Abstracts/Lung Cancer 10 (1994) 395-430 419

A phase I tritd of ifosfamide, mesna, and cisplatin in advanced non- small cell lung cancer: A cancer sod leukemia group B study Graxiano SL. Hemdon JE. II Richards F. DiFino S, Modeas C, Duggan DB, Green MR. Regional Oncofogy Center, SUNY-Health Science Center. 75OEast&amsSireer. Syracuse, NY13210. Cancer 1993:72:62- 8.

Background. This Phase I study was designed to determine the maximum tolerated dose of ifosfamidemesna with a fixed dose of cisplatia without growth factor or bematopoietic precursor support. Merhodr.Tw~nty-fivepatiratswithprrviouslyuntreatadadvancedaoa- small call lung cancer were treated at four dose levels. Initially, the cisplatin dose was 100 mg/mt given on day I. Seven patients were treated with ifosfamide 2.0 g/m? days 1 to 3, and six patients received ifosfamide 2.5 g/mr days I to 3. Mesoa was given at 20% of tbe ifosfamide dose at 0, 4, and 6 hours after ifosfamide. Cycles were repeated every 4 weeks. Rest&s. Dose-limiting toxicities (myelo- suppression and renal toxicity) were seen at dose level 2 (ifosfamide 2.5 s*/mr). Because 5 of tbe first 13 patients experienced Grade 3 renal foxicity, the study was amended to give cisplatin in divided doses. An additional six patients each were treated at dose level 3 (ifosfamide 2.0 p/mr days 1-3) and dose level 4 (ifosfamide 2.5 g/n? days 1-3) with cisplatia 33 mglnidays 1 to 3. Dose-limiting toxicity (myelosuppression) was reached at ifosfamide 2.5 g/3. No further Grade 3 renal toxicity was seen. Grade 3 or worse toxicities were seen as follows: neutropenia 80%. tbrombocytopenia 48%. nausea/vomiting 3646, anemia 32X, renal 20%. central nervoussystem 16%, and infection 16%. Two toxic deaths occurred. both with infection, renal failure. and aeutropeaia. Partial responseswereseeain8of25 dgiblepatirats(32Sb). Conch~ionr. The maximum tolerated dose in this group of patients was detincd as ifosfamide 2.0 g/mr days 1 to 3 when given with cisplatin 33 mg/mz days 1 to 3. When combining high-dose cisplatia with ifosfamide, it is advisable to give cisplatia in divided doses.

Interferon-a and interferon-gamma combined with chemothempy: In vitro sensitivity studies in non-small cell lung cancer ceil lines HandA,PelinK.HaImeM,EkmanA. MattsoaM, VallasMatal. Dept. Industrial Hygiene/Toxicology, Institute of Occupational Health. Topeliuksenkatu41aA.00250Helsinki. Anti-CancerDrugs 1993:4:365- 8.

Non-small cell lung cancer (NSCLC) are often resistant to chemotherapy. Cisplatin has shown the most activity against all the histological subtypes and is now used in most combined treatment programmes. Interferon (IFN)a has been shown to potentiate cisplatin and other dNQS experimentally and in clinical trials involving NSCLC. We are looking at the responses of different NSCLC cell lines to cisplatia (P), etoposide (VP-16) and IFN [recombinant human IFN-aZc (IFNu) and IFN-gamma lb (IFN-gamma)], individually and in combination. We tbeacomparetbe resultswith thosefromaclinical trial of etoposide and cisplatia with interferon in advanced NSCLC. We report bare the results tiom tbe first of our cell lines, established from a large cell anaplastic carcinoma. We have confirmed earlier fmdiigs that NSCLC cell lines are not sensitive to either IFNu or IFN-gamma alone. However a combination of 1FN-a and IFN-gamma does reduce cell proliferation in our cell lins. This IFN combination potentiates tbe response of tbe cells to etoposide far more than to cisplatin. There is a trend towards greater activity when a combination of cisplatin and etoposide is used, compared with tbe activity of either drug alone. This effect is further increased by the interferon combination.

Chamcterisation of a vindesinen?sistant human small-cell lung cancer call line Obta S, Nishio K. Kubo S. Nishio M, Ohmori T, Takahashi T et al.

Pharmacology Division, National Cancer Center Research Inst. Tstkji 5-l-l. Chuo-ku. Tohyo 104. Br J Cancer 1993:68:74-9.

We established a vindesioe-resistaot (x 11.6) human small-cell lung cancer cell line (H691VDS) by stepwise exposure of parent line H69 to vindesine. H69NDSshowedcmss-resistancetotaxol (x IO. 1). vincristine (x 6.9) sad colchiae (x 3.4) but not to doxorubicin. cisplatia or etoposide. There was no significant difference in intracellular rH]- vincristiae and doxotubicin accumulation between H69 and H69/VDS cells. Tbahuman auk1 a&h’Awasaotdetectedineitherofthecell lines. These results indicated that H69NDS did not express a typical multidrug resistant phenotype. Addition of 20 M verapamil enhanced the growth inhibitory effect of viadesiae on both H69NDS (x 12.0) sad H69 cells (X 3.8). The amount of total tubulia ia H69NDS cells was lower than that in the H69 parental cells. No significant increase was observed in the amount of total and polymer&d tubulins of H69 cells. In H69/VDS cells, however, vempamil increased the amount of total tubulia to the level of parental cells. but decreased the amount of polymer&d tubulin. Modulation of tubulii may play a role in the resistance to vindesino.

Immunotherapy with inbalesional and systemic interleukin-2 of prtients with non-small-cell lung cancer Scudaletti M, Filaci G, Imm MA, Motta G, Di Gaetano M, Pierri I et al. Dipartimetuo di Medicina Interna, Kale Benederto XV 6. I-l 6132 Geneva. Cancer Immtmol Immunother 1993;37: 119-24.

Eightpatientsaffectsbynon-smalI~l1 lungcancerweretreatedwitb intralesionalandsystemicrecombmant II-2(rII-2)injectionwiththeaim of activating both tumour-infihrating lymphocytes and circulating cytotoxic or killer cells. The schedule of treatment was as follows: a daily line-needle tmnsparietal intr&sioaaI rIL-2 injection (1 x IoS Cetus units) from day I to day 5 and systemic rIL-2 infusion (I x lb Cents units kg“ day-‘) from day 6 to day IO. One to four cycles of treatment were received by each patient. Clinical and immunological evaluations were performed (a) before treatment, (b) following the intralesioaal rIL-2 administration (c) 1 b after the beginning of dL-2 infusion and (d) at the end of tbe systemic rIL-2 infusion. No complete remission was achieved, two patients showed a partial remission, three resulted in stable disease and three patients progressed. Natural killer and lymphokine-activated killer cell activity dramatically decreased 1 h after the beginning of rIL-2 infusion and increased at the and of treatment. A progressive increase of circulating CD8 and HLA class IF T cells as well as of CD8’ T cell clones, most of which displayed NK activity was recorded following rIL-2 infusion. Present data indicate that (a) the local administration of rIL-2 coupled with systemic rIL-2 infusion may be suggested as an alternative approach for the immunotherapy of lung cancer, (b) rlL-2 inducesdifferent immunological modifications according to the mute and the time of its administration and(c) rIL-2 administration increases &amount of circulating immune cells with potential antitumour activity.

Phase I5 study of sulofenttr (L.Y 186641): A novel nntineoplnstic agent in advanced non-stnall cell lung cancer Munshi NC, Seitx DE, Fosaella F, Lippman SM. E~D~ON LH. Section oJHematology/Oncology, Arknsas Uttiwrsiry Muiical Sciences, 4301 Whfarkham. LinleRockAR 72205. Invest New Drugs 1993;11:87-90.

Sulofenur is a member of a new class of antineoplastic agents with a novel chemical structure and unique pharmacological and biological properties. Preclinical studies have demonstrated a wide spectrum of antitumor activity against murine solid tumors and human Nmor xenografts. In phase I trials, only mild toxicities went. observed. Twenty-six patients @.a). hvoofwbom were inevaluable, with advanced

this phase II trial. &.s received 800 kg/m sulofenur G Monday-Friday