLC, we determined the effects of SCF/c-Kit and HGF/c-Met signaling on topo-I activity. We demonstrate that with SCF stimulation over 16 hours (dose response O-100 rig/ml), H526 SCLC cells (c-Kit positive, SCF responsive), a decrease in topo-I activity was observed; whereas, in H82 SCLC cells (c-Kit negative, SCF unresponsive) there was no modulation of topo-I activity by SCF. We also demonstrate that with HGF stimulation over 16 hours (dose response O-100 rig/ml,) in H69 SCLC cells (c-Met positive, HGF responsive), a decrease in topo-I activity was observed with increasing concentration of HGF used. It would now be useful to determine the synergism between the inhibition of these receptor tyrosine kinases and topo-I inhibition.
s43
NSCLC Phase II Innovutionu
TUESDAY, 12 AUGUST 2003
Chemotherapy Innovations
NSCLC Phase II
1 O-l 40 1 Phase 2 Study of First Line Chemotherapy Using CT-21 03 (XYOTAXTM)in Patients with Non-Small-Cell Lung Cancer Who are 570 years of Age or Performance Status (PS) = 2 David Bodkin’, Marcus Neubaue?, Mary G. Bolton3. ’ Sharp Health Care, San Diego, USA; *US Oncology, Da//as, USA; 3 Cell Therapeutics, Inc., Sea tt/e, USA CT-2103 (XYOTAXm) is a tumor-targeted taxane designed to concentrate selectively in tumors. CT-2103 exposes normal organs to conjugated paclitaxel, which is non-toxic in vitro, thus minimizing overall toxicity. CT-2103 showed enhanced efficacy compared to paclitaxel/Cremophor in syngeneic and xenogeneic in vivo tumor models including lung tumors. Conjugation of paclitaxel to poly-L-glutamate enhances aqueous solubility and eliminates the need for Cremophor, resulting in a convenient IO-min infusion. Chemotherapy na’ive patients (pts) with non-small-cell lung cancer (NSCLC) who are ~70 years of age or with ECOG PS = 2 are eligible for this open-label, multicenter study. Pts receive a conjugated paclitaxel dose of 175 mg/m2 CT-2103 as a IO-minute IV infusion every 21 days for up to 6 cycles. Safety was assessed using NCI CTC (v 2). Efficacy assessments were done after every second cycle using RECIST. Twenty-eight pts have been treated. The median age was 76 (range, 49-88). Seven pts (25%) were PS=2; 4 of these were also > 70. Seventeen pts (71%) achieved disease control; partial response, 2 pts (8%) or stable disease, 15 pts (63%). Fourteen pts (50%) completed 4 or more cycles of therapy. In the PS=2 pts median overall survival (OS) is 5.4 months. In the PS = 0 or 1 pts, median OS is 7.8 months. Eleven of 28 pts are alive. Grade 4 drugrelated neuropathy occurred in 2 pts. No other clinically significant drug related grade 4 adverse events occurred. Grade 3 toxicities were limited to generalized weakness/fatigue (5), neuropathy (3) and febrile neutropenia (1). Neuropathy and weakness/fatigue were seen in pts with concomitant progressive disease and significant disease-related comorbidities. CT-2103 has demonstrated activity and was well tolerated in elderly and PS=2 pts with NSCLC. Based on these encouraging results, enrollment in this study will continue at a higher dose of 235 mg/m2 in pts with PS=2 only. Two randomized phase 3 studies using CT2103 as a single agent and in combination with carboplatin (Stellar 3 and 4) have been initiated in PS=2 pts.
1O-141 ) Gemcitabine (GEM) and carboplatin (CARB) in patients (pts) with advanced non-small cell lung cancer (NSCLC): Update of a randomized phase II study Greaorv A. Masters’, Athanassios Argiris’, Elizabeth Hahn3, Marie Neale3, J. Beck4, P G. Rauschs. ’ Christiana Health Care, Graham Cancer Center, Newark, USA; 2 Northwestern University: Chicago, USA; 3 Evanston Northwestern Healthcare, Evanston, USA; 4 Highlands Oncology, FayetteMe, USA; 5 Oncology Frederick, USA This trial was performed to study two schedules of GEM and CARB: Arm A GEM (1100 mg/m2 days 1, 8) and CARB (AUC=5 day 8) q 28 days; or Arm B GEM (1000 mg/m’ days 1,8) and CARB (AUC=5 day 1) q 21 days. The primary objective was to evaluate progression free survival (PFS). Secondary objectives were response rate, overall median survival (MS), and toxicities. Eligible pts were chemotherapy-na’ive and had stage IIIB (malignant pleural effusion) or stage IV NSCLC. 100 pts were enrolled from October 2000 to January 2002 on this multi-institutional study (48 arm A, 52 arm B). There were 61 males and 39 females, 85 stage IV and 15 stage 1116,and the median age was 66 years (range 38-82). 36 pts had ECOG PS=O and 64 had P&l. The median number of cycles was 4 for arm A and 6 for arm B. The principal grade 3-4 toxicities were hematologic (see Table 1). Table 1. Outcome ARM A B
by treatment
ANC (Gr 314)
Plat (Gr 314)
1 o/3 12/12
1612 25/l
arm Non-Heme (Gr 314) 14/l 1710
No grade 3-4 non-hematologic toxicity in more than 10% of pts. No CR and 11 PR were observed on arm B. PFS was while MS was higher in arm A (p=O.52). and 33.5% in arm B.
Reswnse W 23 40
rate
PFS (months)
MS (months)
3.7 4.9
a.7 7.3
except nausea/vomiting was observed PR were seen on arm A; 1 CR and 20 numerically higher for arm B (p=O.96) One-year survival was 33.7% in arm A
Oral Sessions/Chemotherapy
s44
In conclusion, GEM-CARB is well tolerated with mainly hematologic toxicity. Non-significant differences in toxicity and efficacy allow either schedule to serve as a standard chemotherapy backbone for integration with targeted biologic agents in future trials in advanced NSCLC.
I 0 142
Phase I and Pharmacokinetic Doxorubicin (ResmyciW”)
Trial of Inhalational
John R. Murren’, D. D. White’, N. Rizvis, M. Krise, .I. Schillers, A. Sandle?, C. Ryans, M. Ratains, H. I, Pass6, G. Otterson’. ’ Yale University School of Medicine, Yale Cancer Center, New Haven, USA; s Memorial Sloan-Kettering Cancer Center, New York, USA; 3 U. Wisconsin, Madison, USA; 4 Vanderbilt University Nashville, USA; s U. Chicago, Chicago, USA; 6 Karmanos Cancer Institute, Detroit, USA; ‘The Arthur James Cancer Center and RichardJ. Solove Research Institute, Columbus, USA The OncoMyst@ Model CDD-2a inhalation device aerosolizes drug to particles of 2-3 microns and prevents exhaled aerosol from escaping into the ambient environment. Animal studies indicate that delivery of doxorubicin by this device results in a 15fold increase in pulmonary tissue concentrations compared to delivery of the same dose by the intravenous route, concentration of drug in the regional pulmonary lymphatics, and corresponding lower exposure of drug in plasma and to the heart muscle. We have conducted a phase I study of doxorubicin delivered by this device for patients with malignant disease in the lung. Deposition efficiency of inhaled Tc-99m was used to predict deposition efficiency of doxorubicin. Courses were repeated every 3 weeks. No more than moderate pulmonary dysfunction was permitted (FEVl, FVC, DLCO all ? 50% predicted, resting Sa02 >90%). Fifty patients have been enrolled, including 2 patients that were re-entered at a higher starting dose level. Thirteen dose levels ranging from 0.4 mg/ma to 9.4 mglm” were evaluated. The most common histologic diagnoses were sarcoma (21) and NSCLC (11). The total number of cycles has exceeded 140, and the maximum cumulative dose delivered to a single patient was 53.4 mg/m’. Two of the four patients treated at 9.4 mg/m’ experienced DLTs: one developed acute respiratory distress (ARDS) and died after the first cycle, and the other experienced chemical pneumonitis following the second course of treatment. Findings at autopsy of the first patient were extensive bilateral bronchioloalveolar carcinoma and bronchopneumonia. Nine patients have been treated on the 7.5 mg/ma and two experienced a DLT, one after Course 1 consisting of a decline in FVC of 120% from baseline and the second after Course 4 (decrease of ~20% in FVC and DLCO). There has been no evidence of significant systemic drug-related toxicity or myelosuppression. Several patients experienced significant declines in PFTs, which were attributed to progressive disease, and two patients had significant hypoxemia during the study. Two patients had transient tachycardia during the inhalation. One patient developed bronchospasm from treatment. Approximately one-third of the patients reported local/pulmonary adverse experiences such as taste alteration, dyspnea and cough. Non- specific symptoms (grade 1 or 2) such as nausea, loss of appetite were also reported. There has been no evidence of dose-response for these symptoms. The peak plasma concentration of doxorubicin at doses 5 9.4 mg/m* is c 50 rig/ml. The relationship between inhaled or deposited dose and plasma AUC was dose-related. Observed activity included a PR in a patient with metastatic soft tissue sarcoma previously treated with intravenous doxorubicin and ifosfamide, and stable disease in 8 of 32 evaluable patients. The study is continuing at the recommended dose of 7.5 mg/m’; future studies will evaluate this approach in combination with systemic chemotherapy for patients with advanced NSCLC.
I. 0 143
Gemcrtabme-oxaliplatin (GEMOX) chemotherapy as : frrst-lme treatment in advanced non-small cell lung cancer (NSCLC): Preliminary results of a multicenter phase II study
Lucia Crino’, Silvia Novello2, Filippo De Marinis3, Michela Maur4, Giorgio Scagliottis, S. Salvagni5, E. Crucittas, Antonio Maestri’, Stefania Bartolini’ , Federico Cappuzzo’ ’ Be//aria Hospital-Division of Medical Oncology Bologna, Italy; s S. Luigi Gonzaga Hospital-Orbassano, Torino, ha/v; 3 S. Camille-For/a&i Hospital, Roma, ha/y; 4 Policlinico di Modena, Modena, Italy; s Azienda Ospedaliera di Parma, Parma, Italy; 6 Eli Li//y Italy Firenze, ha/y
Background: Platinum-based chemotherapy is considered the standard treatment of advanced NSCLC. Oxaliplatin (OX) is active against NSCLC and the low incidence of severe hematologic toxicity makes it an attractive compound for combination with other anticancer drugs, Gemcitabine (GEM) is considered one of the most active drugs against NSCLC and preclinical studies show a synergistic effect when combined with OX. Patients and Methods: Chemonaive patients (pts) with locally advanced or metastatic NSCLC were eligible for this phase II multicenter study. GEMOX therapy consisted of GEM on days 1 and 8 at the dose of 1000 mg/m’ as a
NSCLC Phase II Innovutions 30-min IV infusion, followed by OX at the dose of 130 mg/m* on day 1, every 21 days for 2-8 cycles. Results: From February 2002 to December 2002, 54 pts were enrolled. At the time of this analysis, data from the first 36 pts are available, including the following characteristics: median age of 62 yrs (range, 36-73,); male/female: 24/12; stage lllB/IV: 6/30; and ECOG PS of O-1 in all 36 pts. The main histology types were adenocarcinoma in 16 (44%) pts and squamous cell in 10 (28%) pts. Response rate was evaluated on the first 25 pts. So far, a total of 94 cycles (range, l-6) has been administered. We observed 5 (20%) partial responses and 9 (36%) patients with stable disease. The main WHO toxicities, evaluated on 39 pts and on the first 61 cycles, were hematologic, consisting of grade 3/4 neutropenia in 4/l cycles and grade 3 thrombocytopenia in only 1 cycle. Grade 3 non-hematologic toxicities consisted of nausea/vomiting in 3 cycles, and neurotoxicity, skin toxicity, and asthenia in 1 cycle each. Because of side effects, 2 pts withdrew consent (1 for grade 3 neurotoxicity and 1 for grade 3 vomiting). Conclusions: At this time, although analyses are ongoing, the combination of GEMOX appears active with a manageable toxicity profile. Definitive data will be ready for the meeting
0 144
El.
Result of a phase II study conducted in elderly patients wrth unresectable localised or metastatic non-small-cell-lung cancer (NSCLC) with oral vinorelbine given as a weekly monotherapy
Cesare Gridelli’, Filippo De Marinis2, Christian Manegold3, Pekka Mali“, Luigi Portalones, Olivier Castelnaus, Rolf Stahel’, Daniel Bettichers, Ralf Herrmanng, Josefa Terrasa Pans”‘, Delphine Aubert” , Jean-Philippe Burillon” , Ulrich Gatzemeier’“. ’ Sg Moscati Hospital Monteforte Avellino, Italia; s Ospedale C. Forlanini, Roma, ha/v; 3 Thorax Klinik, Heidelberg, Germany; 4 Paimion Sairaala, Preitila, Fin/and; s Ospedale C. Forlanini, Roma, Italia; s lnstitut Arnaud Tzanck, Saint Laurent Du Var, France; 7 Universitatsspital, Zurich, Switzerland; s lnsel Hospital, Bern, Zwitzerfand; 9 Kantonsspital Base/, Basem, Zwitzerland; ‘O Hospital Son Dureta, Pa/ma De Mallorca, Baleares; ” lnstitut De Recherche Pierre Fabre, Boulogne, France; rp Krankenhaus Grosshansdod, Grosshansdon, Germany This phase 2 study was conducted to determine the response rate of weekly oral vinorelbine given as first line monotherapy in locally unresectable or metastatic NSCLC elderly patients (pts). Fifty-six pts over 70 years old were recruited from April 2001 to March 2002 in 6 European countries. Treatment consisted of oral vinorelbine given weekly at 60mg/mz for 3 weeks (one cycle) and then upgraded to 80mg/ma if no grade 4 neutropenia or no more than one grade 3 occurred during the first 3 doses, given up to progression. At the dose of bOmg/m*, if one grade 4 or two consecutive grade 3 neutropenia occurred, the dose was reduced back to 60mg/m2. Median age was 74 (70-82) 75% were male with a performance status of 80 in 27 pts, 90 in 19 and 100 in IO. Forty-three pts (76.8%) had metastatic disease at inclusion with 1 or 2 organs involved in 64.3% and 3 3 in 35.7%. Comorbidities were present in most pts: 39 (69.6%) had 1 or 2 and 10 (17.9%) had 3 3 comorbidities. As expected in this population, cardiovascular morbidity was present in 36 pts (64.3%). All pts were treated, 47 are evaluable for response, 200 cycles (cy) were evaluable (median = 3/pts, range:l-lo), median dose intensity (DI): 47,2mg/m*/w (21-77,3) with a relative DI of 66%. A total of 472 oral administrations were administered (median = 7). Out of 56 pts receiving 1st cy, 45 received also 2d cy and 29 (84,4%) at 80 mg/ma. Thirteen pts received s 6 cy. A total of 125 doses (20,9%) were cancelled, of which 91 (72,8%) due to related haematological toxicity. Grade 3/4 neutropenia was present in 61 cy (30.8% with grade 4 = 12.1%), infection + neutropenia in 5 (2.5%) leucopenia in 43 (21.5%) and anemia in 2 (1%). Grade 3 non-haematological toxicities were only fatigue (4%) nausea (2.5%), diarrhoea (1.5%). One pt had a grade 4 thrombosis (0.5%). Six partial responses (12.8%, 3.2-22.2) and 25 stable disease (disease control = 66%) were reported. Duration of response was 5,9 months (3,6-9,l) and median progression free survival, 3,6 months (2,5-4,5). Survival data will be presented at the meeting. The pharmacokinetics performed in 52/56 pts reported similar bioavailability and blood profiles compared to a large adult database. Oral vinorelbine given as weekly monotherapy was easy to administer and well tolerated, offering an optimal disease control in such elderly population leading to a favourable activity/toxicity ratio.
0 138 El
Tumour Necrosis Factor-alpha Cell Signalling Events in Human Bronchoepithelial Cells
William A. Swain, Kenneth J. O’Byrne.
University of L&ester,
Leicester, UK
Recent experimental evidence indicates that chronic immune activation, associated with angiogenesis, suppression of cell mediated immunity and inhibition of apoptosis, plays a central role in the development of malignant disease. In particular the interplay between cell death and survival/proliferation is crucial in the early stages of carcinogenesis. On a molecular level, the activation and integration of cell signalling pathways influence how this balance is set. Central to the instigation and propagation of a chronic immune response is the cytokine TNF-cc, which can exert a number of effects depending on cell type and context. The studies outlined here were designed to investigate if TNF-ol activates signalling pathways in a bronchoepithelial cell line (BEASPB) that could facilitate entry into the multistage carcinogenesis paradigm. In particular we have focused upon possible crosstalk with the EGFR/P13tVAkt pathway, which is integral in cell survival under conditions that would normally eliminate damaged cells. Furthermore, this pathway is known to be constitutively active in a variety of human tumours and as such represents a valid target for future pharmacological therapies. TNF-c( induces increased expression and tyrosine phosphorylation of EGFR over a range of time points, most notably at 8 hrs. In addition these conditions resulted in increased phosphorylation of Akt at SeP3, with the peak induction also at 8 hrs. Moreover, activation of Akt by TNF-CY was shown to be dependent upon oxidative stress as preincubation with N-ace@ cysteine attenuated this effect. In contrast, treatment with EGF or H202 resulted in transient activation of EGFR/Akt, which peaked at 15 mins. These results demonstrate for the first time that TNF-a can transactivate EGFR in this cell line. Furthermore, exposure to this cytokine activates AM in an oxidative stress dependent manner. Together, these events may contribute to cell survival under inflammatory conditions designed to eliminate cells in the early stages of carcinogenesis. Therefore, therapies designed to interfere with these processes may prove to be beneficial in the chemoprevention of lung cancer in the future.
0 139
EII
Expression and Modulation of c-kit and c-Met Receptor . Tyrosme Kinases and Downstream Effects On Topoisomerase-I activity in Small Cell Lung Cancer
Gautam Maulik’, Ajit Bharti’, Meghavi Rajgor’ , Simha Jagadeesh’ , Erik Schaefer’, Eshan Khan’, Patrick C. Ma’, Ravi Salgia’ ’ Dana Farber Cancer Institute, Boston, USA; a Biosource International, Hopkinton, USA Small cell lung cancer (SCLC) is an aggressive illness, for which cytotoxic chemotherapy appears to have reached its maximal efficacy. We have shown that SCLC is characterized by the overexpression of several receptor tyrosine kinases (RTKs), especially c-Kit, c-Met and Ret. These are key regulators of cell growth, differentiation, survival and motility. The ligands for c-Kit and cMet are stem cell factor (SCF), and hepatocyte growth factor (HGF) respectively. In SCLC, SCF and HGF can influence c-Kit and c-Met activation by autocrine or paracrine mechanisms. Utilizing 10 SCLC cell lines, there was cKit expression in 6/10 cell lines and c-Met expression in 7/i 0 cell lines. H526 SCLC cells overexpress c-Kit, and in stimulation of these cells with SCF (100 rig/ml, 30 min), tyrosines at position 703 (binding site of Grb2 and the activation of Ras-RatERK1&2 signaling pathway) and Y823 (a major autophosphorylation site) are phosphorylated as determined by unique phosphospecific antibodies. In a similar fashion, H69 SCLC cells overexpress c-Met, and in stimulation of these cells with HGF (40 rig/ml, 7.5 min), tyrosines at position 1003, 1230/1234/1235, 1313, 1349 and 1365 are phosphorylated. Since the inhibition of topoisomerase-I (topo-I) is one approach used to treat SCLC, we determined the effects of SCF/c-Kit and HGF/c-Met signaling on topo-I activity. We demonstrate that with SCF stimulation over 16 hours (dose response O-100 rig/ml), H526 SCLC cells (c-Kit positive, SCF responsive), a decrease in topo-I activity was observed; whereas, in H82 SCLC cells (c-Kit negative, SCF unresponsive) there was no modulation of topo-I activity by SCF. We also demonstrate that with HGF stimulation over 16 hours (dose response O-100 rig/ml,) in H69 SCLC cells (c-Met positive, HGF responsive), a decrease in topo-I activity was observed with increasing concentration of HGF used. It would now be useful to determine the synergism between the inhibition of these receptor tyrosine kinases and topo-I inhibition.
s43
NSCLC Phase II Innovutionu
TUESDAY, 12 AUGUST 2003
Chemotherapy Innovations
NSCLC Phase II
1 O-l 40 1 Phase 2 Study of First Line Chemotherapy Using CT-21 03 (XYOTAXTM)in Patients with Non-Small-Cell Lung Cancer Who are 570 years of Age or Performance Status (PS) = 2 David Bodkin’, Marcus Neubaue?, Mary G. Bolton3. ’ Sharp Health Care, San Diego, USA; *US Oncology, Da//as, USA; 3 Cell Therapeutics, Inc., Sea tt/e, USA CT-2103 (XYOTAXm) is a tumor-targeted taxane designed to concentrate selectively in tumors. CT-2103 exposes normal organs to conjugated paclitaxel, which is non-toxic in vitro, thus minimizing overall toxicity. CT-2103 showed enhanced efficacy compared to paclitaxel/Cremophor in syngeneic and xenogeneic in vivo tumor models including lung tumors. Conjugation of paclitaxel to poly-L-glutamate enhances aqueous solubility and eliminates the need for Cremophor, resulting in a convenient IO-min infusion. Chemotherapy na’ive patients (pts) with non-small-cell lung cancer (NSCLC) who are ~70 years of age or with ECOG PS = 2 are eligible for this open-label, multicenter study. Pts receive a conjugated paclitaxel dose of 175 mg/m2 CT-2103 as a IO-minute IV infusion every 21 days for up to 6 cycles. Safety was assessed using NCI CTC (v 2). Efficacy assessments were done after every second cycle using RECIST. Twenty-eight pts have been treated. The median age was 76 (range, 49-88). Seven pts (25%) were PS=2; 4 of these were also > 70. Seventeen pts (71%) achieved disease control; partial response, 2 pts (8%) or stable disease, 15 pts (63%). Fourteen pts (50%) completed 4 or more cycles of therapy. In the PS=2 pts median overall survival (OS) is 5.4 months. In the PS = 0 or 1 pts, median OS is 7.8 months. Eleven of 28 pts are alive. Grade 4 drugrelated neuropathy occurred in 2 pts. No other clinically significant drug related grade 4 adverse events occurred. Grade 3 toxicities were limited to generalized weakness/fatigue (5), neuropathy (3) and febrile neutropenia (1). Neuropathy and weakness/fatigue were seen in pts with concomitant progressive disease and significant disease-related comorbidities. CT-2103 has demonstrated activity and was well tolerated in elderly and PS=2 pts with NSCLC. Based on these encouraging results, enrollment in this study will continue at a higher dose of 235 mg/m2 in pts with PS=2 only. Two randomized phase 3 studies using CT2103 as a single agent and in combination with carboplatin (Stellar 3 and 4) have been initiated in PS=2 pts.
1O-141 ) Gemcitabine (GEM) and carboplatin (CARB) in patients (pts) with advanced non-small cell lung cancer (NSCLC): Update of a randomized phase II study Greaorv A. Masters’, Athanassios Argiris’, Elizabeth Hahn3, Marie Neale3, J. Beck4, P G. Rauschs. ’ Christiana Health Care, Graham Cancer Center, Newark, USA; 2 Northwestern University: Chicago, USA; 3 Evanston Northwestern Healthcare, Evanston, USA; 4 Highlands Oncology, FayetteMe, USA; 5 Oncology Frederick, USA This trial was performed to study two schedules of GEM and CARB: Arm A GEM (1100 mg/m2 days 1, 8) and CARB (AUC=5 day 8) q 28 days; or Arm B GEM (1000 mg/m’ days 1,8) and CARB (AUC=5 day 1) q 21 days. The primary objective was to evaluate progression free survival (PFS). Secondary objectives were response rate, overall median survival (MS), and toxicities. Eligible pts were chemotherapy-na’ive and had stage IIIB (malignant pleural effusion) or stage IV NSCLC. 100 pts were enrolled from October 2000 to January 2002 on this multi-institutional study (48 arm A, 52 arm B). There were 61 males and 39 females, 85 stage IV and 15 stage 1116,and the median age was 66 years (range 38-82). 36 pts had ECOG PS=O and 64 had P&l. The median number of cycles was 4 for arm A and 6 for arm B. The principal grade 3-4 toxicities were hematologic (see Table 1). Table 1. Outcome ARM A B
by treatment
ANC (Gr 314)
Plat (Gr 314)
1 o/3 12/12
1612 25/l
arm Non-Heme (Gr 314) 14/l 1710
No grade 3-4 non-hematologic toxicity in more than 10% of pts. No CR and 11 PR were observed on arm B. PFS was while MS was higher in arm A (p=O.52). and 33.5% in arm B.
Reswnse W 23 40
rate
PFS (months)
MS (months)
3.7 4.9
a.7 7.3
except nausea/vomiting was observed PR were seen on arm A; 1 CR and 20 numerically higher for arm B (p=O.96) One-year survival was 33.7% in arm A
Oral Sessions/Chemotherapy
s44
In conclusion, GEM-CARB is well tolerated with mainly hematologic toxicity. Non-significant differences in toxicity and efficacy allow either schedule to serve as a standard chemotherapy backbone for integration with targeted biologic agents in future trials in advanced NSCLC.
I 0 142
Phase I and Pharmacokinetic Doxorubicin (ResmyciW”)
Trial of Inhalational
John R. Murren’, D. D. White’, N. Rizvis, M. Krise, .I. Schillers, A. Sandle?, C. Ryans, M. Ratains, H. I, Pass6, G. Otterson’. ’ Yale University School of Medicine, Yale Cancer Center, New Haven, USA; s Memorial Sloan-Kettering Cancer Center, New York, USA; 3 U. Wisconsin, Madison, USA; 4 Vanderbilt University Nashville, USA; s U. Chicago, Chicago, USA; 6 Karmanos Cancer Institute, Detroit, USA; ‘The Arthur James Cancer Center and RichardJ. Solove Research Institute, Columbus, USA The OncoMyst@ Model CDD-2a inhalation device aerosolizes drug to particles of 2-3 microns and prevents exhaled aerosol from escaping into the ambient environment. Animal studies indicate that delivery of doxorubicin by this device results in a 15fold increase in pulmonary tissue concentrations compared to delivery of the same dose by the intravenous route, concentration of drug in the regional pulmonary lymphatics, and corresponding lower exposure of drug in plasma and to the heart muscle. We have conducted a phase I study of doxorubicin delivered by this device for patients with malignant disease in the lung. Deposition efficiency of inhaled Tc-99m was used to predict deposition efficiency of doxorubicin. Courses were repeated every 3 weeks. No more than moderate pulmonary dysfunction was permitted (FEVl, FVC, DLCO all ? 50% predicted, resting Sa02 >90%). Fifty patients have been enrolled, including 2 patients that were re-entered at a higher starting dose level. Thirteen dose levels ranging from 0.4 mg/ma to 9.4 mglm” were evaluated. The most common histologic diagnoses were sarcoma (21) and NSCLC (11). The total number of cycles has exceeded 140, and the maximum cumulative dose delivered to a single patient was 53.4 mg/m’. Two of the four patients treated at 9.4 mg/m’ experienced DLTs: one developed acute respiratory distress (ARDS) and died after the first cycle, and the other experienced chemical pneumonitis following the second course of treatment. Findings at autopsy of the first patient were extensive bilateral bronchioloalveolar carcinoma and bronchopneumonia. Nine patients have been treated on the 7.5 mg/ma and two experienced a DLT, one after Course 1 consisting of a decline in FVC of 120% from baseline and the second after Course 4 (decrease of ~20% in FVC and DLCO). There has been no evidence of significant systemic drug-related toxicity or myelosuppression. Several patients experienced significant declines in PFTs, which were attributed to progressive disease, and two patients had significant hypoxemia during the study. Two patients had transient tachycardia during the inhalation. One patient developed bronchospasm from treatment. Approximately one-third of the patients reported local/pulmonary adverse experiences such as taste alteration, dyspnea and cough. Non- specific symptoms (grade 1 or 2) such as nausea, loss of appetite were also reported. There has been no evidence of dose-response for these symptoms. The peak plasma concentration of doxorubicin at doses 5 9.4 mg/m* is c 50 rig/ml. The relationship between inhaled or deposited dose and plasma AUC was dose-related. Observed activity included a PR in a patient with metastatic soft tissue sarcoma previously treated with intravenous doxorubicin and ifosfamide, and stable disease in 8 of 32 evaluable patients. The study is continuing at the recommended dose of 7.5 mg/m’; future studies will evaluate this approach in combination with systemic chemotherapy for patients with advanced NSCLC.
I. 0 143
Gemcrtabme-oxaliplatin (GEMOX) chemotherapy as : frrst-lme treatment in advanced non-small cell lung cancer (NSCLC): Preliminary results of a multicenter phase II study
Lucia Crino’, Silvia Novello2, Filippo De Marinis3, Michela Maur4, Giorgio Scagliottis, S. Salvagni5, E. Crucittas, Antonio Maestri’, Stefania Bartolini’ , Federico Cappuzzo’ ’ Be//aria Hospital-Division of Medical Oncology Bologna, Italy; s S. Luigi Gonzaga Hospital-Orbassano, Torino, ha/v; 3 S. Camille-For/a&i Hospital, Roma, ha/y; 4 Policlinico di Modena, Modena, Italy; s Azienda Ospedaliera di Parma, Parma, Italy; 6 Eli Li//y Italy Firenze, ha/y
Background: Platinum-based chemotherapy is considered the standard treatment of advanced NSCLC. Oxaliplatin (OX) is active against NSCLC and the low incidence of severe hematologic toxicity makes it an attractive compound for combination with other anticancer drugs, Gemcitabine (GEM) is considered one of the most active drugs against NSCLC and preclinical studies show a synergistic effect when combined with OX. Patients and Methods: Chemonaive patients (pts) with locally advanced or metastatic NSCLC were eligible for this phase II multicenter study. GEMOX therapy consisted of GEM on days 1 and 8 at the dose of 1000 mg/m’ as a
NSCLC Phase II Innovutions 30-min IV infusion, followed by OX at the dose of 130 mg/m* on day 1, every 21 days for 2-8 cycles. Results: From February 2002 to December 2002, 54 pts were enrolled. At the time of this analysis, data from the first 36 pts are available, including the following characteristics: median age of 62 yrs (range, 36-73,); male/female: 24/12; stage lllB/IV: 6/30; and ECOG PS of O-1 in all 36 pts. The main histology types were adenocarcinoma in 16 (44%) pts and squamous cell in 10 (28%) pts. Response rate was evaluated on the first 25 pts. So far, a total of 94 cycles (range, l-6) has been administered. We observed 5 (20%) partial responses and 9 (36%) patients with stable disease. The main WHO toxicities, evaluated on 39 pts and on the first 61 cycles, were hematologic, consisting of grade 3/4 neutropenia in 4/l cycles and grade 3 thrombocytopenia in only 1 cycle. Grade 3 non-hematologic toxicities consisted of nausea/vomiting in 3 cycles, and neurotoxicity, skin toxicity, and asthenia in 1 cycle each. Because of side effects, 2 pts withdrew consent (1 for grade 3 neurotoxicity and 1 for grade 3 vomiting). Conclusions: At this time, although analyses are ongoing, the combination of GEMOX appears active with a manageable toxicity profile. Definitive data will be ready for the meeting
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Result of a phase II study conducted in elderly patients wrth unresectable localised or metastatic non-small-cell-lung cancer (NSCLC) with oral vinorelbine given as a weekly monotherapy
Cesare Gridelli’, Filippo De Marinis2, Christian Manegold3, Pekka Mali“, Luigi Portalones, Olivier Castelnaus, Rolf Stahel’, Daniel Bettichers, Ralf Herrmanng, Josefa Terrasa Pans”‘, Delphine Aubert” , Jean-Philippe Burillon” , Ulrich Gatzemeier’“. ’ Sg Moscati Hospital Monteforte Avellino, Italia; s Ospedale C. Forlanini, Roma, ha/v; 3 Thorax Klinik, Heidelberg, Germany; 4 Paimion Sairaala, Preitila, Fin/and; s Ospedale C. Forlanini, Roma, Italia; s lnstitut Arnaud Tzanck, Saint Laurent Du Var, France; 7 Universitatsspital, Zurich, Switzerland; s lnsel Hospital, Bern, Zwitzerfand; 9 Kantonsspital Base/, Basem, Zwitzerland; ‘O Hospital Son Dureta, Pa/ma De Mallorca, Baleares; ” lnstitut De Recherche Pierre Fabre, Boulogne, France; rp Krankenhaus Grosshansdod, Grosshansdon, Germany This phase 2 study was conducted to determine the response rate of weekly oral vinorelbine given as first line monotherapy in locally unresectable or metastatic NSCLC elderly patients (pts). Fifty-six pts over 70 years old were recruited from April 2001 to March 2002 in 6 European countries. Treatment consisted of oral vinorelbine given weekly at 60mg/mz for 3 weeks (one cycle) and then upgraded to 80mg/ma if no grade 4 neutropenia or no more than one grade 3 occurred during the first 3 doses, given up to progression. At the dose of bOmg/m*, if one grade 4 or two consecutive grade 3 neutropenia occurred, the dose was reduced back to 60mg/m2. Median age was 74 (70-82) 75% were male with a performance status of 80 in 27 pts, 90 in 19 and 100 in IO. Forty-three pts (76.8%) had metastatic disease at inclusion with 1 or 2 organs involved in 64.3% and 3 3 in 35.7%. Comorbidities were present in most pts: 39 (69.6%) had 1 or 2 and 10 (17.9%) had 3 3 comorbidities. As expected in this population, cardiovascular morbidity was present in 36 pts (64.3%). All pts were treated, 47 are evaluable for response, 200 cycles (cy) were evaluable (median = 3/pts, range:l-lo), median dose intensity (DI): 47,2mg/m*/w (21-77,3) with a relative DI of 66%. A total of 472 oral administrations were administered (median = 7). Out of 56 pts receiving 1st cy, 45 received also 2d cy and 29 (84,4%) at 80 mg/ma. Thirteen pts received s 6 cy. A total of 125 doses (20,9%) were cancelled, of which 91 (72,8%) due to related haematological toxicity. Grade 3/4 neutropenia was present in 61 cy (30.8% with grade 4 = 12.1%), infection + neutropenia in 5 (2.5%) leucopenia in 43 (21.5%) and anemia in 2 (1%). Grade 3 non-haematological toxicities were only fatigue (4%) nausea (2.5%), diarrhoea (1.5%). One pt had a grade 4 thrombosis (0.5%). Six partial responses (12.8%, 3.2-22.2) and 25 stable disease (disease control = 66%) were reported. Duration of response was 5,9 months (3,6-9,l) and median progression free survival, 3,6 months (2,5-4,5). Survival data will be presented at the meeting. The pharmacokinetics performed in 52/56 pts reported similar bioavailability and blood profiles compared to a large adult database. Oral vinorelbine given as weekly monotherapy was easy to administer and well tolerated, offering an optimal disease control in such elderly population leading to a favourable activity/toxicity ratio.