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116 441 442 Phase II study of Gemcitabine + Vindeeine in patiente with previously untreated, inoperable non small cell lung cancer (NSCLC). J.B. Ssrensen’ , A.L. Nielsen’ , M. Krarup’ , P. Dombernoweky2, H.H. Hansen’ . Depts of Oncology, ‘State University Hospital (Rigshospitalet) and ‘Herlev Hospital, Copenhagen, Denmark. Thirtytwo patients (pts.) with previously untreated, inoperable NSCLC received a combination of Gemcitabine 1000 mg/m’ i.v. weekly x 3 every 4 weeks as a X-hour infusion and Vindesine 3mg/mz i.v. bolus weekly x 7, then biweekly. pts. characteristics: Median age 53years (range 37-&?), 11 males/21 females, median performance status 1 (range O-2), 17 adenocarcinomas/l 0 squamous cell carcinomas/4 large cell carcinomas/i poorly differentiated NSCLC. Toxicity: Leucopenia WHO grade 3-4 (4 pts., 13%), thrombocytopenia grade 3-4 (3 pts., 9%), liver toxicity grade 2 (15 pts., 47%), grade 3 (4 pts., 13%), grade 4 (0 pts.). Ten pts. (31%) had a grade 3-4 hematologic or liver toxicity. Three pts. (9%) had an acute decrease in ventilation capacity with a peak-flow reduction of more than 50% within 2 hours after drug infusion compared to pre-infusion level. The peak-flow alteration caused hospitalization in 2 pts. but were uniformly reversible. Four pts. (13%) developed renal toxicity with glomerular filtration rates below normal limits, which was reversible in 3 pts. while 1 pt. developed irreversible renal insufficiency. Among 30 pts. evaluable for response there were 7 partial and 1 complete remissions (response rate 27%, 95% confidence limits (12%- 46%). This is similar to the activity obtained by either drug as a single agent. In conclusion the combination of Gemcitabine + Vindesine in the applied doses and schedules was not more active than either drug as single agent. 443 High-do** tsmoxif." in colbinstion with cisp1sti” in non- small cell Lug cancer (NSCLC)! Phae. I trill snd phsrmscokinetic seslysie. Perez EA. Gsndsrs DR, Webber L.M, Edelma" X.7,and DeGregorio MU. university of Cslifor"is, Davis, Sacramento, CP. 95817 and University of Texas, Health Sciences Center. San Antonio. TX 78284. Recent studie. support the uee of tamoxife” (TAH) in combination with traditional cytotoxic agents for s variety of malig"a"ciea. Preclinicsl studies (Hoffman, 1988, WcClsy, 1993) demonstrate that TAM cs" enhance the activity of cieulsti" ICDDP) at concentrations > 1uH. We conducted s etuciyof e&A&ing high-dose TAM in &abinstion with CDDP in order to determine TAM phsrmscokinetics and marlmum tolerated dose (I4TD). TAM was administered days 1-7 at 16Omg/d (n-5) and 2OOmg/m* (n-6) per day followed by CDDP st lOOmg/m' on day 8. Eleven patients with advanced NSCLC received 15 cycle8 and 20 cycles of treatment at 160mg/m2 and ZOOmg/m' TAM, respectively. Pharmscokinetic s"alysis of TAM by HPLC shows plasma levela of 4.5-S.2@ on day 7 in 5 patients tested to date. TAW MTD analysis: grade 314 non-hemstologic toxicity occurred in Of5 and l/6 patients at the 160mg/d and 2OOmg/m' doee levale, respectively. There have bee" no grade 4 hemstologic toxicities. TO date, TAM MTD hse not bee" reached. We plan continued dose eecslstion of TAN at 25Omg/m' to optimize plssms levels. One patient wse ineligible due to staging error, and 1 patient never received protocol treatment. I" 9 sssesssble patients, 3 partial responses were observed. Co"~lueio"~: 1) TAM levels predicted to enhance CDDP eeneitivity i" vitro are clinically achievable with scceptsble toxicity. 2) Preliminary activity in NSCLC is encouraging. A phaee II atudy in NSCLC is planned. PEASE I STUDY OF GRMCITABINR (GEM) AM) CISPWTIN (CP) FOR ADVANCFJI NON-SMALL CELL LUNG CANCER (NSCLC). F. Shepherd, Y. tinnier, R. Burkes, M. Camp, R. Feld, T. Strack. The University of Toronto, Toronto, and U”iversite Lava&Quebec City, Canada Single-agent GEM, 1250 mp/m' weekly x 3 is active against NSCLC, and induces respoose in up to 20% of untreated patients (Proc ASCO 12: 330, 1993). This study was undertaken to determine the maximum tolerated doses for a four week cycle of GEM and CP administered weekly x 3 with a one week rest period. Patients < tha”75yearsofagewereeligibleiftheyhadstageIIyIVbiopsy proven NSCLC, life expectancy 2 12 weeks, adequate hematology (Hgb 2 10 g/dl, gmnulocytes 2 2 x lop/L, platelets 2 100 x lop/L), adequate hepatic and renal function (AST and ALT ( 3 x “onnal, and creatiaine 5 130 mmol/L). The starting doses of GEM and CP WEX~ 1000 mg/m* and 25 Is/m3*eek x 3. At dose level 2 only the CP was increased to 30 mg/m’/week x 3, and thereafter dose escalations were made only for GEM. To date, 25 patients (24 eligible) have entered the study. There were 17 males and 7 females, median age 63 years (range 43 - 74). Pathology included: adenocarcinoma-16 patients; squamous-4 patients; large cell-3 patients; mixed-l oatient. Seven oatients had stage III and 17 “atients had stare IV tumors. -3/4 . . 3,4 3,4 3,4 lcm 25 w26 tn 2P o 0 4/6 loo0 M 6no 14 uo 0 0 3/6 1250 30 7ll in 1x1 0 0 TooEarly 15w 30 s- TaoEvlv TooEarh There were no other WHO grade 3 or4 “on-hematoloaicto~~ties. and since dose-liking toxicity has not bee” reached, study entry continues. The prelkninary response data suggest that GEM and CP is an active regimen against NSCLC. It is well tolerated, and deserves further study in comparison with other chemotherapy combinations. Supported by Eli Lilly, Canada. 444 Ifosfam~de(IFO)+V~norelbine(VRL )as Treatment for advanced, non operaple Non Small Cell Lung Canser (NSCLC) J.v.Pawet ,M.Schroeder,J2Grote-Klehn ,S.Kerpel-Fron,us3, P.Tresca ,M.Westerhausen . Zentralkrankenhauy Gaut,ng,‘Med.Klinlk II,St.Johaunes- Hospltal,Dulsburg, Farmltalla Carlo Erba,Frelburg, Pierre Fabre Medlcament,Parls. We report a Phase II study of a romblnatlon therapy of Vlnorelbine(Navelblne),a new semi-synthetic Vlnca-Alkaloid and Ifosfamlde, both effective in NSCLC. To date 40 Pts entered the study.Age (modIan): years, sex(M/F):30/10; Performance Status:WHO 0 13 Pts(33?;), WHO 1 27 Pts(67X); Stage:IIIAZ patients (X),IIIB 10 Pts(35X),IV28Pts(625);Cell Type:AdenoCa.EO, SCC 15, LCC 3, MlxFd 1, no speclflcatlonl; Treatment schedule: VRL 20 mg/y dl and 5 IF0 1500 mg/m dl-5, every 4 weeks. From the 40 Pts enrolled 3 are too early to be evaluable, 3 refused treatment, 2 were removed due to severe toxlclty, and 3 Pts died early wlthin 4 weeks.In one case protocol vlolatlon was observed,furthermore 3 early tumor pregres- s~ons were observed. In 28 Pts who completed at least ‘2 cycles the followng results were noted. Complete remission O/28 Partial rem,ss1on 7/28 (25X) No change 7/28 (29%) Progressive Disease lo/28 (36%) Complete data on myelotox>city lncludlng haematologlc con- trol at days lo-12 are available for 39Pts at present.WHO grade 3 and 4 leucopen~a was present I” 41 and 36% of Pts, granulacytopenic fever was observed in 10 X of cases.The regeneration of WBC was completed irrespertlve of the nadir value by day 28 in all cases. Thrombocytopenla WHO grade 3 occurred ,n 3X.Perlpheral neurotox?clty was weak:14 neuro- toxlclty grade 1 and 2 was seen I" 26 and 6% of cases. CNS toxlcrty grade 3 was noted in 1 patlent.

Phase I study of gemcitabine (GEM) and cisplatin (CP) for advanced non-small cell lung cancer (NSCLC)

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441 442

Phase II study of Gemcitabine + Vindeeine in patiente with previously untreated, inoperable non small cell lung cancer (NSCLC). J.B. Ssrensen’, A.L. Nielsen’, M. Krarup’, P. Dombernoweky2, H.H. Hansen’. Depts of Oncology, ‘State University Hospital (Rigshospitalet) and ‘Herlev Hospital, Copenhagen, Denmark.

Thirtytwo patients (pts.) with previously untreated, inoperable NSCLC received a combination of Gemcitabine 1000 mg/m’ i.v. weekly x 3 every 4 weeks as a X-hour infusion and Vindesine 3mg/mz i.v. bolus weekly x 7, then biweekly. pts. characteristics: Median age 53years (range 37-&?), 11 males/21 females, median performance status 1 (range O-2), 17 adenocarcinomas/l 0 squamous cell carcinomas/4 large cell carcinomas/i poorly differentiated NSCLC. Toxicity: Leucopenia WHO grade 3-4 (4 pts., 13%), thrombocytopenia grade 3-4 (3 pts., 9%), liver toxicity grade 2 (15 pts., 47%), grade 3 (4 pts., 13%), grade 4 (0 pts.). Ten pts. (31%) had a grade 3-4 hematologic or liver toxicity. Three pts. (9%) had an acute decrease in ventilation capacity with a peak-flow reduction of more than 50% within 2 hours after drug infusion compared to pre-infusion level. The peak-flow alteration caused hospitalization in 2 pts. but were uniformly reversible. Four pts. (13%) developed renal toxicity with glomerular filtration rates below normal limits, which was reversible in 3 pts. while 1 pt. developed irreversible renal insufficiency. Among 30 pts. evaluable for response there were 7 partial and 1 complete remissions (response rate 27%, 95% confidence limits (12%- 46%). This is similar to the activity obtained by either drug as a single agent. In conclusion the combination of Gemcitabine + Vindesine in the applied doses and schedules was not more active than either drug as single agent.

443

High-do** tsmoxif." in colbinstion with cisp1sti” in non- small cell Lug cancer (NSCLC)! Phae. I trill snd phsrmscokinetic seslysie. Perez EA. Gsndsrs DR, Webber L.M, Edelma" X.7, and DeGregorio MU. university of Cslifor"is, Davis, Sacramento, CP. 95817 and University of Texas, Health Sciences Center. San Antonio. TX 78284.

Recent studie. support the uee of tamoxife” (TAH) in combination with traditional cytotoxic agents for s variety of malig"a"ciea. Preclinicsl studies (Hoffman, 1988, WcClsy, 1993) demonstrate that TAM cs" enhance the activity of cieulsti" ICDDP) at concentrations > 1uH. We conducted s etuciy of e&A&ing high-dose TAM in &abinstion with CDDP in order to determine TAM phsrmscokinetics and marlmum tolerated dose (I4TD). TAM was administered days 1-7 at 16Omg/d (n-5) and 2OOmg/m* (n-6) per day followed by CDDP st lOOmg/m' on day 8. Eleven patients with advanced NSCLC received 15 cycle8 and 20 cycles of treatment at 160mg/m2 and ZOOmg/m' TAM, respectively. Pharmscokinetic s"alysis of TAM by HPLC shows plasma levela of 4.5-S.2@ on day 7 in 5 patients tested to date. TAW MTD analysis: grade 314 non-hemstologic toxicity occurred in Of5 and l/6 patients at the 160mg/d and 2OOmg/m' doee levale, respectively. There have bee" no grade 4 hemstologic toxicities. TO date, TAM MTD hse not bee" reached. We plan continued dose eecslstion of TAN at 25Omg/m' to optimize plssms levels. One patient wse ineligible due to staging error, and 1 patient never received protocol treatment. I" 9 sssesssble patients, 3 partial responses were observed. Co"~lueio"~: 1) TAM levels predicted to enhance CDDP eeneitivity i" vitro are clinically achievable with scceptsble toxicity. 2) Preliminary activity in NSCLC is encouraging. A phaee II atudy in NSCLC is planned.

PEASE I STUDY OF GRMCITABINR (GEM) AM) CISPWTIN (CP) FOR ADVANCFJI NON-SMALL CELL LUNG CANCER (NSCLC). F. Shepherd, Y. tinnier, R. Burkes, M. Camp, R. Feld, T. Strack. The University of Toronto, Toronto, and U”iversite Lava& Quebec City, Canada

Single-agent GEM, 1250 mp/m' weekly x 3 is active against NSCLC, and induces respoose in up to 20% of untreated patients (Proc ASCO 12: 330, 1993). This study was undertaken to determine the maximum tolerated doses for a four week cycle of GEM and CP administered weekly x 3 with a one week rest period.

Patients < tha”75yearsofagewereeligibleiftheyhadstageIIyIVbiopsy proven NSCLC, life expectancy 2 12 weeks, adequate hematology (Hgb 2 10 g/dl, gmnulocytes 2 2 x lop/L, platelets 2 100 x lop/L), adequate hepatic and renal function (AST and ALT ( 3 x “onnal, and creatiaine 5 130 mmol/L). The starting doses of GEM and CP WEX~ 1000 mg/m* and 25 Is/m3*eek x 3. At dose level 2 only the CP was increased to 30 mg/m’/week x 3, and thereafter dose escalations were made only for GEM.

To date, 25 patients (24 eligible) have entered the study. There were 17 males and 7 females, median age 63 years (range 43 - 74). Pathology included: adenocarcinoma-16 patients; squamous-4 patients; large cell-3 patients; mixed-l oatient. Seven oatients had stage III and 17 “atients had stare IV tumors.

-3/4 . ’ . 3,4 3,4 3,4 lcm 25 w26 tn 2P o 0 4/6 loo0 M 6no 14 uo 0 0 3/6 1250 30 7ll in 1x1 0 0 TooEarly 15w 30 s- TaoEvlv TooEarh There were no other WHO grade 3 or 4 “on-hematoloaicto~~ties. and since dose-liking toxicity has not bee” reached, study entry continues. The prelkninary response data suggest that GEM and CP is an active regimen against NSCLC. It is well tolerated, and deserves further study in comparison with other chemotherapy combinations. Supported by Eli Lilly, Canada.

444

Ifosfam~de(IFO)+V~norelbine(VRL )as Treatment for advanced, non operaple Non Small Cell Lung Canser (NSCLC) J.v.Pawet ,M.Schroeder,J2Grote-Klehn ,S.Kerpel-Fron,us3, P.Tresca ,M.Westerhausen .

Zentralkrankenhauy Gaut,ng,‘Med.Klinlk II,St.Johaunes- Hospltal,Dulsburg, Farmltalla Carlo Erba,Frelburg, Pierre Fabre Medlcament,Parls. We report a Phase II study of a romblnatlon therapy of Vlnorelbine(Navelblne),a new semi-synthetic Vlnca-Alkaloid and Ifosfamlde, both effective in NSCLC. To date 40 Pts entered the study.Age (modIan): years, sex(M/F):30/10; Performance Status:WHO 0 13 Pts(33?;), WHO 1 27 Pts(67X); Stage:IIIAZ patients (X),IIIB 10 Pts(35X),IV28Pts(625);Cell Type:AdenoCa.EO, SCC 15, LCC 3, MlxFd 1, no speclflcatlonl; Treatment schedule: VRL 20 mg/y dl and 5

IF0 1500 mg/m dl-5, every 4 weeks. From the 40 Pts enrolled 3 are too early to be evaluable, 3 refused treatment, 2 were removed due to severe toxlclty, and 3 Pts died early wlthin 4 weeks.In one case protocol vlolatlon was observed,furthermore 3 early tumor pregres- s~ons were observed. In 28 Pts who completed at least ‘2 cycles the followng results were noted. Complete remission O/28 Partial rem,ss1on 7/28 (25X) No change 7/28 (29%) Progressive Disease lo/28 (36%) Complete data on myelotox>city lncludlng haematologlc con- trol at days lo-12 are available for 39Pts at present.WHO grade 3 and 4 leucopen~a was present I” 41 and 36% of Pts, granulacytopenic fever was observed in 10 X of cases.The regeneration of WBC was completed irrespertlve of the nadir value by day 28 in all cases. Thrombocytopenla WHO grade 3 occurred ,n 3X.Perlpheral neurotox?clty was weak:14 neuro- toxlclty grade 1 and 2 was seen I" 26 and 6% of cases. CNS toxlcrty grade 3 was noted in 1 patlent.