A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors.

BACKGROUND: To evaluate the toxicity and pharmacological and biological properties of the farnesyl protein transferase (FPTase) inhibitor, tipifarnib (R115777, ZARNESTRAtrade mark) and capecitabine administered for 14 days every 3 weeks. PATIENTS AND METHODS: Patients with advanced cancers received twice daily tipifarnib (100-500 mg) and capecitabine (1000-1125 mg/m(2)) for 14 days every 3 weeks. Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined. Peripheral blood mononuclear cells were analyzed for farnesylation of the HDJ2 chaperone protein and FPTase activity. RESULTS: Forty-one patients received 185 courses of treatment. Diarrhea and palmar-plantar erythrodysesthesia were dose limiting at 300 mg tipifarnib/1125 mg/m(2) capecitabine b.i.d. When the capecitabine dose was fixed at 1000 mg/m(2) b.i.d., neutropenia was dose limiting at 400 and 500 mg b.i.d. of tipifarnib. Capecitabine did not affect the pharmacology of tipifarnib at 100-300 mg b.i.d., although tipifarnib significantly increased the C(max) of 5-FU at 400 mg b.i.d. HDJ2 farnesylation and FPTase activity decreased between 200 and 400 mg b.i.d. doses of tipifarnib, without a dose-response relationship. Five patients demonstrated partial remissions and 11 patients maintained prolonged stable disease. CONCLUSIONS: Tipifarnib and capecitabine are well tolerated at 300 mg/1000 mg/m(2) b.i.d., respectively, resulting in biologically relevant plasma concentrations and antitumor activity. The recommended dose for further disease-focused studies is 300 mg b.i.d. tipifarnib and 1000 mg/m(2) b.i.d. capecitabine, given for 14 days every 3 weeks.

Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer.

PURPOSE: To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer (CRC) in a multicenter, double-blind, prospective randomized study. PATIENTS AND METHODS: Three hundred sixty-eight patients were randomly assigned to R115777 (300 mg twice daily) orally for 21 days every 28 days or placebo in a 2:1 ratio. All patients received best supportive care. The primary end point was overall survival; secondary end points were progression free survival, tumor response, toxicity, and quality of life. RESULTS: The two treatment groups were well balanced for baseline demographics, including previous chemotherapy for advanced CRC. The median overall survival for R115777 was 174 days (95% CI, 157 to 198 days), and 185 days (95% CI, 158 to 238 days) for those patients receiving placebo (P =.376). One patient achieved a partial response in the R115777 arm. Stable disease (> 3 months) was observed in 24.3% patients in the R115777 group compared to 12.8% in the placebo arm. This did not translate into a statistically significant increase in progression-free survival. Overall, treatment was well tolerated. There was an increased incidence of reversible myelosuppression (neutropenia, thrombocytopenia), rash, and grade 1 to 2 diarrhea in the R115777 arm. There was no statistically significant difference in quality of life between arms. CONCLUSION: Single agent R115777, given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.

Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor.

The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of R115777 (continuously or on days 1-14, and repeated every 21 days). In total, 35 patients were entered onto the trial for a median duration of treatment of 43 days (range, 5-224 days). Neutropenia and thrombocytopenia were the dose-limiting toxicities; other side effects were mostly mild. The MTD was established at R115777 300 mg b.i.d. for 14 consecutive days with irinotecan 350 mg x m(-2) given every 3 weeks starting on day 1. Three patients had a partial response and 14 had stable disease. In the continuous schedule, the area under the curves of irinotecan and its active metabolite SN-38 were 20.0% (P=0.004) and 38.0% (P<0.001) increased by R115777, respectively. Intermittent dosing of R115777 at a dose of 300 mg b.i.d. for 14 days every 3 weeks is the recommended dose of R115777 in combination with the recommended single-agent irinotecan dose of 350 mg x m(-2).

Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetics of R115777, a farnesyl transferase inhibitor, when administered continuously via the oral route. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with R115777 using an interpatient dose escalation scheme starting at 50 mg bid. Pharmacokinetics were assessed on days 1, 28, and 56. RESULTS: Twenty-eight patients were entered onto the study and the median duration of treatment was 55 days. The dose-limiting toxicities were myelosuppression and neurotoxicity. At a dose of 400 mg bid, grade 4 leukocytopenia and neutropenia were seen in two of four patients. Neurotoxicity grade 3 developed in one of five patients at 500 mg bid and in one of 13 at 300 mg bid after 8 weeks of treatment. Common nonhematologic toxicities were nausea, vomiting, and fatigue. The recommended dose for phase II/III testing in this scheme is 300 mg bid. The pharmacokinetic studies indicated dose proportionality. Little accumulation occurred and steady-state levels were reached within 2 to 3 days. Analyses of historic tumor material showed that five of 15 of patients had a K-ras mutation in codon 12. Three patients with pancreatic, colon, and cervix carcinomas had stable disease and one patient with a colon carcinoma had a minor response accompanied by a more than 50% decrease in carcinoembryonic antigen tumor marker. A fifth patient, with platinum-refractory non-small-cell lung cancer, showed a partial response that lasted for 5 months. CONCLUSION: Continuous dosing of R115777 is feasible with an acceptable toxicity profile at a dose of 300 mg bid.

Evaluation of the bioequivalence of tablets and capsules containing the novel anticancer agent R115777 (Zarnestra) in patients with advanced solid tumors.

R115777 (Zamestra) is a novel anticancer agent, currently undergoing phase III clinical testing. An open, cross-over trial was performed in 24 patients with solid tumors to compare the bioavailability of a new tablet formulation with the standard capsule formulation. Both dosage forms were administered once daily in doses of 300 or 400 mg. Patients received R115777 as a capsule on day I and as a tablet on day 2, or vice versa. Blood samples were drawn up to 24 hours after drug intake and R115777 levels were measured using a validated high performance liquid chromatography (HPLC) method. The following pharmacokinetic parameters were determined and compared for the two formulations: time to maximal plasma concentration (Tmax), half-life (t 1/2), maximal plasma concentration (Cmax) and area under the curve at twenty-four hours (AUC24h). For the latter two parameters, 90% classical confidence intervals of the ratio tablet/capsule were calculated after a log-transformation, using an Analysis of Variance (ANOVA). For t 1/2 and Tmax, no statistically significant differences were found between tablet and capsule. The point estimates of the ratio's of the log-normalized Cmax and AUC24h were 0.94 and 0.92, respectively, and the 90% confidence intervals were 0.81-1.09 and 0.83-1.03, which is within the critical range for bioequivalence of 0.80-1.25. In conclusion, the established pharmacokinetic parameters demonstrate that the capsule and tablet formulations of R115777 are interchangeable.

Disposition of docetaxel in the presence of P-glycoprotein inhibition by intravenous administration of R101933.

Recently, a study of docetaxel in combination with the new orally administered P-glycoprotein (P-gp) inhibitor R101933 showed that this combination was feasible. However, due to the low oral bioavailability of R101933 and high interpatient variability, no further attempts to increase the level of P-gp inhibition were made. Here, we assessed the feasibility of combining docetaxel with intravenously (i.v.) administered R101933, and determined the disposition of docetaxel with and without the P-gp inhibitor. Patients received i.v. R101933 alone at a dose escalated from 250 to 500 mg on day 1 (cycle 0), docetaxel 100 mg/m(2) as a 1-h infusion on day 8 (cycle 1) and the combination every 3 weeks thereafter (cycle 2 and further cycles). 12 patients were entered into the study, of whom 9 received the combination treatment. Single treatment with i.v. R101933 was associated with minimal toxicity consisting of temporary drowsiness and somnolence. Dose-limiting toxicity consisting of neutropenic fever was seen in cycles 1 and 2 or in further cycles at both dose levels. The plasma pharmacokinetics of docetaxel were not changed by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 22.5+/-6.2 l/h/m(2) and 24.2+/-7.4 l/h/m(2) (P=0.38) in cycles 1 and 2, respectively. However, the faecal excretion of unchanged docetaxel decreased significantly after the combination treatment from 2.5+/-2.1% to less than 1% of the administered dose of docetaxel, most likely due to inhibition of the intestinal P-gp by R101933. Plasma concentrations of R101933 were not different in cycles 0 or 2 and the concentrations achieved in the first 12-h period after i.v. infusion were capable of inhibiting P-gp in an ex vivo assay. We conclude that the combination of 100 mg/m(2) i.v. docetaxel and 500 mg i.v. R101933 is feasible, lacks pharmacokinetic interaction in plasma, and shows evidence of P-gp inhibition both in an ex vivo assay and in vivo as indicated by the inhibition of intestinal P-gp.

The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel.

This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 +/- 7.78 liters/h/m2 and 23.4 +/- 4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics.

A phase III study of recombinant interleukin-2, 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in patients with unresectable or metastatic colorectal carcinoma.

135 patients with locally advanced or metastatic colorectal cancer were entered into a phase III trial evaluating the efficacy of chemoimmunotherapy [recombinant interleukin 2 (rIL2)/5-fluorouracil (5-FU) and leucovorin (LV)] versus chemotherapy alone (5-FU/LV). A cycle of chemoimmunotherapy comprised a constant intravenous infusion of rIL2 at a dose of 18 x 10(6) U/m2/24 h for 120 h, followed by three bolus injections of 5-FU (600 mg/m2) and LV (25 mg/m2) at weekly intervals. Patients receiving chemotherapy alone received 5-FU/LV at the same dose at weekly intervals for 6 weeks followed by a rest period of 2 weeks, constituting one cycle of therapy. A maximum of 6 months therapy was given in both arms of the study. The response rates (complete and partial responses) were 17% in patients receiving rIL2/5-FU/LV versus 16% in those in the 5-FU/LV arm of the study. Median survival and progression-free survival were comparable for the two groups of patients, although there was a trend for a prolongation of survival in patients receiving chemoimmunotherapy compared with chemotherapy alone, beyond 12 months. Retrospective subgroup analyses revealed a significantly increased survival in poor prognosis patients (ECOG 1) treated with rIL2/5-FU/LV when compared to those receiving chemotherapy alone. Therefore, further studies evaluating the dose and duration of chemoimmunotherapy in patients with metastatic colorectal cancer seem warranted.

Intratumoral PEG-interleukin-2 therapy in patients with locoregionally recurrent head and neck squamous-cell carcinoma.

BACKGROUND: An enhanced efficacy of local as compared to systemic administration of interleukin-2 (IL-2) has been demonstrated in several experimental tumors. We previously reported that guinea pigs with palpable tumors and regional micrometastases could be cured by intratumoral injections of polyethylene glycol-modified IL-2 (PEG-IL-2). In the present study this treatment schedule was applied in a clinical situation. PATIENTS AND METHODS: Nineteen patients with 11 local and 11 regional recurrences of head and neck squamous cell carcinoma (HNSCC) were treated with intratumoral injections of 200,000 U of PEG-IL-2 3 times weekly in courses of 4 weeks. RESULTS: Treatment was given on an out-patient basis, and was well tolerated. Temporary regional swelling and redness developed in 10 patients, and in 9 of them systemic eosinophilia was documented. Median duration of treatment was 4 weeks (range 2-14 weeks). Seventeen patients were evaluable for response. One complete response (CR; 6%; duration 91 weeks), and 6 stable diseases (SDs; duration 8-57+ weeks) were recorded. The CR and the 3 best SDs (23, 40, 57+ weeks) occurred in patients with a single regional tumor recurrence of relatively small size. During treatment, all 4 developed locoregional edema and redness, and high levels of circulating eosinophils. Median survival was 23 weeks for all patients, and 45+ weeks for the patients with SD. CONCLUSION: Intratumoral injection of PEG-IL-2 in patients with HNSCC is feasible. This treatment appears beneficial for highly selected patients. The objective response rate is insufficient to justify wide clinical application.

Persistent augmentation of natural-killer- and T-cell-mediated cytotoxicity in peripheral blood mononuclear cells pulsed in vitro with high-dose recombinant interleukin-2 prior to culturing with a low maintenance dose.

The toxicity of high-dose recombinant interleukin-2 (rIL-2) treatment limits its use in tumour therapies. This paper describes in vitro studies of whether a single, peak rIL-2 dose, followed by low maintenance doses, could enhance the cytotoxic potential of peripheral blood mononuclear cells (PBMC) without inducing a significant sustained release of secondary cytokines, known to contribute to undesirable side-effects of therapy. Pre-pulsing of PBMC with high-dose rIL-2 (16,000 IU/ml for 30 min), followed by low-dose (5 IU/ml) maintenance culturing, was found to induce persistent augmentation of cytotoxic activity towards natural-killer(NK)-sensitive and -insensitive tumour targets, as well as increased T-cell-mediated target cell killing. Under these conditions the level of killing was as high as that achieved by higher maintenance doses (20-100 IU/ml). Although not reflected by overexpression of cell surface markers, enhanced activation of cytotoxic capacities by high-dose pre-pulsing remained clearly apparent for at least 12 days of culture. Increased secondary cytokine production (tumour necrosis factor, interleukin-6 and interferon gamma) was only evident during the first 24-72 h after pulsing, and not at later stages of culturing at the low maintenance dose of 5 IU rIL-2/ml. These results may warrant a human phase-1 B study to investigate the in vivo effect of high-dose prepulsing, followed by low-dose maintenance.

The development of anti-interleukin-2 (IL-2) antibodies in cancer patients treated with recombinant IL-2.

Serum samples from 217 cancer patients participating in phase I/II clinical trials were analysed for the development of anti-interleukin-2 (IL-2) antibodies. Patients received recombinant human IL-2 (rIL-2) by continuous intravenous infusion (c.i.v.; n = 86) or by subcutaneous (s.c.) injections (n = 131). Both patient groups developed anti-rIL-2 antibodies as detected by ELISA with similar frequencies and titres: 52% (median titre, 23) and 47% (median titre, 24), respectively. Using an IL-2-dependent T-cell proliferation assay, sera from 5 c.i.v.-treated patients (6%) and 13 s.c.-treated patients (10%) exhibited neutralising activity. Immunoabsorption studies with rIL-2-coated beads, demonstrated that in 8 of 15 patients with neutralising sera, the neutralising activity was correlated with specific anti-rIL-2 immunoglobulin. All 8 patients had received at least two cycles of rIL-2 by s.c. injections. Specific IL-2 neutralising activity affected both recombinant and natural IL-2 in all 8 patients. Development of anti-rIL-2 antibodies, irrespective of whether these exhibited neutralising activity or not, did not affect the frequency or duration of clinical responses.

A comparison of 2 modes of administration of recombinant interleukin-2: continuous intravenous infusion alone versus subcutaneous administration plus interferon alpha in patients with advanced renal cell carcinoma.

PURPOSE: To compare 2 treatment modalities with recombinant Interleukin-2 (rIL-2) for patients with advanced Renal Cell carcinoma (RCC): continuous intravenous infusion (CIV) alone versus subcutaneous (s/c) rIL-2 + Interferon-alpha (IFN-alpha). PATIENTS AND METHODS: Data have been collected on 425 patients with RCC, treated CIV rIL-2 alone, (225 patients), or rIL-2 by the s/c route (200 patients). Patients receiving s/c rIL-2 also received s/c IFN-alpha both drugs being administered on an outpatient basis. Patients receiving CIV rIL-2 were treated as inpatients. Patient eligibility criteria were similar on all studies, and included patients with progressive, advanced disease, but with an ambulatory performance status. RESULTS: The overall response rate for the CIV schedules was not significantly different from the s/c regimens: 15% (95% confidence limits (CL) 10-20%) vs 20% (95%CL 14-26%) with 4% CR in both approaches. Durable responses were seen in both CIV and s/c schedules and there was no evidence of a significant difference in survival in multivariate analysis. There was however an important shift in the toxicity profile. The s/c regimens do not induce a clinically detectable capillary leak syndrome, which is the dose limiting toxicity for CIV regimens. CONCLUSION: Although the introduction of CIV regimens of rIL-2 was a major step forward compared to high-dose bolus, because most patients could be treated in a normal oncology ward, the s/c schedule of rIL-2 + IFN-alpha offers the possibility of outpatient (home) therapy, with no evidence of a reduction in efficacy.

Subcutaneous recombinant interleukin-2 and alpha-interferon in patients with advanced renal cell carcinoma: results of a multicenter Phase II Study.

A phase II multiinstitutional clinical trial was conducted to evaluate the safety and efficacy of the subcutaneous outpatient administration of recombinant human interleukin-2 and alpha-interferon in patients with progressive metastatic renal cell carcinoma. One hundred and forty-five patients were entered on this study between October 1989 and May 1991. Among 134 patients evaluable for treatment response, there were six complete (4.5%) and twenty partial (14.9%) responders, with an overall response rate of 19.4% (95% confidence interval, 13-26%). The median duration of complete remissions was 228 (range 51(+)-520+) days; the median duration of partial tumor regressions was calculated at 226 (range 112-473+) days. The overall median survival from start of therapy was 14.2 (range 1-23+) months. Fever, chills and general fatigue occurred in the majority of patients treated and were measured at grade II, III and IV in up to 55%, 24% and 3% of all evaluable patients, respectively. Three patients each developed grade III hypotension, dyspnea and diarrhea; two patients each had grade III and grade IV elevations of alkaline phosphatase; two and one patients respectively, exhibited grade III anemia and grade IV thrombocytopenia; two patients experienced severe cutaneous toxicity. The majority of patients received treatment in the outpatient setting. In summary, the outpatient use of subcutaneous interleukin-2 and alpha-interferon was effective in patients with advanced metastatic renal cell carcinoma; it was associated with less toxicity and thus, could improve the therapeutic index of interleukin-2 based biologic therapy when compared against high dose intravenous therapy.

Prognostic factors for survival in patients with advanced renal cell carcinoma treated with recombinant interleukin-2.

A database of 327 patients with advanced Renal Cell Carcinoma (RCC) has been analyzed in order to identify potential baseline prognostic factors predicting for survival, following recombinant Interleukin-2 treatment (rIL-2). All patients received a continuous infusion (CIV). Eligibility criteria were uniform across studies, and included patients with an ambulatory performance status (PS), measurable disease, no CNS metastases, and no major organ compromise. Multivariate analyses identified baseline PS (ECOG 0 vs. 1), time from diagnosis to treatment (DTI greater than 24 months vs. less than or equal to 24 months), and the number of metastatic sites (1 vs. greater than or equal to 2, where lung, bone and other sites are considered as separate sites) as important predictors for survival. Patients can be classified into 4 subgroups, which are a function of the number of risk factors present. Median survival for each subgroup is 28, 17, 10 and 5 months, respectively. The model was validated in an independent cohort of 125 patients with RCC treated with subcutaneous (s/c) rIL-2, and predicted for survival accurately. By determining in which risk group category patients may fall, treating physicians may be better equipped to decide on patient management. The model may also be of value in order to stratify patients in randomized clinical trials.

Phase I trial of recombinant interleukin-2 followed by recombinant tumor necrosis factor in patients with metastatic cancer.

In this Phase I trial, the feasibility of sequential administration of continuous intravenous recombinant interleukin-2 (rIL-2) at 18 x 10(6) IU/m2/day for 6 days, followed by three daily bolus intravenous recombinant tumor necrosis factor (rTNF) infusions at doses escalating between 10 and 120 micrograms/m2/day, was investigated in 31 patients with metastatic malignancies. Prophylactic use of indomethacin prior to and during rTNF administration was found to significantly reduce toxicity. However, despite prophylactic indomethacin, a maximum tolerated dose of rTNF of 120 micrograms/m2 was reached. The limiting toxicity was hypotension. Predictable flu-like toxicities (i.e., fever/chills, hypotension, gastrointestinal toxicity, edema, malaise) were seen in most patients. These started during the rIL-2 infusion and continued during rTNF administration, particularly in the absence of indomethacin. Hematological, renal, and hepatic toxicities were not dose limiting. These toxicities were all reversible after treatment interruption. Pulmonary toxicity [i.e., anaphylactic-like reactions, bronchospasms, and adult respiratory distress syndrome (ARDS)] was seen in several patients immediately after rTNF infusions, irrespective of the rTNF dose or treatment cycle, and mainly in patients with extensive pulmonary metastases. The combined effect of treatment-related ARDS, lung metastases, and a Guillain-Barré syndrome led to the death of one patient. Two partial responses were seen in this study (i.e., breast and renal cancer). Based on these results, a Phase II trial of rIL-2 followed by rTNF has been initiated in metastatic breast cancer patients.

Atrial natriuretic factor prohormone peptides are present in a variety of tissues.

Utilizing two sensitive and specific radioimmunoassays which immunologically recognize 1) the 98 amino acid (a.a.) N-terminus and 2) the 28 a.a. C-terminus (i.e., a.a. 99-126) of the 126 a.a. atrial natriuretic (ANF) prohormone, various tissues including aorta, kidney, small intestine, colon, liver, spleen, lung, and testis were investigated to determine if the ANF prohormone was present in any of these tissues in addition to its previously demonstrated presence in heart and brain. Aorta with 62.3 +/- 3 ng of the N-terminus/g of tissue and 51.6 +/- 1.8 ng of the C-terminus of the ANF prohormone/g of tissue had the highest concentration of the ANF prohormone of the previously undescribed ANF prohormone-containing tissues. The next highest concentration of the ANF prohormone was in the intestine, followed by lung and spleen. Pancreas, liver and kidney had similar levels of immunologically recognized ANF prohormone (approximately 1/50 of the aorta), while the testis and cerebrum had low levels. These results suggest that a much larger variety of tissues synthesize and/or store the ANF prohormone than is presently thought.

Intravesical therapy of superficial bladder transitional cell carcinoma with tumor necrosis factor-alpha: preliminary report of a phase I-II study.

A phase I-II trial of intravesical immunotherapy with tumor necrosis factor (TNF)-alpha in 24 patients affected by superficial bladder tumors is herein presented. Of these, 11 patients were submitted, at weekly intervals, after complete TUR, to 8 instillations of TNF-alpha at increasing doses from 50 to 600 micrograms. Tolerability was excellent, even at the highest dose. In a second group of 13 patients with a histologically proved papillary marker lesion, TNF-alpha was instilled at weekly intervals at the dose of 500 micrograms for 8 weeks. Three complete responses (23%) were obtained.

Continuous infusion of recombinant interleukin-2 with or without autologous lymphokine activated killer cells for the treatment of advanced renal cell carcinoma.

Data have been analysed for 327 patients with advanced renal cell carcinoma receiving a continuous infusion of recombinant interleukin 2 (rIL-2) alone (225 patients) or rIL-2 plus lymphokine activated killer (LAK) cells (102) on a normal oncology ward. Eligibility criteria were uniform across protocols, all patients having advanced progressive disease, but with an ambulatory performance status. The baseline characteristics of patients receiving rIL-2 alone did not differ significantly from those receiving LAK, with the exception that the LAK treated patients had a better performance status. Despite similar treatment intensity, toxicity was more severe in the patients receiving LAK. The addition of LAK did not lead to higher response rates or to prolonged response duration, progression-free survival or survival. This review confirms the activity of rIL-2 for the treatment of advanced renal cell carcinoma and demonstrates that the addition of LAK cells does not lead to increased efficacy.

A phase II study of sequential recombinant interleukin-2 followed by dacarbazine in metastatic melanoma.

16 patients with disseminated malignant melanoma (1 with primary ocular melanoma) entered a multicentre phase II study of recombinant interleukin-2, (rIL-2) given by continuous intravenous infusion on days 1-5 at 18 x 10(6) IU/m2 per day, followed by dacarbazine 850 mg/m2 on day 8. After a 2 week rest, a second course was given. In the absence of disease progression, monthly maintenance cycles were given for up to four cycles. 16 patients received one cycle, 14 received two and 6 patients three or more. All 16 patients are evaluable for toxicity and 15 for response. 2 patients responded (13%). 1 patient with lung and pleural metastases achieved partial remission after two cycles and went off treatment after six cycles. 3 months later a complete response was noted lasting 396+ days. A second patient with lung metastases had a partial response lasting 153 days. 3 patients (20%) had stable disease. Mean rebound lymphocytosis (24-48 h after the end of rIL-2 therapy), cell count 4.9 x 10(9)/l (2.6-8.8 x 10(9)/l) was within the expected limits. Other toxicity was as expected. Thus sequential treatment with rIL-2 and dacarbazine is feasible but synergy did not occur.