119

453

CONSECUTIVE PHASE II TRIALS OF DOCETAXEL (TAXOTERE@) 100 MG/M* AND 75 MG/M1 WlTH PREDNISONE IN PATIENTS WlTH STAGE IIIB AND IV NON-SMALL CELL LUNG CANCER JR Riias, VA Miller, PA Francis, KMW Piiters, SC Grant, KJ Wooley, RT Heelan, MG Kris Memorial Sloan-Kettering Cancer Center, New York, NY 10021 USA

Docetaxel, a new hemisynthetic taxoid from the harvestable needles of Tax+ baccsta has demonstrated antitumor responses in non-small cell lung cancer (NSCLC) in phase I trials. Major toxicities noted were leukopenia, infusion related reactions, rash and fluid retention. We conducted two consecutive phase II trials of docetaxel in NSCLC patients (pts). Forty-nine pts with Ill6 or IV NSCLC untreated with chemotherapy received ekher 100 mg/m* of docetaxel without prednisone (n=29) or 75 mg/mZof docetaxel with prednisone (n=20). Five doses of prednisone (50 mg) were given: 2 doses the day before treatment then a daily dose for 3 days. Characteristics: men 29; median age 60; Karnofsky performance status 66-90 (25pts), 66-70 (24pts); stage IV (40pts); adenocarcinoma in 36, large cell and epidermoid in 13; LDH > 200 in 29; weight loss 5 6% in 16; prior irradiation in 11; bone metastases in IO. Prognostic factors were similar for the 2 studies. Preliminary results:

Major Response Leukopenia

klfusiin- Fluid Rash related retention

Dose n (95% Cl) NClgrade z3+ z2+ z2+ Z2+

100 29 38% (21-56) 45% 41% 34% 10%

75 20 25% (9-49) 55% 25% 25% 0%

Conclusions: Docetaxel demonstrates signifllant anttumor activity in NSCLC pts. Leukopenia appears comparable for 75 and 106 mg/m? Infusion-related reactions, rash and fluid retention were seen less commonly at 75 mg/m2 with prednisone. A dose of 100 mg/m* with premeditation is recommended.

455

MULTICENTER, RANDOMIZED TRIALS in 673 COMPARING THE COMBINATION OF EDATREXATE, MITOMYCIN, AND VINBLASTINE (EMV) WITH MITOMYCIN AND VINBLASTINE (MV) IN PATIENTS WITH STAGE III AND IV NON-SMALL CELL LUNG CANCER. R. Comis, MG Kris, JS Lee, RJ Gralla, K Shridhar, J Crawford, G Batist, J Wernz, C Belani, Vokes E, A Einzig, SE Grunberg, J Niedbart, M Blumenreich, H Mau;rer, W Evans, The Edatrexate Study Group, Summit, NJ.

Edatrexate (E) demonstrated activity as a single agent and in combination with MV, a Z-drug regimen effective in NSCLC. These trials, enlisting 673 previously untreated NXLC patients with DPS ~60 % from 30 North American centers, tested whether the addition of E to MV improved survival in individuals with stage III and IV lesions. All

received mitomycin (M) 8 mg/m2 d1,29, and 71 only and vinblastine (V)

4.0 mg/m2 dl, 2 mg/m2 d8, 4.5 mg/m2 d15,22,29, then every 2 weeks. Patients were randomized to either no additional drugs or edatrexate (E)

80 mg/m* d8.80 mg/m* d15.2229 then every 2 weeks. Groups were well- matched for KPS and stage. Results:

Mv EMV ‘P” Entered 334 339 - Median Survival (mo) 7.8 7.5 0.45 1 Year survival 31% 32% 0.91 Time to Progression (mo) 3.7 4.1 0.002 Major Resp RaC 16% 24% 0.016 Grade 3/4 Leukopenia 15% 39% O.cKxll Grade 3/4 Thmmbocytopenia 0.3% 9% O.CQX Grade 3/4 Stomatitis 0.3% 18% O.CKXX Conclusions: 1) Median and l-yr survivals are similar with MV or EMV. 2) Response rates and time to progression were improved by E. 3) Myelosuppression and stomatitis occurred more often with EMV. Significant leukopenia occurred in only 15% with MV; other major toxicities occurred in ~1% of pts. Supported by Ciba-Geigy, Inc.

SCHEDULE OF GRANULOCYTE COLONY STIMULATING FACTOR (G-CSF) IN DOSE INTENSIVE CHEMOTHERAPY WITH CISPLATIN, ETOPOSIDE, MITOMYCIN IN NON-SMALL CELL LUNG CANCER (NSCLC). S. Koinumaru. J. Salto, T. Tsukamoto. Y. Naka. Tohoku Lung Cancer Chemotherapy Group, Sendal, Japan.

In a previous study we obtalned 45% response rate(RR) with a comblnatlon of clsplatln(P). etoposlde (E). mltomycln(M), but due IO profound myelosuppression, time Interval of chemotherapy(CT) often prolonged (Lung Cancer 75, 125, 1991 1,

We conducted a study to determlne the efficacy and optlmal rlmlng of G-CSF(Lenograstlm, Chugal. Tokyo) to improve thera- peutlc result through increasing dose ,ntens,ty (01).

Treatment schedules:CT IS P ZOng/mZ dayl-5, E 6@/m2 dl -5, M 6ng, m’2 dl repeated every 21 days. G-CSF. Zug;kg,‘d 5.c. for 12 days 1s randomly asslgned to start either d6:arm A or d10; arm B. Results. During Feb. ‘92, and June ‘93. fifty four patients<27 for

each arm) of NSCLC with stagellla/b, lV, ECOG PS O-2. no prior treatment were enrolled. Twenty four in arm A, 20 in arm B were

evaluable. Mean values of nadir neutrocytes (ANC ), days to nadlr, days to recovery, dose Intensity (DI) 1.e. mea,, dellvery of the planned dose Intensity, I” first cycle of CT were llsted below along with our hlstortcal control.

day nadir days to days to dose start (N) ANC(/&) nadir recovery lntenslty

G-CSF (6) (24) 2144 1 5. 9 6. 1 0. 85 (10) (20) 2668 14.0 6. 8 0. 85

no G-CSF (23) 562 19. 7 11.9 0. 63

RR was 29% in arm A, 40% $n arm B,all PR. There were no difference between two arms I” regard to hematologlcal and other toxIcltles. 01. RR, and frequency of InfectIons. No ma,or adverse sffects to G-CSF was reported.

Conclusion: G-CSF started d6 or d10 of CT equally reduced the depth and duration of nuetropenla. so afforded 35% dose lntenslflcation over conventlonal CT without G-CSF.

456

VINORBLBINE (NAVELBINB) IN COMBINATION WITH CISPLATIN OR MITOMYCIN: ENHANCING SAFETY, EFFICACY, AND DOSE-INTENSITY. RI Grab, CG lhlhal, MC Gttm, BI Brooks, CN Rittmberg, Gchsner Cancer Institute, New Orleans, LA.

A randmhd study in non-snmll c&l hug cancar (NSCLC) with Navelbine (NVB) given in co&nation with cisplath (DDP) mported avpsriar reapam and ~urvi~sl rates compsred with vindesine+~~~. but hd gf6a tt6ttbpph (hoe ASCO 11:289,1992). We studied mhalule al- with NVB to improve. dose- intmsity while lowering nsutmpmiil. 84 pmviously lmttmkd ptimts fpts) with stage III or IV NSCLC received c.mbhtim of NVB plus either DDP or mitomycin (M). DDPwr9given1(100mglMZon&ys1,29~~avcry6wmLs. Mwrsgiven at 8mg/M’ on the suoe hedule an DDP. NVB wan glvan weekly (days 1,8,15,22, 29)for.5dosesmdthmevery2we&s. AlI5dosclevdsgm.onlyhalfthe&y1 dose of NVB on day 8; levels IV and V ah gave half doses aa day 22. Pt cluuacteristics: md .ge 62; mzd KPS 80; males 65%. Raoltx

NVB DOSE WBC NADIR WITH: TGTAL NVB DGSE GIVEN/MONTH: 1 NVPfmn/M LEVEL m/M’ NVB+M NVB+DDP NVB- ‘+ppE1

I 25 2.4 3.8 110 108 II 30 2.0 1.9 112.5 107

III 35 1.2 2.6 140 134 IV 30 2.4 102 V 35 2.4 2.5 132 129

LevelV(withplnnnedhlfdosesondnys8md22)~~intb.highastdoses adminiti per mm& with 98% done-intmity of M atut of DDP; NVB was given at94%oftheidealdcw.stlevelV. Only3of84pts(4%)Mf&ilensutropenia. 0th toxicities: veaow initaticm 18% of pts; alopecia 10%; pulm tax 8%; thmmbocytope&4%. Major respoasai occurredin37%cmNVB+DDPwithmd survival &imated at 12.4 mrmths; a 34% mspmw rate with aim&d IO-mcathned muvival oamned with NVB+M. We coaclude U; 1) NVB can be safely sdndnistered~~of35mg~waddyxSifhlfdoersuegiv~on&y688 22 (Law1 V); 2) the Level V sckedh delivera 20% to 30% nwm NVB, with less myelosuppression than older NVB combhaiml mgimmls; ami 3) the Level v dose and scheduleisrsmmwhdiafuhlrctrialsiapmviowlyuntmhd ptints, with NVB+DDP or NVB+M. (Suppmted by Bumugbs WeIlmnm Company.)