Phase I study of subcutaneously administered recombinant human interleukin 12 in patients with advanced renal cell cancer.

A phase I study was conducted to characterize the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of a single dose followed by three times weekly s.c. injections of recombinant human interleukin 12 (rHuIL-12). The study encompassed 28 patients with advanced renal cell carcinoma. rHuIL-12 was administered on day 1, followed by an observation period of 7 days. Starting on day 8, repeated s.c. injections were administered 3 times a week for 2 weeks. The MTD of the initial injection was evaluated at dose levels of 0.1, 0.5, and 1.0 microg/kg. DLT was observed at 1.0 microg/kg and consisted of fever, perivasculitis of the skin, and leukopenia. The MTD of the subsequent repeated injections after 1 week of rest was studied at dose levels 0.5, 1.0, and 1.25 microg/kg. DLT at 1.25 microg/kg comprised deterioration of performance status, fever, vomiting, mental depression, and leukopenia. Other notable toxicities were oral mucositis and elevation of hepatic enzymes. Fever, leukopenia, and elevation of hepatic enzymes were more severe after the initial injection than after repeated injections at the same dose level. At dose level 0.5 microg/kg, the mean area under the plasma concentration-time curve decreased from 7.4 ng/h/ml after the first injection to 3.3 ng x h/ml (P = 0.034) after repeated administrations, and at dose level 1.0 microg/kg, it ranged from 31.8 ng/h/ml to 6.0 ng x h/ml (P = 0.041). One patient had a partial response and seven had stable disease. The MTD of a single s.c. injection of rHuIL-12 was 0.5 microg/kg, and the MTD of three subsequent administrations per week was 1.0 microg/kg. In comparison with a single administration, the three times weekly administrations at the same dose level was accompanied with a milder pattern of side effects and a reduction of the area under the plasma concentration-time curve.     

Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis.

PURPOSE: A single-institution phase II study was undertaken to evaluate the efficacy and toxicity of interleukin-2 (IL-2) administered by subcutaneous injection. PATIENTS AND METHODS: Twenty-seven unselected patients (15 male) with a mean age of 60 years (range, 42 to 76 years) who had advanced renal cell cancer were treated as outpatients. IL-2 was given once a day, 5 days per week for 6 weeks. During the first 5-day cycle, 18 x 10(6) IU was given once daily; in the following cycles, the doses in the first 2 days were reduced to 9 x 10(6) IU. After a 3-week rest period, treatment was repeated in patients who had a response or stable disease (SD). To prevent pyretic reactions, patients also received acetaminophen (250 to 500 mg given orally every 4 to 6 hours). RESULTS: After 6 weeks, 26 patients were assessable for response. Two patients (8%) had a complete remission (CR), four (15%) had a partial remission (PR), and 13 (50%) had SD. A second cycle of 6 weeks was given to 19 patients; one patient with a PR and six with SD showed progression. Duration of the CR was 17+ and 19+ months, and length of the PR was 2, 8, 11, and 11+ months. The median survival of the patients who were nonresponders and responders was 10 and 20+ months, respectively, and for all patients was 13 months. One patient died as a result of myocardial infarction and brain stem ischemia. Systemic side effects in the other patients were tolerated and accepted, and included transient inflammation and local induration at the injection sites, fever and chills, and nausea. CONCLUSION: Subcutaneous IL-2 is clinically active, has an acceptable toxicity, and can be given to patients with concomitant disease.     

Daily subcutaneous ultra-low-dose interleukin 2 with daily low-dose interferon-alpha in patients with advanced renal cell carcinoma.

A limited institution Phase II pilot study was performed using a very low-dose combination of daily s.c. interleukin (IL)-2 with IFN-alpha-2b in patients with advanced renal cancer in an attempt to duplicate or increase the response documented with higher dose schedules without the attendant toxicity profile. We selected a dose of IL-2 with documented immunological activity and combined it with clinically active low-dose IFN. Between August 1994 and September 1996, 19 patients with metastatic renal cell carcinoma, who had been judged incapable of tolerating high-dose i.v. IL-2, were treated with IL-2 (1 million units/m2/day) and IFN (1 million units/day), administered s.c. daily. All treatments were administered on an outpatient basis. Virtually all patients had bulky tumor burden with multiple sites of involvement, including five patients with bone metastases. No major objective responses were observed; however, one patient experienced a minor response lasting 13 months, with an associated improvement in performance status. Median survival was 6 months, and 1-year survival was 16%. Toxicity was generally mild and consisted almost entirely of constitutional symptoms. No serious grade 3 or 4 toxicity was observed, although two patients withdrew from treatment due to treatment-related fatigue. On therapy, mild eosinophilia but no lymphocytosis was noted; in fact, peripheral lymphocyte counts decreased, only to rebound after treatment was discontinued. No toxic deaths occurred. Despite the reasonable tolerability of this daily low-dose s.c. regimen, we conclude that this regimen is an ineffective treatment in metastatic renal cell carcinoma patients who are incapable of tolerating high-dose i.v. IL-2.     

Phase I study of anticolon cancer humanized antibody A33.

PURPOSE: Humanized A33 (huA33; IgG1) monoclonal antibody detects a determinant expressed by 95% of colorectal cancers and can activate immune cytolytic mechanisms. The present study was designed to (a) define the toxicities and maximum tolerated dose of huA33 and (b) determine huA33 immunogenicity. EXPERIMENTAL DESIGN: Patients (n = 11) with advanced chemotherapy-resistant colorectal cancer received 4-week cycles of huA33 at 10, 25, or 50 mg/m(2)/week. Serum samples were analyzed using biosensor technology for evidence of human antihuman antibody (HAHA) response. RESULTS: Eight of 11 patients developed a HAHA response. Significant toxicity was limited to four patients who developed high HAHA titers. In two of these cases, infusion-related reactions such as fevers, rigors, facial flushing, and changes in blood pressure were observed, whereas in the other two cases, toxicity consisted of skin rash, fever, or myalgia. Of three patients who remained HAHA negative, one achieved a radiographic partial response, with reduction of serum carcinoembryonic antigen from 80 to 3 ng/ml. Four patients had radiographic evidence of stable disease (2, 4, 6, and 12 months), with significant reductions (>25%) in serum carcinoembryonic antigen levels in two cases. CONCLUSIONS: The complementarity-determining region-grafted huA33 antibody is immunogenic in the majority of colon cancer patients (73%). HAHA activity can be measured reproducibly and quantitatively by BIACORE analysis. Whereas the huA33 construct tested here may be too immunogenic for further clinical development, the antitumor effects observed in the absence of antibody-mediated toxicity and in this heavily pretreated patient population warrant clinical testing of other IgG1 humanized versions of A33 antibody.     

Phase I study of intravenously administered bacterially synthesized granulocyte-macrophage colony-stimulating factor and comparison with subcutaneous administration

A Phase I study of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was undertaken in 21 patients with advanced malignancy or neutropenia. rhGM-CSF was administered once daily by i.v. bolus injection (0.3 to 3 micrograms/kg/day) or 2-h i.v. infusion (3 to 20 micrograms/kg day) for 10 days. rhGM-CSF at all i.v. doses caused an immediate transient decrease in circulating neutrophils, eosinophils, and monocytes. By 6 h after rhGM-CSF, circulating leukocyte levels were restored. Daily i.v. bolus dosing (0.3 to 3 micrograms/kg/day) did not elevate leukocyte levels except in one neutropenic patient. Daily 2-h i.v. infusions (10 to 20 micrograms/kg/day) caused a dose-dependent leukocytosis with increased levels of neutrophils (up to 4.3-fold), eosinophils (up to 18-fold), and monocytes (up to 3.5-fold). Marrow aspirates showed increased proportions of promyelocytes and myelocytes during rhGM-CSF administration. Retreatment after 10 days without rhGM-CSF resulted in a more marked leukocytosis at doses greater than or equal to 10 micrograms/kg/day. Platelet levels decreased for the first 3 days and then increased during the first course of rhGM-CSF administration. Two patients with chronic lymphocytic leukemia had a transient reduction in lymphocytosis. Serum cholesterol and albumin levels decreased, and vitamin B12 levels increased during rhGM-CSF treatment. At doses of up to 15 micrograms/kg/day, rhGM-CSF was relatively well tolerated by the patients, but adverse effects included bone pain, lethargy, fever, rash, and weight gain. A first dose reaction characterized by hypoxia and hypotension was identified at dose levels greater than or equal to 1 microgram/kg. Dosing i.v. was less potent at inducing a leukocytosis than previously observed for equivalent s.c. doses and was associated with a higher incidence of generalized rash and first dose reactions. The maximal tolerated dose of i.v. rhGM-CSF was 15 micrograms/kg/day. Phase II studies in which the derived effect is to raise leukocyte levels should be undertaken at rhGM-CSF doses of 3 to 15 micrograms/kg/day.     

A randomised dose escalation study of subcutaneous interleukin 2 with and without levamisole in patients with metastatic renal cell carcinoma or malignant melanoma.

We have examined the efficacy, toxicity and host immunological response of two different dose schedules of interleukin 2 (IL-2) given subcutaneously, daily for 3 months in patients with renal cell carcinoma (RCC) or metastatic melanoma (MM). We also examined the effect of adding the immune modulator levamisole to the two different schedules of IL-2. Thirty-nine patients were entered into two sequential phase I/II studies. Eighteen patients entered study 1 and were randomised to receive IL-2, 3 x 10(6) IU m-2 day-1, subcutaneously for 3 months with or without levamisole 50 mg t.d.s. p.o. on days 1-3 on alternate weeks. Twenty-one patients entered study 2 and were randomised to receive 5.4 x 10(6) IU m-2 day-1 subcutaneously for 3 months with or without levamisole 50 mg t.d.s. p.o. on days 1-3 on alternate weeks. Blood was taken for peripheral blood lymphocyte (PBL) phenotype analysis, and measurement of IL-2, soluble IL-2 receptor (sIL-2R) and neopterin concentration. Two patients with metastatic melanoma, one in each study, responded (11.8%); both received IL-2 alone. Observations of immunological parameters showed that treatment with subcutaneous IL-2 resulted in a significant rise in the percentage of PBLs bearing CD25, CD3/HLA-DR, CD56 and levels of IL-2 receptor and neopterin. The total white blood cell count (WBC) and total lymphocyte count rose significantly on day 18 compared with pretreatment levels. The addition of levamisole to either IL-2 schedule resulted in no significant changes in any immunological parameters. This study illustrates that prolonged subcutaneous IL-2 can be given safely in the outpatient setting. There was no evidence that levamisole acts as an immunomodulator in this study.     

Identification of a novel CD56- lymphokine-activated killer cell precursor in cancer patients receiving recombinant interleukin 2.

Circulating lymphokine-activated killer (LAK) cell activity in cancer patients receiving recombinant interleukin 2 (rIL-2) therapy is confined to cells expressing the CD56- surface marker. However, CD56- cells from these patients but not normal individuals have been reported to exhibit LAK cytotoxicity only following in vitro activation with rIL-2. Studies were performed to document the existence of CD56- LAK precursor cells and to phenotypically characterize this population in patients receiving rIL-2 therapy using fluorescence-activated cell sorter-purified CD56- cell subsets. Initial studies confirmed that CD56- cells exhibit NK activity [20 +/- 7 (SE) LU/10(6) cells] but not LAK activity (0 +/- 0 LU/10(6) cells) when evaluated directly from peripheral blood of patients receiving rIL-2. CD56- cells from patients but not normal individuals developed significant LAK cytolytic activity against NK-resistant COLO 205 targets (16 +/- 3 LU/10(6) cells) when cultured for 3 days with 1500 units/ml rIL-2. The CD56- LAK precursor activity was confined to cells expressing a CD56-CD16+ phenotype and a large granular lymphocyte morphology; little or no NK or LAK precursor activity was detectable in CD56-CD5+ T-cells from patients. Phenotypic characterization of CD16+CD56- cells revealed that this population is uniformly CD11a+,CD18+, and CD38+ and is heterogeneous in its expression of CD11b, CD11c, and CD16/Leu 11c. These results indicate that rIL-2 administration induces enhanced LAK precursor activity in a novel population of CD5-CD16+CD56- cells.     

Phase I trial of combined immunotherapy with subcutaneous granulocyte macrophage colony-stimulating factor, low-dose interleukin 2, and interferon alpha in progressive metastatic melanoma and renal cell carcinoma.

The purpose of our study was to determine the maximally tolerated dose (MTD) and DLT of combined administration of granulocyte macrophage colony-stimulating factor (GM-CSF), low-dose interleukin 2 (IL-2) and IFN-alpha in patients with progressive metastatic melanoma or renal cell carcinoma (RCC). In addition, the activation and expansion of effector cells were measured. Cohorts of three patients were treated with increasing doses of IL-2 (1, 4, and 8 MIU/m2) and GM-CSF (2.5 and 5 microg/kg) with a constant dose of IFNalpha (5 million units) s.c. for 12 days every 3 weeks. An additional six patients were treated at the MTD. Immune activation was monitored during the first cycle. Response was evaluated after two cycles. The MTD was found to be 2.5 microg/kg GM-CSF, 4 MIU/m2 IL-2, and 5 mega units of IFNalpha. DLT was grade 4 fever, chills with hypotension, grade 3 fatigue/malaise, and fluid retention. Dose reduction of IL-2 to 2 MIU/m2 was necessary in three of nine patients who initially received the MTD. Treatment was initiated in the hospital but could be continued at home after 3-4 days. Significant increases in lymphocytes, (activated) T cells (CD4+ and CD8+), NK cells, monocyte DR expression, neutrophils, and eosinophils were found. CD8+ T-cell activation (sCD8) and NK cell expansion was mainly present in patients receiving 2 or 4 MIU/m2 IL-2. Of eight patients with progressive metastatic RCC after nephrectomy, three achieved a complete remission, and 1 of 7 patients with metastatic melanoma achieved a partial remission. In our study, the MTD of combined immunotherapy with GM-CSF, IL-2, and IFNalpha was established; DLT was: (a) grade 4 fever with hypotension needing i.v. fluid support; and (b) grade 3 fluid retention and/or fatigue/malaise. The scheme resulted in considerable expansion and/or activation of various effector cells. The complete responses in RCC patients are promising but need to be confirmed in Phase II studies.     

A randomised study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma.

Our previous experimental studies have shown that the best approach to increase the biological anti-tumour activity of interleukin 2 (IL-2) is not co-administration of another cytokine, but the association with immunomodulating neurohormones, in an attempt to reproduce the physiological links between psychoendocrine and immune systems, which play a fundamental role in the regulation of the immune responses. In particular, the association with the pineal neurohormone melatonin (MLT) has been shown to cause tumour regressions in neoplasms that are generally non-responsive to IL-2 alone. To confirm these preliminary results, a clinical trial was performed in locally advanced or metastatic patients with solid tumours other than renal cell cancer and melanoma. The study included 80 consecutive patients, who were randomised to be treated with IL-2 alone subcutaneously (3 million IU day-1 at 8.00 p.m. 6 days a week for 4 weeks) or IL-2 plus MLT (40 mg day-1 orally at 8.00 p.m. every day starting 7 days before IL-2). A complete response was obtained in 3/41 patients treated with IL-2 plus MLT and in none of the patients receiving IL-2 alone. A partial response was achieved in 8/41 patients treated with IL-2 plus MLT and in only 1/39 patients treated with IL-2 alone. Tumour objective regression rate was significantly higher in patients treated with IL-2 and MLT than in those receiving IL-2 alone (11/41 vs 1/39, P < 0.001). The survival at 1 year was significantly higher in patients treated with IL-2 and MLT than in the IL-2 group (19/41 vs 6/39, P < 0.05). Finally, the mean increase in lymphocyte and eosinophil number was significantly higher in the IL-2 plus MLT group than in patients treated with IL-2 alone; on the contrary, the mean increase in the specific marker of macrophage activation neopterin was significantly higher in patients treated with IL-2 alone. The treatment was well tolerated in both groups of patients. This study shows that the concomitant administration of the pineal hormone MLT may increase the efficacy of low-dose IL-2 subcutaneous therapy.     

Phase I study of toremifene in patients with advanced cancer.

A phase I multicenter evaluation of a novel antiestrogen, toremifene, was undertaken in postmenopausal women with various advanced difficult-to-treat malignancies. One hundred and seven women were treated at one of six dosage levels (10, 20, 40, 60, 200, or 400 mg/d orally) for at least 8 weeks. Weekly evaluations for toxicity were conducted. The most common side effects were nausea (31%), vomiting (12%), and hot flashes (29%). Five patients were removed from the study for possible adverse reactions: three patients experienced hypercalcemia; one experienced tremulousness, fatigue, and inability to think clearly; and one had vaginal bleeding. Twelve patients died while on study, 11 with disease progression and one with a pulmonary embolus. Sex hormone-binding globulin (SHBG) levels increased and there was a modest decline in serum antithrombin III levels. Four of 48 assessable patients had partial responses: three with breast cancer and one with endometrial cancer. Toremifene was generally well tolerated at the doses tested.     

Phase I/II study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer

Twelve patients with advanced small cell carcinoma of the bronchus were treated by continuous infusion of recombinant human granulocyte colony-stimulating factor (rhG-CSF) at the following dose levels: 1 microgram, 5 micrograms, 10 micrograms, 20 micrograms and 40 micrograms kg-1 day-1 for 5 days. No toxicities resulted from the treatment and in all 12 patients the number of peripheral neutrophils increased rapidly to a maximum of 100 x 10(9) l-1 at 10 micrograms kg-1 day-1. The neutrophils were shown to be functionally normal in tests of their mobility and bactericidal activity. During the phase II part of the study the patients were treated by a combination of intravenous adriamycin 50 mg m-2, ifosfamide 5 g m-2 by i.v. infusion with mesna 8 g m-2 on day 1, and etoposide 120 mg m-2 on days 1, 2 and 3 also intravenously. The chemotherapy regime was repeated every 3 weeks. RhG-CSF was given to each patient for 14 days on alternate cycles of chemotherapy and reduced the period of absolute neutropenia considerably (median of 80%), with a return to normal, or above normal, neutrophil counts within 2 weeks after day 1 of chemotherapy. Six severe infective episodes were observed during the cycles of chemotherapy which did not include rhG-CSF, while no infective episodes occurred when patients were treated with rhG-CSF. These results demonstrate the utility of rhG-CSF in restoring functional neutrophils to patients undergoing intensive chemotherapy.     

Phase I evaluation of a combination of monoclonal antibody R24 and interleukin 2 in patients with metastatic melanoma

A combination of recombinant human interleukin 2 (rhIL-2) and mouse monoclonal antibody R24 (recognizing the ganglioside GD3) was evaluated in patients with metastatic melanoma in a phase I trial. rhIL-2 was given at a constant daily dose of 1 x 10(6) units/m2 i.v. over 6 h on days 1-5 and 8-12. R24 was given on days 8-12 at four dose levels (1, 3, 8, and 12 mg/m2 daily). Twenty patients were evaluable for toxicity and response, five at each dose level. The toxicity of the combination was not overlapping and generally mild. There was a rebound peripheral blood T-lymphocytosis at the end of treatment increasing with the dose of R24. The median lymphocyte count on day 12 of treatment was 3108 +/- 554/ml in patients treated at R24 doses of 8 and 12 mg/m2 versus 2239 +/- 672/ml at doses of 1 and 3 mg/m2. This evidence and other data suggested that R24 enhanced IL-2-mediated T-cell activation in vivo. Two patients demonstrated increases in R24-mediated antibody-dependent cellular cytotoxicity for GD3-expressing cells during treatment. rhIL-2 appeared to accelerate the development of human anti-mouse antibody; three patients developed human anti-mouse antibody by the fifth day of R24 treatment, earlier than observed in prior studies using R24 alone and one patient during the first week of rhIL-2 alone, prior to R24 treatment. One patient had a partial response in soft tissue sites lasting 6 months and two patients had minor responses. This clinical trial extends the previous observation that R24 enhances lymphocyte proliferation in vitro.     

Phase I trial of everolimus plus sorafenib for patients with advanced renal cell cancer

Background

Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, and sorafenib, a RAF kinase inhibitor, has shown efficacy in renal cell cancer (RCC) as single agents. We conducted a phase I study to evaluate the maximum tolerated dose (MTD) of combining these agents for potential additive or synergistic effects when treating progressive metastatic RCC (mRCC).

Patients and Methods

The 15 patients enrolled in the study had predominantly clear cell RCC (cRCC) and progressive measurable disease with previous treatment that included immunotherapy, tyrosine kinase inhibitors, and/or everolimus. Patients received daily everolimus and twice-daily sorafenib at escalating dose levels of 2.5 mg/400 mg (cohort 1), 5 mg/400 mg (cohort 2), and 10 mg/400 mg (cohort 3), and they were evaluated weekly for toxicity and every 8 weeks for response, using computed tomography/positron emission tomography (CT/PET) and CT at baseline and at first staging.

Results

In cohort 1, 2 of 6 patients experienced dose-limited toxicity (DLT) of thrombocytopenia/leukopenia and pneumonitis. In cohort 2, 1 of 6 patients experienced a DLT of pulmonary embolism, and the 3 patients in cohort 3 experienced no DLTs. The MTD was 10 mg/400 mg. Common adverse events included grade 1/2 hand-foot syndrome. Using Response Evaluation Criteria in Solid Tumors (RECIST), 1 patient achieved a pathologic complete response (CR), 1 patient achieved a radiographic CR, and 1 patient achieved a surgical CR. Seven patients achieved stable disease; 10 patients had decreased fluorine-18 fluorodeoxyglucose uptake. Median progressive-free survival was 5.6 months; overall survival was 7.9 months.

Conclusion

The MTD of daily everolimus 10 mg and twice-daily sorafenib 400 mg is safe and effective for progressive mRCC.     

Phase I study of combination therapy with interleukin 2 and beta-interferon in patients with advanced malignancy

Based on a preclinical study demonstrating the synergistic antitumor effect of recombinant interleukin 2 (rIL-2) and beta-interferon (IFN-beta) on mouse tumors and previous results of a phase I study of rIL-2, a phase I study of combination therapy with human rIL-2 and IFN-beta was conducted in 26 patients with advanced malignancy. Patients were given rIL-2 by 24-h continuous i.v. infusion and IFN-beta by 2-h i.v. infusion for 5 days each week for 4 weeks. The common side-effects were fever, malaise, chills, appetite loss, and diarrhea. Leukocytosis and eosinophilia were observed in 56% and 69% of the patients, respectively. Transient leukopenia and thrombocytopenia were also observed in some patients. Dose-limiting manifestations were intolerable fatigue and liver dysfunction, and it was concluded that the maximum tolerated doses of rIL-2 combined with IFN-beta were 1.1 x 10(6) U/m2/day for rIL-2 and 6.0 x 10(6) IU/m2/day for IFN-beta. No patients achieved complete and partial response to therapy in this study. One patient with pulmonary metastasis from pharyngeal cancer showed a minor response. Natural killer (NK) and lymphokine-activated killer (LAK) activities increased during the 5 days of treatment and decreased during the 2-day intermission. The percentage of IL-2 receptor-positive cells increased markedly until Day 12, and gradually decreased thereafter. The percentage of OKT 4-positive cells and the OKT 4/OKT 8 ratio increased. In contrast, the percentage of Leu 7- or Leu 11-positive cells decreased over the 4-week treatment. A phase II study of this combination therapy is ongoing against head and neck cancer, and renal cell carcinoma.     

Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients

We report a phase I study in cancer patients being treated with i.v. bolus injections of highly purified lipopolysaccharide (LPS) Salmonella abortus equi. Twenty-four patients with disseminated cancer received escalating doses of LPS at 2-week intervals. Dose escalation was performed in six dose levels treating 3-6 patients at each level. Dose levels 1 and 2 consisted of 0.15 and 0.3 ng/kg, respectively. Further dose escalation up to 5.0 ng/kg was enabled by pretreatment with ibuprofen, which attenuated the constitutional side effects of LPS. The maximum tolerated dose was 4.0 ng/kg with dose-limiting toxicity being World Health Organization grade III hepatic toxicity. Hematological changes included transient decreases in WBCs affecting granulocytes, monocytes, and lymphocytes in a marked different pattern. Endogenous cytokine release occurred in an LPS dose-dependent manner as measured by tumor necrosis factor-alpha, interleukin-6, and macrophage colony-stimulating factor serum levels. Moderate antitumor activity in colorectal cancer was observed in the case of 2 patients. Phase II trials of LPS are currently in progress.     

Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study.

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4-week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.     

Phase I/II study of thalidomide in combination with interleukin-2 in patients with metastatic renal cell carcinoma

BACKGROUND: The purpose of the study was to determine, in a Phase I/II study, the efficacy and safety profile of thalidomide with interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma (MRCC). METHODS: Fifteen patients (8 of whom were previously treated) enrolled in Phase I were treated with escalating doses of oral thalidomide (200-600 mg) and a fixed dose of IL-2 (7 mIU/m(2)) by subcutaneous injection. A course was 6 weeks, with the exception of Course 1, which was 7 weeks. Thirty-seven Phase II patients who had not received prior chemotherapy or immunotherapy for renal cell carcinoma (RCC) received an initial thalidomide dose of 200 mg at Week 0, which was escalated to 400 mg after 48 hours. Subcutaneous IL-2 was administered at the same fixed daily dose used in Phase I. RESULTS: Fifty-one of 52 Phase I/II patients were evaluable. Twenty-seven patients (52%) experienced disease control, including 4 (8%) complete responses, 15 (29%) partial responses, and 8 (15%) cases of stable disease. Disease progression was observed in 24 patients (47%). Survival in the 2 phases ranged from 4 weeks to 45.2+ months. At the time of last follow-up, 2 of 51 patients (4%) remained on maintenance thalidomide therapy and continue to be followed. Three of the 51 patients with CRs (6%) ceased thalidomide therapy at 23-25 months and have maintained their responses to date. One complete responder was lost to follow-up. As of January 2005, 14 of 51 patients (27%) remained alive. Toxicities were mild to moderate, including Grade 1 to 2 somnolence, constipation, neuropathy, rash, flu-like symptoms, fluid retention, hypotension, and hypothyroidism (according to version 2.0 of National Cancer Institute Common Toxicity Criteria). In addition, two patients experienced deep venous thrombosis. CONCLUSIONS: Thalidomide in combination with IL-2 is tolerable and can produce durable, active responses in patients with MRCC. To evaluate the merits of thalidomide as a valuable agent against MRCC and to more fully determine the efficacy of thalidomide/IL-2 combination therapy, the scrutiny of Phase III testing is required. Further development of thalidomide/IL-2 combination therapy will be the focus of this group.     

Treatment of metastatic renal cell carcinoma with subcutaneous interleukin 2: evidence for non-renal clearance of cytokines.

The circulating cytokine concentrations following administration of subcutaneous recombinant interleukin 2 (IL-2) in combination with interferon alpha and 5-fluorouracil used to treat advanced renal cancer were studied. One patient was anephric and on dialysis, and seven had normal biochemical renal function, although five had undergone single nephrectomy. The pharmacokinetics of IL-2 and changes in IL-6 and tumour necrosis factor (TNF)-alpha were essentially similar in all patients including the anephric patient, irrespective of the periods of dialysis, although at some time points, IL-2 concentrations were slightly higher in the anephric patient than in the others. These results show that for subcutaneous administration of low-dose IL-2, renal clearance of IL-2 is not important. This contrasts with high-dose, intravenous IL-2 where blood concentrations are higher and renal clearance seems to occur, perhaps because of saturation of the non-renal mechanisms of clearance. The subcutaneous route is certainly preferred if IL-2 is used in anephric patients and in those with impaired renal function, and it may be generally preferred for most purposes.     

Treatment of metastatic renal cell cancer patients with recombinant subcutaneous human interleukin-2 and interferon-alpha

We treated 17 patients who had progressive metastatic renal carcinoma with a combination of subcutaneous recombinant human interleukin-2 (administered every 12 hours, at 9.0 million IU/m2 on days one and two, followed by 1.8 million IU/m2, five days per week, over six consecutive weeks) and interferon-alpha 2b (given at 5 million U/m2 three times weekly, for six consecutive weeks). Treatment courses were repeated in patients presenting with stable or regressive disease after the six weeks of combination therapy (11 of 14 evaluable). Two and three of 14 evaluable patients achieved complete and partial remissions, respectively. Toxicity of this regimen was moderate, with local inflammation of the injection sites, grade I-II (WHO) fevers, chills, malaise, nausea/vomiting, and anorexia in more than two-thirds of the patients treated.     

Adjuvant subcutaneous interleukin-2 in patients with resected renal cell carcinoma: a pilot study

Background

A pilot study was conducted to investigate the toxicity and tolerance to low-dose subcutaneous interleukin-2 (IL-2) for patients with resected renal cell carcinoma (RCC) at high risk for recurrent disease (TNM stages III and IV resected distant metastases).

Patients and Methods

Patients with surgically resected locally advanced (T3-4 or N1-2) or metastatic RCC were randomly assigned to 1 of 4 treatment groups that received different dose levels and schedules of subcutaneous IL-2 as follows: dose level 1, 4 MIU/m² per day, every other week for 24 weeks (n = 10); dose level 2, 8 MIU/m² per day, every other week for 24 weeks (n = 9); dose level 3, 4 MIU/m² per day, weeks 1-4, 9-12, and 17-20 (n = 11); and dose level 4, 8 MIU/m² per day, weeks 1-4, 9-12, and 17-20 (n = 10). Interleukin-2 was administered in 2 daily doses on days 1-5 of each week indicated. A dose level was considered tolerable if no more than 2 patients experienced grade 3/4 toxicity.

Results

Forty-one patients were entered in the study and 40 were evaluable for toxicity. Therapy was well tolerated at all dose levels and schedules, with most patients (98%) experiencing mild-to-moderate constitutional symptoms. Grade 3/4 toxicity was seen in 8 patients (20%). Interleukin-2 dose reductions were required in 7 patients, and no patient discontinued therapy secondary to toxicity. Of 39 patients evaluable for efficacy, 31 have experienced relapse (79%), and 15 have died (38%). Median survival was 1.4 years, and the 3-year disease-free survival rate was 33%. Median overall survival has not been reached; however, the 3-year survival rate was 70%. There was no statistically significant difference between any of the treatment arms with respect to disease-free survival or 3-year survival (P > 0.54 and P ≥ 0.09 for all pairwise comparisons), schedules (dose level 1/2 vs. 3/4; P = 0.46 and P = 0.5), or dose of IL-2 administered (dose level 1/3 vs. 2/4; P = 0.99 and P = 0.1).

Conclusion

Subcutaneous IL-2 was well tolerated for 6 months in patients with surgically resected RCC at high risk of recurrence. Future adjuvant trials in this setting are not likely to include IL-2 in view of the clinical efficacy and favorable toxicity profiles of selected multitargeted kinase inhibitors.