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CDDP (P), 5FU (F), leucovorin (L) and VP16 (PFL-VP16) in advanced non small cell lung cancer (NSCLC)
126 481
482
A PHASE I TRIAL OF COMBINATION CHEMOTHERAPY WITH IRINOTECAN(CPT-II), CISPLATIN AND VINDESINE IN ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) N.Nomura. T.Shiokai, T.Yajima. M.Aodoh. JShiraishi, N.Yamamoto, M.Fukuda. H.Arioka, F.Oshita, Y.Ohe, T.Tamura. K.Eguchi, NSaijo National Cancer Center.Tokyo. Japan. In order to evaluate the potential benefit of the additioo of Cm-11 to cisplatin and vindesioe, we conducted two combination phase I studies with high-dose cisplatin (100mg/m2 : 1st trial) and low-dose cisplatin(6Omg/m2 : 2nd trial) in patients @ts) with advanced NSCLC. Sixteen sod 25 pts have been accrued. respectively. CPT-11 was given on days 188 in combination with cisplatin (dl) and vindesine (3mg&Z dl&8). In the fust study, the starting dose of CPT-11 was 2Smgfm2 and the dose was escalated in incremenu of 12Smg/m2. In the second study, the starting dose was 2Omg/m2 and the escalated dose was ZOmg/mZ at each level. The dose limiting toxicities were gmmdocytopxia and diarrhea In the combination of CPT-11, cisplatin and vindesine. the recommended doses of CPT-11 mmbined with high- and low-dose cisplatin for phase IJ trial were 3l.SmgIto2 and 8Omglm2 on days l&8. respectively.
PHASE II STUDIES OF TOPOTECAN IN PATIENTS WITH NON-SMALL CELL LUNG CANCER (NSCLC) PREVIOUSLY UNTREATED AND PATIENTS WITH SMALL CELL LUNG (SCLC) CANCER REFRACTORY TO ETOPOSIDE. R. Perez-Soler, B.S. Glisson, J. Kane, J.S. Lee, J. Lee, M.N. Raber, W.K. Hong. M.D. Anderson Cancer Center, Houston, TX 77030 Topotecau is a hydrosoluble semisynthetic analogue of the topoisomerase I inhibitor camptothecin that has shown activity in NSCLC in Phase I studies and in untreated SCLC in Phase II studies. Phase II clinical trials of Topotecan in pts with metastatic NSCLC previously untreated and pts with SCLC refractory to etoposide are in progress. Topotecan is administered i.v. as a 30 min daily infusion for 5 consecutive days at a dose of 1.5 mg/ma/day (NSCLC) or 1.25 mg/mVday (SCLC). Thirty seven pts (NSCLC) and 16 pts (SCLC) are evaluable for response and toxicity. In the NSCLC study, 5 pts have achieved a partial remission (PR) (overal response rate 13.5%. duration 2,12+, 6,5+, and 2+ months) and 3 pts (8%) a minor responseThe difference in PR rate between squamous and adenoca pts is statistically significant (4/l 1 vs l/17, p= 0.04). In the SCLC study, 3 pts have achieved a PR (19% duration 1.2, and +2 months) and 1 pt (6%) a minor response. Grade 3 or 4 toxicities have been limited to myelosuppression (grade 3 or 4 granulocytopenia in 81% of cycles, grade 3 or 4 thrombocytopenia in 13% of cycles) lasting <7 days in most cases. No toxic deaths or withdrawals due to toxicity have occurted. Other toxicities include alopecia in all pts and grade 1 or 2 nausea and vomiting in about 50% of patients. The results indicate that Topotecan 1) is easily tolerated, 2) has moderate activity in previously untreated NSCLC pts, squamous ca pts being most sensitive, and 3) has definite activity in SCLC pts that are refractory to the topoisomerase II active drug etoposide.
Dose mghnl
No. of pts/ courses
m-11
cisplatin
First trial 25 loo 37.5 100 so 100 Second trial 20 60 40 60 60 60 80 60 100 60
6/l 1 Ill3 3r3 319 3113 3l7 llR2 519
ECOG toxicity No. of pts Graoulocyte Diarrhea 4 >3 4(l) 5(l) 2(l) 2 1 2 8(2) 4(2)
No. of response(PR)
/evaluablepts Liver 3
2 1 3
0 1 0
0 0 0 2 2
0 0 0 1 1
3/s 2l6 Ox)
l/3 2l3 l/3 4/a 1n ( ) : No. of pts with grade 4 graoulocytopenia lasting for? 7 days
483
484
CDDP (P), 5FU (F), LEUCOVORIN (L) AND VP16 (PFL*VPl6) IN ADVANCED NON SMALL CELL LUNG CANCER (NSCLC). 0. Rixe*, B. Maim?, T. Petit*, , B. Orcel”, A. Benbammouda*, Ch. Borel*, M. Weil*, JP. Derenne’. D. Khayat*. I*1 \ , SOMPS. --~~~ CD)Service de F’neumoloeie,Hooiral de la Saloe!ri&e, Paris, France, Recent St&s (V&SEE a 01, Ann 6ncoL i. 727,19921h&e shown higher response rate (RR) for PFL compared to PF. We aimed this phase 11 trial at studying the feasability and the benefit of the adding of VP16 to PFL regimen in inoperable NSCLC. 18 patients were treated by this combination including CDDP 100 mg/m2 day 1. 5FU 5M) mg/m%y and to L 500 mg/m?iday by continous infusion days 1-4. VP16 70 mglm?lday, days 1-t. Cycles were administrated every 21 days.
PACLITAXEL
Numberof
patients Medianage Sex (M/F) ECCC (PS)
Slal”PMB IV r
I
180s waluabla. s tm CdyIY) 58 (48-72) 15/3
1(O-2) 4 14
Histology ndenocarcinoma SCpC?“O”S
mixed Mediannumberof metasIaticsite Toxicity grade III-IV : Anemia
7 6
PR
3
SD PD Median Response
I(7%) 3(21%) 4
I I 14Q8%)
6 8 months
Sculier M.D., Department of Medicine, Institut Jules Bordet, Universiti Libre de Bnuelles. 1 roe H&w-Boxlet 1000 Broxelles, Belgium. P was admini;ered as a continuous infusion over 3 hours; C was administered after P. as a 30 minutes infusion. with hvoerhydration. The patients were under constant c&ii monitoring and were prwne~iteh with dexame&e, pmmedwioe and cimetidine. Antiemetics consisted of metaclopramide, dexametbasone and 10raZepam. At the first level (P 135 mg/m2 and C 100 mg/m2) no toxicity was observed among the 3 treated patients, except for moderate alopecia and mild nausea and/or vomiting. At the next steps (7 patients), toxicities that have been observed so far are indicated in the following table : Cisplatin (100 mg/m2) + Taxol(170 7 8 9 10 4 5 6 Neanopenia 0,7 3,1 2,2 0,s 1,6 1.9 0,8 nadir (mm3xlooo) 8 10 17 11 14 14 15 nadir (dav) . lhIOlllbocytOpenia
2 2 (l-4) 7
Ck
(P) PLUS CISPLATIN (C) IN NON SMALL CELL LUNG CANCER : A DOSE FINDING STUDY. J. Klastersky, M.D., J.P.
I
We conclude that this regimen can be administrated safely and have shown some activity in NSCLC (specialy in squamous cell carcinoma). However, VP 16 does not seem to increase RR compare to the classical PFL combination (29 % RR).
nadir (mm3xlooo) 233 11 nadir (day) Highest toxicity (WHOgrade) 3 dOpecia 1 nausea-vomiting 0 renal neurological : hypersensitivity 0 mucositis 0 caldix 0 infection 1 bypotension 0 diaobea
272 14
117 10
111 10
383 312 1 10
195 7
An objective response was seen in 5 out of 10 patients: one patient died.
482
A PHASE I TRIAL OF COMBINATION CHEMOTHERAPY WITH IRINOTECAN(CPT-II), CISPLATIN AND VINDESINE IN ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) N.Nomura. T.Shiokai, T.Yajima. M.Aodoh. JShiraishi, N.Yamamoto, M.Fukuda. H.Arioka, F.Oshita, Y.Ohe, T.Tamura. K.Eguchi, NSaijo National Cancer Center.Tokyo. Japan. In order to evaluate the potential benefit of the additioo of Cm-11 to cisplatin and vindesioe, we conducted two combination phase I studies with high-dose cisplatin (100mg/m2 : 1st trial) and low-dose cisplatin(6Omg/m2 : 2nd trial) in patients @ts) with advanced NSCLC. Sixteen sod 25 pts have been accrued. respectively. CPT-11 was given on days 188 in combination with cisplatin (dl) and vindesine (3mg&Z dl&8). In the fust study, the starting dose of CPT-11 was 2Smgfm2 and the dose was escalated in incremenu of 12Smg/m2. In the second study, the starting dose was 2Omg/m2 and the escalated dose was ZOmg/mZ at each level. The dose limiting toxicities were gmmdocytopxia and diarrhea In the combination of CPT-11, cisplatin and vindesine. the recommended doses of CPT-11 mmbined with high- and low-dose cisplatin for phase IJ trial were 3l.SmgIto2 and 8Omglm2 on days l&8. respectively.
PHASE II STUDIES OF TOPOTECAN IN PATIENTS WITH NON-SMALL CELL LUNG CANCER (NSCLC) PREVIOUSLY UNTREATED AND PATIENTS WITH SMALL CELL LUNG (SCLC) CANCER REFRACTORY TO ETOPOSIDE. R. Perez-Soler, B.S. Glisson, J. Kane, J.S. Lee, J. Lee, M.N. Raber, W.K. Hong. M.D. Anderson Cancer Center, Houston, TX 77030 Topotecau is a hydrosoluble semisynthetic analogue of the topoisomerase I inhibitor camptothecin that has shown activity in NSCLC in Phase I studies and in untreated SCLC in Phase II studies. Phase II clinical trials of Topotecan in pts with metastatic NSCLC previously untreated and pts with SCLC refractory to etoposide are in progress. Topotecan is administered i.v. as a 30 min daily infusion for 5 consecutive days at a dose of 1.5 mg/ma/day (NSCLC) or 1.25 mg/mVday (SCLC). Thirty seven pts (NSCLC) and 16 pts (SCLC) are evaluable for response and toxicity. In the NSCLC study, 5 pts have achieved a partial remission (PR) (overal response rate 13.5%. duration 2,12+, 6,5+, and 2+ months) and 3 pts (8%) a minor responseThe difference in PR rate between squamous and adenoca pts is statistically significant (4/l 1 vs l/17, p= 0.04). In the SCLC study, 3 pts have achieved a PR (19% duration 1.2, and +2 months) and 1 pt (6%) a minor response. Grade 3 or 4 toxicities have been limited to myelosuppression (grade 3 or 4 granulocytopenia in 81% of cycles, grade 3 or 4 thrombocytopenia in 13% of cycles) lasting <7 days in most cases. No toxic deaths or withdrawals due to toxicity have occurted. Other toxicities include alopecia in all pts and grade 1 or 2 nausea and vomiting in about 50% of patients. The results indicate that Topotecan 1) is easily tolerated, 2) has moderate activity in previously untreated NSCLC pts, squamous ca pts being most sensitive, and 3) has definite activity in SCLC pts that are refractory to the topoisomerase II active drug etoposide.
Dose mghnl
No. of pts/ courses
m-11
cisplatin
First trial 25 loo 37.5 100 so 100 Second trial 20 60 40 60 60 60 80 60 100 60
6/l 1 Ill3 3r3 319 3113 3l7 llR2 519
ECOG toxicity No. of pts Graoulocyte Diarrhea 4 >3 4(l) 5(l) 2(l) 2 1 2 8(2) 4(2)
No. of response(PR)
/evaluablepts Liver 3
2 1 3
0 1 0
0 0 0 2 2
0 0 0 1 1
3/s 2l6 Ox)
l/3 2l3 l/3 4/a 1n ( ) : No. of pts with grade 4 graoulocytopenia lasting for? 7 days
483
484
CDDP (P), 5FU (F), LEUCOVORIN (L) AND VP16 (PFL*VPl6) IN ADVANCED NON SMALL CELL LUNG CANCER (NSCLC). 0. Rixe*, B. Maim?, T. Petit*, , B. Orcel”, A. Benbammouda*, Ch. Borel*, M. Weil*, JP. Derenne’. D. Khayat*. I*1 \ , SOMPS. --~~~ CD)Service de F’neumoloeie,Hooiral de la Saloe!ri&e, Paris, France, Recent St&s (V&SEE a 01, Ann 6ncoL i. 727,19921h&e shown higher response rate (RR) for PFL compared to PF. We aimed this phase 11 trial at studying the feasability and the benefit of the adding of VP16 to PFL regimen in inoperable NSCLC. 18 patients were treated by this combination including CDDP 100 mg/m2 day 1. 5FU 5M) mg/m%y and to L 500 mg/m?iday by continous infusion days 1-4. VP16 70 mglm?lday, days 1-t. Cycles were administrated every 21 days.
PACLITAXEL
Numberof
patients Medianage Sex (M/F) ECCC (PS)
Slal”PMB IV r
I
180s waluabla. s tm CdyIY) 58 (48-72) 15/3
1(O-2) 4 14
Histology ndenocarcinoma SCpC?“O”S
mixed Mediannumberof metasIaticsite Toxicity grade III-IV : Anemia
7 6
PR
3
SD PD Median Response
I(7%) 3(21%) 4
I I 14Q8%)
6 8 months
Sculier M.D., Department of Medicine, Institut Jules Bordet, Universiti Libre de Bnuelles. 1 roe H&w-Boxlet 1000 Broxelles, Belgium. P was admini;ered as a continuous infusion over 3 hours; C was administered after P. as a 30 minutes infusion. with hvoerhydration. The patients were under constant c&ii monitoring and were prwne~iteh with dexame&e, pmmedwioe and cimetidine. Antiemetics consisted of metaclopramide, dexametbasone and 10raZepam. At the first level (P 135 mg/m2 and C 100 mg/m2) no toxicity was observed among the 3 treated patients, except for moderate alopecia and mild nausea and/or vomiting. At the next steps (7 patients), toxicities that have been observed so far are indicated in the following table : Cisplatin (100 mg/m2) + Taxol(170 7 8 9 10 4 5 6 Neanopenia 0,7 3,1 2,2 0,s 1,6 1.9 0,8 nadir (mm3xlooo) 8 10 17 11 14 14 15 nadir (dav) . lhIOlllbocytOpenia
2 2 (l-4) 7
Ck
(P) PLUS CISPLATIN (C) IN NON SMALL CELL LUNG CANCER : A DOSE FINDING STUDY. J. Klastersky, M.D., J.P.
I
We conclude that this regimen can be administrated safely and have shown some activity in NSCLC (specialy in squamous cell carcinoma). However, VP 16 does not seem to increase RR compare to the classical PFL combination (29 % RR).
nadir (mm3xlooo) 233 11 nadir (day) Highest toxicity (WHOgrade) 3 dOpecia 1 nausea-vomiting 0 renal neurological : hypersensitivity 0 mucositis 0 caldix 0 infection 1 bypotension 0 diaobea
272 14
117 10
111 10
383 312 1 10
195 7
An objective response was seen in 5 out of 10 patients: one patient died.