Phase I dose-finding and pharmacokinetic trial of irinotecan (CPT-11) administered every two weeks.

OBJECTIVES: This trial was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of irinotecan (CPT-11) when administered on a once-every-2-week schedule. PATIENTS AND METHODS: CPT-11 was administered to successive cohorts of patients at progressively increasing starting doses ranging from 125 to 350 mg/m2. The MTD and DLTs were determined both for CPT-11 alone and for CPT-11 followed by filgrastim (G-CSF). Plasma samples were obtained during the first 24 hours after initial dosing to determine the total concentrations (lactone + carboxylate forms) of CPT-11; of the active metabolite SN-38; and of SN-38 glucuronide (SN-38G). RESULTS: Neutropenic fever was the DLT for CPT-11 at the 300 mg/m2 dose level. When G-CSF was added, dose escalation beyond 350 mg/m2 could not be achieved due to grade 2-3 toxicities that prevented on-time retreatment with CPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasma concentrations of SN-38 and SN-38G were approximately 2.5% and 4.2% of the corresponding peak plasma concentration for CPT-II, respectively The harmonic mean terminal half-lives for CPT-11, SN-38, and SN-38G were 7.1 hours, 13.4 hours, and 12.7 hours, respectively. No predictive correlation was observed between CPT-11 or SN-38 peak concentration or AUC and first-cycle diarrhea, neutropenia, nausea, or vomiting. Across the range of doses studied, mean CPT-11 clearance was 14.0 +/- 4.0 l/h/m2 and volume of distribution was 146 +/- 45.9 l/m2. CONCLUSIONS: When administered every two weeks, the recommended phase II starting dose of CPT-11 is 250 mg/m2 when given alone and 300 mg/m2 when supported by G-CSF. This every-two-week regimen offers a tolerable and active alternative to weekly or every-three-week single-agent CPT-11 therapy.

A phase I trial of gemcitabine and infusional 5-fluorouracil (5-FU) in patients with refractory solid tumors: Louisiana Oncology Associates protocol no. 1 (LOA-1).

The major purposes of this study were to determine the maximally tolerated dose (MTD), dose-limiting toxicity (DLT), toxicity profile, and antitumor activity of gemcitabine (GEM) (Gemzar) and 5-fluorouracil (5-FU) combination therapy when administered to patients with advanced solid tumors. GEM was administered intravenously over 30 minutes on days 1, 8, and 15, and 5-FU was administered as a continuous intravenous infusion from day 1 through day 15 of each 28-day treatment course. Seventeen patients (13 men and 4 women, median age 57, all previously treated with chemotherapy) were treated with 68 courses at 3 dose levels: 800/200, 1,000/200, and 1,000/300 [GEM (mg/m2/week)/ 5-FU (mg/m2/day)]. Two further patients were not fully evaluable for toxicity; one died from a probable pulmonary embolism, and one refused further treatment after developing grade II mucositis and dermatitis after her day 1 to 7 treatment. At the third dose level, 2 of 4 patients developed grade III mucositis; one also developed grade IV neutropenia with fever and grade III thrombocytopenia. Patient accrual then resumed at the second dose level. At this level, 10 patients were treated, with two developing grade III mucositis. One of these patients also developed grade IV dermatitis. No other patient developed grade III or IV side effects. Prophylactic dexamethasone was initiated after 4 of the first 7 patients (including 1 of the not fully evaluable patients) developed dermatitis-grade IV in 1 patient and grade II in the remaining 3 patients. After the steroids were initiated, 4 of the last 11 patients treated developed dermatitis, but grade 1 in all cases. One patient with metastatic gastric cancer achieved a near-complete response of his gastric mass and adrenal metastasis. Minor responses were achieved in a patient with colon carcinoma and a patient with an ethmoid sinus adenoid cystic carcinoma. The MTD and recommended dose for phase II clinical trials of GEM and 5-FU on the above schedule is 1,000 mg/m2 and 200 mg/m2 respectively, with mucositis as the DLT.

Overview of phase I trials of multitargeted antifolate (MTA, LY231514).

Multitargeted antifolate (MTA, LY231514) is a novel antifolate antimetabolite, with antitumor activity via inhibition of thymidylate synthase, glycinamide formyl transferase, and dihydrofolate reductase. Three dosing schedules have been investigated in the phase I setting: daily x5 every 21 days, weekly x4 every 42 days, and once every 21 days. The maximum tolerated doses on these schedules were 4.0 mg/m2, 30 mg/m2, and 600 mg/m2, respectively. The major dose-limiting toxicity seen on all schedules was neutropenia, with a greater degree of reversible liver biochemistry disturbances observed on the daily x5 schedule. Given that toxicities were manageable and reversible, the antitumor activity exhibited, and the convenience of an every-21-day dosing schedule, this schedule was selected for phase II evaluation.

Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies.

PURPOSE: To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients. PATIENTS AND METHODS: Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m(2)/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses. RESULTS: Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m(2)/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (Cl(S/F)) averaging 1.8 hours and 115 mL/min/m(2), respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in Cl(S/F) was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration( )(median 16 v 9.5 microg/mL, P =. 0084) and area under the concentration-time curve (median 36 v 23 microg-h/mL, P =.0019) values on day 5. CONCLUSION: Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m(2)/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.

A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation.

PURPOSE: To determine toxicities, maximally tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of MTA, a novel antifolate compound which inhibits the enzymes thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR). METHODS: Patients with advanced solid tumors were given MTA intravenously over 10 min every 21 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS: A total of 37 patients (27 males, 10 females, median age 59 years, median performance status 90%) were treated with 132 courses at nine dose levels, ranging from 50 to 700 mg/m(2). The MTD of MTA was 600 mg/m(2), with neutropenia and thrombocytopenia, and cumulative fatigue as the dose-limiting toxicities. Hematologic toxicity correlated with renal function and mild reversible renal dysfunction was observed in multiple patients. Other nonhematologic toxicities observed included mild to moderate fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase elevations. Three patients expired due to drug-related complications. Pharmacokinetic analysis during the first course of treatment at the 600 mg/m(2) dose level demonstrated a mean harmonic half-life, maximum plasma concentration (Cpmax), clearance (CL), area under the curve (AUC), and apparent volume of distribution at steady state (Vdss) of 3.08 h, 137 microg/ml, 40.0 ml/min per m(2), 266 microg. h/ml, and 7.0 l/m(2), respectively. An average of 78% of the compound was excreted unchanged in the urine. Partial responses were achieved in two patients with advanced pancreatic cancer and in two patients with advanced colorectal cancer. Minor responses were obtained in six patients with advanced colorectal cancer. CONCLUSIONS: The MTD and dose for phase II clinical trials of MTA when administered intravenously over 10 min every 21 days was 600 mg/m(2). MTA is a promising new anticancer agent.

Phase II trial of docetaxel for cholangiocarcinoma.

The authors evaluated the activity and toxicity of docetaxel given as a 1-hour infusion every 21 days in patients with unresectable cholangiocarcinoma. Seventeen patients with cytologically or histologically confirmed cholangiocarcinoma received intravenous docetaxel over 1 hour, repeated every 21 days. The initial dose of docetaxel was 100 mg/m2, with a subsequent 25% dose reduction for patients experiencing grade 3 or 4 toxicities. Treatment was continued until disease progression or occurrence of intolerable side effects. All patients received premedication with dexamethasone 8 mg by mouth twice daily for 5 days, starting 1 day before docetaxel infusion. Sixteen of the 17 patients were assessable for response and toxicity; one patient was removed from the trial for intercurrent illness. Thirty-eight cycles of docetaxel were delivered (median, two cycles). No complete or partial responses were noted. Fourteen patients had progressive disease, one patient had stable disease, and one patient died of septic shock shortly after starting treatment. Granulocytopenia was the dose-limiting toxicity. Thirteen patients had grade 4 granulocytopenia, 11 of whom required antibiotics for neutropenic fever. Granulocytopenia was the only grade 4 toxicity observed. Grade 3 toxicities included stomatitis, anemia, fatigue, vomiting, and hypotension. Grade 1 or 2 toxicities included alopecia, diarrhea, peripheral edema, myalgias, and anorexia. Administered on this dose and schedule, docetaxel lacked activity in patients with cholangiocarcinoma. The toxicity profile, including dose-limiting granulocytopenia, has been previously described in patients receiving docetaxel.

Phase I trial of paclitaxel and gemcitabine administered every two weeks in patients with refractory solid tumors.

PURPOSE: Paclitaxel and gemcitabine possess broad spectra of clinical activity, distinct mechanisms of cytotoxicity, and are differentially affected by mutations in cell-cycle regulatory proteins, such as bcl-2. This phase I trial was designed to identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of paclitaxel and gemcitabine when both drugs were given together on a once-every-two-week schedule in patients with solid tumors. PATIENTS AND METHODS: A total of 37 patients were treated at nine different dose levels ranging from paclitaxel 75-175 mg/m2 administered over three hours followed by gemcitabinc 1500-3500 mg/m2 administered over 30-60 minutes. Both drugs were administered on day 1 of a 14-day cycle. Dose escalation was performed in a stepwise manner in which the dose of one drug was escalated while the dose of the other drug was kept constant. RESULTS: Dose limiting toxicity (DLT) was observed at dose level 9: paclitaxel 175 mg/m2 and gemcitabine 3500 mg/m2 in the form of grade 4 neutropenia lasting for > or = 5 days (one patient) and grade 3 elevation of alanine aminotransferase (AST/SGPT) (one patient). An analysis of delivered dose intensity (DI) over the first three cycles revealed that higher dosages of both drugs were delivered at dose level 7, paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2 dose level, than at the MTD, dose level 8, paclitaxel 150 mg/m2 and gemcitabine 3500 mg/m2. Partial responses were confirmed in two patients with transitional cell carcinoma (one of the bladder, one of the renal pelvis) and in one patient with adenocarcinoma of unknown primary. CONCLUSIONS: Paclitaxel and gemcitabine is a promising drug combination that can be administered safely and repetitively on an every-other-week schedule. Using this drug administration schedule, the recommended phase II dose is paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2.

A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea.

Despite the widespread usage of hydroxyurea in the treatment of both malignant and nonmalignant diseases and a recent expansion in the recognition of its potential therapeutic applications, there have been few detailed studies of hydroxyurea's pharmacokinetic (PK) behavior and oral bioavailability. Parenteral administration schedules have been evaluated because of concerns about the possibility for significant interindividual variability in the PK behavior and bioavailability of hydroxyurea after oral administration. In this PK and bioavailability study, 29 patients with advanced solid malignancies were randomized to treatment with 2, 000 mg hydroxyurea administered either orally or as a 30-minute intravenous (IV) infusion accompanied by extensive plasma and urine sampling for PK studies. After 3 weeks of treatment with hydroxyurea (80 mg/kg orally every 3 days followed by a 1-week washout period), patients were crossed over to the alternate route of administration, at which time extensive PK studies were repeated. Three days later, patients continued treatment with 80 mg/kg hydroxyurea orally every 3 days for 3 weeks, followed by a 1-week rest period. Thereafter, 80 mg/kg hydroxyurea was administered orally every 3 days. Twenty-two of 29 patients had extensive plasma and urine sampling performed after treatment with both oral and IV hydroxyurea. Oral bioavailability (F) averaged 108%. Moreover, interindividual variability in F was low, as indicated by 19 of 22 individual F values within a narrow range of 85% to 127% and a modest coefficient of variation of 17%. The time in which maximum plasma concentrations (Cmax) were achieved averaged 1.22 hours with an average lag time of 0.22 hours after oral administration. Except for Cmax, which was 19. 5% higher after IV drug administration, the PK profiles of oral and IV hydroxyurea were very similar. The plasma disposition of hydroxyurea was well described by a linear two-compartment model. The initial harmonic mean half-lives for oral and IV hydroxyurea were 1.78 and 0.63 hours, respectively, and the harmonic mean terminal half-lives were 3.32 and 3.39 hours, respectively. For IV hydroxyurea, systemic clearance averaged 76.16 mL/min/m2 and the mean volume of distribution at steady-state was 19.71 L/m2, whereas Cloral/F and Voral/F averaged 73.16 mL/min/m2 and 19.65 L/m2, respectively, after oral administration. The percentage of the administered dose of hydroxyurea that was excreted unchanged into the urine was nearly identical after oral and IV administration-36. 84% and 35.82%, respectively. Additionally, the acute toxic effects of hydroxyurea after treatment on both routes were similar. Relationships between pertinent PK parameters and the principal toxicity, neutropenia, were sought, but no pharmacodynamic relationships were evident. From PK, bioavailability, and toxicologic standpoints, these results indicate that there are no clear advantages for administering hydroxyurea by the IV route except in situations when oral administration is not possible and/or in the case of severe gastrointestinal impairment.

A randomized phase I study of oral etoposide with or without granulocyte-macrophage colony-stimulating factor for the treatment of patients with advanced cancer.

The purpose of this study was to evaluate the feasibility of chronic oral administration of etoposide with granulocyte-macrophage colony-stimulating factor (GM-CSF) [sargramostim (Immunex)] coadministration or premedication; to estimate and compare the frequency of toxicities accompanying etoposide administration alone, etoposide/GM-CSF coadministration and etoposide with GM-CSF premedication. Thirty-nine patients with advanced treatment-refractory malignancies were enrolled to this study. Eligible patients were randomized to one of three treatment arms: daily oral etoposide alone for 21 days (arm A); daily oral etoposide for 21 days with GM-CSF, 250 micrograms/m2, s.c. twice daily for the first 10 days of etoposide administration (arm B); or daily oral etoposide for 21 days with GM-CSF twice daily for the sixth through second days preceding etoposide administration (arm C). Courses of treatment were repeated every 28 days. Etoposide dosages for each arm were 25, 50, 75 and 100 mg/m2/day. At least three patients were treated at each dosage level until dose-limiting toxicity was observed. Patients had twice weekly blood counts and weekly clinical examinations to assess toxicity. Patients with measurable or evaluable evidence of cancer were assessed for antitumor response after every other course of therapy. Nadir neutrophil counts at each dosage level were compared between treatment arms by non-parametric Wilcoxen rank sum tests. GM-CSF coadministration (arm B) or premedication (arm C) with daily chronic oral etoposide was feasible and did not lead to excessive hematological toxicity. Pairwise comparisons of neutrophil nadirs for the first course of therapy for each treatment arm did not demonstrate any significant differences and, at most, a slight trend favoring improved neutrophil nadirs was shown for arm C compared to arm A (p = 0.07). Dose intensity as measured by mean days of etoposide administered per patient for each arm suggested only slight improvement in etoposide tolerance for treatment arms B and C. The conclusion, GM-CSF can be safely administered to patients receiving chronic daily oral etoposide. It appears that GM-CSF provides no clinically useful improvement in granulocyte tolerance of therapy.

Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer.

PURPOSE: To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS: Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response. RESULTS: One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case. CONCLUSION: Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.

Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.

PURPOSE: To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. PATIENTS AND METHODS: Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS: Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer. CONCLUSION: The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.

Phase I and pharmacokinetic studies of topotecan administered as a 72 or 120 h continuous infusion.

Topotecan (SK&F 104864-A, NSC 609699) is a water-soluble, semi-synthetic analog of camptothecin which is an inhibitor of topoisomerase I. Since topoisomerase I is cell specific for S phase, we undertook a phase I study to determine the maximum tolerated dose and toxicities of continuous infusion (CI) topotecan. This phase I trial first explored a 5 day CI every 21 day schedule. Doses of topotecan included 0.17, 0.34 and 0.68 mg/m2/day. Fourteen patients [median age 60; median performance status (PS) of 1] with refractory malignancies received 59 courses of drug. Hematologic toxicities occurred only at the highest dose level; NCI grade 3-4 granulocytopenia and thrombocytopenia occurred in 4/8 and 3/8 patients, respectively. The protocol was amended to a 3 day infusion in an effort to ameliorate toxicity and obtain greater dose intensity (DI). Doses of 0.68, 0.85, 1.05, 1.3 and 1.6 mg/m2/day were evaluated. Thirty-two patients (median age 60; median PS of 1) received a total of 115 courses. The major toxicity seen was hematologic with 9/32 and 5/32 patients demonstrating grade 3-4 granulocytopenia and thrombocytopenia, respectively. Non-hematologic toxicities were mild (grade 1-2) in the two schedules and included nausea, vomiting, fatigue and alopecia. At the maximum tolerated dose (MTD) on the 5 day schedule, patients received 0.87 mg/m2/week, whereas they received 1.08 mg/m2/week at the MTD on the 3 day schedule (24% increase in relative dose intensity). A steady-state plasma lactone concentration of 5.5 mg/ml of topotecan was achieved at the phase II recommended dose of 1.6 ng/m2/day as a 3 day continuous infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized phase I trial of chronic oral etoposide with or without granulocyte-macrophage colony-stimulating factor in patients with advanced malignancies.

Data from an in vitro human tumor-cloning assay suggested synergistic cytotoxicity when etoposide (VP16) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined. To explore this potential, we undertook a prospectively randomized three-arm trial in a phase I setting with various schedules of VP16 and GM-CSF. Thirty-one patients were enrolled in the three-arm trial. Arm A consisted of oral VP16 daily for up to 21 days with cycles repeated every 35 days. Arm B included oral VP16 daily for up to 21 days plus concomitant GM-CSF at 5 micrograms/kg/day s.c. days 1-10. Arm C included oral VP16 daily for up to 21 days plus pretreatment with GM-CSF at the same dose for 5 days (days -6 to -2). VP16 was begun at 25 mg/m2/day on level 1 and increased to 50 mg/m2/day on level 2. Twenty-seven patients were evaluable for toxicity, nine on each arm (six patients on each arm on level 1, three patients on each arm on level 2). Neutropenia on arm B (concomitant VP16 and GM-CSF) was earlier and more profound than on arm A or C. The median absolute neutrophil count and day of nadir for arms A, B, and C were 3295, 988, and 1600/mm3 and days 23, 15, and 26, respectively. Thrombocytopenia was generally uncommon except on arm C level 2, where the median platelet count was 26,000/mm3. One partial response (arm B) in a patient with non-small cell lung cancer was seen. Dose intensity favored arm A. Neither concomitant therapy with VP16 and GM-CSF (arm B) nor pretreatment with GM-CSF (arm C) improved dose intensity over VP16 alone (arm A), and arms B and C were complicated by increased neutropenia and thrombocytopenia.

Phase II study of 13-cis-retinoic acid and interferon-alpha 2a in patients with advanced squamous cell lung cancer.

The combination of interferon (IFN)-alpha 2a and 13-cis-retinoic acid (13-cRA) has demonstrated significant antitumor activity in patients with advanced squamous cell cancer of the skin and cervix. We performed a prospective phase II trial of this combination in patients with locally advanced or metastatic squamous cell lung cancer. Twenty-one patients were enrolled on the study. All patients were evaluable for toxicity and 17 were evaluable for response, four with locally advanced and 13 with metastatic disease. One partial response was obtained in a patient with locally advanced disease. Toxicity consisted mainly of constitutional side effects (fatigue, anorexia), which resulted in eight patients coming off-study. The combination of IFN-alpha 2a and 13-cRA is unlikely to exhibit significant clinical activity in patients with metastatic squamous cell lung cancer, but activity in patients with locally advanced disease has not been excluded.