Recombinant alpha-interferon and vinblastine in metastatic renal cell carcinoma: efficacy of low doses

Twenty-six patients with metastatic renal cell carcinoma (RCC) were treated in a phase I-II trial with recombinant interferon alpha-2b (alpha-IFN) and vinblastine (VBL) in combination. Patients received IFN at a starting dose of 3 x 10(6) IU/m2 subcutaneously three times a week and VBL 0.1 mg/kg intravenously every 3 weeks, with dose modification for toxicity. All patients were evaluable for toxicity; 18 patients were evaluable for efficacy. An objective response rate of 44% was observed (eight of 18 patients, with one complete response and seven partial responses). The median duration of response was 5 months. The actuarial survival of responding patients was significantly longer than that of nonresponding patients. In general, the toxicity was tolerable; the subjective toxicity and fever were similar to that reported for the same doses of IFN alone. Only a mild neurotoxicity, usually mixed polyneuropathy, occurred with increased frequency. Alpha-IFN and VBL administered at low doses in combination demonstrated the highest response rate so far reported in RCC without significant toxicity.     

Treatment of Hairy Cell Leukaemia with 2'-Deoxycoformycin

The adenosine deaminase inhibitor 2'-deoxycoformycin (DCF) has been used to treat 40 patients with hairy cell leukaemia (HCL) who have been followed up for a minimum of 6 months. 21 patients had previously undergone splenectomy. 33 had received treatment with alpha-interferon (IFN), half of whom had relapsed and the remainder had either been partially treated due to intolerance or had an incomplete response. Deoxycoformycin was administered by slow intravenous injection at a dose of 4 mg/m² weekly for 4 consecutive weeks and then 2-weekly for 4 doses followed by 4-weekly injections until a complete remission was achieved. No maintenance therapy was given. The overall response rate was 97yi, with 82% complete remission (CR) and 15% partial remission (PR). CR have lasted from 3+ to 30+ months (median 12 +) with no relapses recorded so far. Only one evaluable patient, suffering from a variant form of HCL, failed to respond to DCF, whilst two other HCL-variant cases who had been resistant to alpha-IFN have achieved a PR and are still on treatment. DCF was generally well tolerated, the major toxicity being related to cytopenia and associated infection. Four patients developed severe infections, one of whom died of septicaemia before it was possible to evaluate the response to DCF. A group of 12 patients who had received alpha-IFN immediately prior to treatment with DCF and had obtained clinical and haematological benefit had fewer infections with DCF than the group who had either not received IFN immediately before or who had failed to respond to it. In view of the infections associated with DCF, we would now recommend initial therapy for HCL patients with alpha-IFN for 2-4 months to obtain clinical and haematological improvement, followed by DCF given 2-weekly, to eradicate residual disease. This approach may achieve a higher proportion of sustained CR with a short treatment time and minimal toxicity.     

Evidence for an association between hairy cell leukemia and renal cell and colorectal carcinoma.

BACKGROUND. Hairy cell leukemia (HCL) has been associated with several disease states. In this study, a possible association is reported between HCL and renal cell carcinoma (RCC) and colorectal carcinoma (CRC). METHODS. A retrospective study of the case records of 50 patients with HCL in a study of alpha-interferon (alpha-IFN) treatment of HCL. RESULTS. Three of 50 patients with HCL studied had RCC, and 2 of these also had CRC. In addition, two other patients had CRC. The other malignant lesions developed either before or after the diagnosis of HCL. In all patients, the HCL responded to alpha-interferon (alpha-IFN), but in four patients, the second lesion was diagnosed during IFN treatment. CONCLUSIONS. These findings could indicate that IFN does not correct a possible common basic etiologic defect and shows that even early CRC and RCC do not respond to the IFN doses administered. These findings should be considered in future trials of IFN treatment of these diseases. The authors also recommend a reevaluation of the frequency of second malignant lesions in HCL; this may be important particularly with the increased survival in patients with HCL who receive alpha-IFN treatment.     

A phase I study of recombinant human interleukin-2 and alpha-interferon-2a in patients with renal cell cancer, colorectal cancer, and malignant melanoma

Preclinical data suggest synergy of interleukin-2 (IL-2) combined with alpha-interferon (IFN). In addition, toxicities of IL-2 may be decreased by intermittent continuous infusion. The purpose of this trial was to determine the maximum tolerated dose (MTD) of recombinant IL-2 combined with alpha-IFN in patients with renal cancer, colon cancer, melanoma, and malignant B-cell disease. IL-2 was given by continuous i.v. infusion at an initial dose of 5 X 10(5) units (U)/m2/d for 4 days plus IFN at 6 X 10(6) U/m2/d intramuscularly days 1 and 4 weekly for 4 weeks. Patients who achieved a response or stable disease received an additional 4 weeks of therapy. IL-2 doses were increased to 1, 2, 3, 5, and 7 X 10(6) U/m2/d with three to eight patients at each dose level, at each of the two participating institutions. The dose of IFN was 6 X 10(6) U/m2 days 1 and 4 for all but five patients whose IFN dose was doubled to 12 X 10(6) U/m2/d. Forty-three patients were entered on this study with 34 completing at least 4 weeks of therapy. Six patients were taken off study because of Grades III or IV pulmonary, neurologic, or cardiac toxicity; one for progressive disease; one for CNS metastases, and one for personal reasons. All of the toxicities were reversible. Chills and fever were universal, especially on days 1 and 4. Mild and moderate nausea, vomiting, diarrhea, anorexia, malaise, and cutaneous erythema were present in most patients. Fluid retention and occasional pleural effusions were observed at the higher IL-2 doses but were not dose-limiting. Significant hypotension associated with oliguria was seen, and these patients were treated with vasopressors and colloids. None of the patients required ICU admission. Thirty-four patients were evaluable for response. There were 4/18 (22%) renal cell patients who experienced a partial response. No responses were seen in patients with melanoma, lymphoma, or colorectal cancer. The combined debilitating symptoms of fatigue, diarrhea, hypotension, fluid retention, and anorexia defined the MTD as 5 X 10(6) U/m2/d of IL-2 and 6 X 10(6) U/m2 of alpha-IFN.     

Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon

PURPOSE: We have evaluated the tumor tissue pO2 in cervical cancers during radiotherapy with special emphasis on the course of the pO2 in primarily hypoxic tumors and in patients treated with radiotherapy plus 13-cis-retinoic acid/interferon-alpha-2a. METHODS AND MATERIALS: From June 1995 through April 1997, 49 patients with squamous cell carcinoma FIGO IIB-IVA of the cervix who were treated with definitive radiotherapy with curative intent underwent polarographic measurement of tumor tissue pO2 with an Eppendorf pO2-histograph prior to and during radiation treatment. Radiotherapy consisted of external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus high dose rate (HDR) brachytherapy. Twenty-two patients had additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) and interferon-alpha-2a (IFN-alpha-2a). Therapy with cRA/IFN in these patients started 2 weeks before radiotherapy; during this induction period, cRA was administered in a dosage of 1 mg per kilogram body weight orally daily and IFN-alpha-2a in a dosage of 6x10(6) I.U. subcutaneously daily. After start of external radiotherapy (XRT), cRA/IFN was continued concomitantly with radiotherapy in reduced doses (0.5 mg cRA per kg body weight orally daily plus 3x10(6) I.U. IFN-alpha-2a subcutaneously three times weekly until the end of the radiation treatment). PO2 measurements were performed prior to radiotherapy, at 20 Gy, and at the end of radiotherapy. RESULTS: A poor oxygenation defined as a median pO2 of 10 mm Hg or less was present in 15/38 tumors (39%) in which measurements prior to any treatment were done. Low pO2 readings below 5 mm Hg were present in 70% of all tumors prior to treatment. In 13 of 15 hypoxic tumors, pO2 measurements at 19.8 Gy were performed. In these tumors, a significant increase of the median pO2 from 6.0+/-3.1 mm Hg to 20.7+/-21.2 mm Hg was found, p<0.01. The increase in the median pO2 was more pronounced in patients with radiotherapy plus additional cRA/IFN treatment as compared to patients treated with irradiation alone (median pO2 raised from 7.0+/-3.5 mm Hg to 40.9+/-21.3 mm Hg versus 5.7+/-3.1 mm Hg to 14.7+/-17.9 mm Hg). In a multivariate analysis, both the effect of radiation dose (pretreatment versus 19.8 Gy) and the type of treatment (XRT alone versus XRT plus cRA/IFN) had significant impact on the pO2 (P = 0.003 and p = 0.04). In patients with well-oxygenated tumors (pretreatment median pO2>10 mm Hg), 20/23 (87%) achieved a clinically complete response. In patients with primarily hypoxic tumors, 6/6 patients whose primarily hypoxic tumors showed an increase of the median pO2 above 10 mm Hg at 19.8 Gy achieved a complete remission (CR). In contrast, only 4/7 patients with a low pretreatment and persisting low median pO2 achieved a CR. CONCLUSIONS: There are evident changes in the oxygenation of cervical cancers during a course of fractionated radiotherapy. In primarily hypoxic tumors, a significant increase of the median pO2 was found. An additional treatment with cis-retinoic acid/interferon further improved the oxygenation. An impact of the different patterns of oxygenation on local control is to be evaluated.     

Concomitant administration of recombinant human interleukin-2 and recombinant interferon alfa-2A: an active outpatient regimen in metastatic renal cell carcinoma.

PURPOSE: A phase II trial of interleukin-2 (IL-2) and interferon alfa (IFN-alpha) in metastatic renal cell carcinoma (RCCa) was conducted. A lower dosage of IL-2 was given via continuous intravenous (IV) infusion, a route with documented tumor activity associated with less toxicity, with the purpose of improving the therapeutic index of this treatment in an outpatient setting. PATIENTS AND METHODS: Thirty patients with metastatic RCCa were treated with the combination of IL-2 and IFN-alpha-2A. IL-2 was administered on days 1 through 4 of each treatment week, as a continuous IV infusion at a dose of 2 x 10(6) U/m2/d. IFN-alpha-2A was administered intramuscularly or subcutaneously on days 1 and 4 of each treatment week, at a dose of 6 x 10(6) U/m2/d. One treatment course included 4 weeks of treatment followed by a 2-week rest. Patients received therapy as outpatients except for the first 4 days of treatment, cycle 1 only. All patients were assessable for toxicity and response assessment. A total of 105 courses of therapy were administered, 51% at full dose. RESULTS: Sixteen patients experienced toxicities resulting in dosage modification. The major treatment-limiting toxicities were gastrointestinal, neurologic, and fatigue. Nine patients (30%) had partial remissions (PRs) with a median duration of responses of 12+ months. The median time to response was 11 weeks. Two partial responders whose sites of metastatic disease were renal fossa and mediastinal lymph nodes (LN), respectively, were found to have achieved a pathologic complete remission (pCR) after surgery. A third patient with a pCR of axillary LN was rendered into a surgical complete remission (sCR) with salvage nephrectomy. Median survival of patients obtaining a PR has not been reached with a median follow-up time of 19+ months. CONCLUSION: IL-2 and IFN-alpha-2A is well tolerated in the outpatient treatment setting and demonstrates significant clinical activity against RCCa.     

Response to alpha-interferon in children with Philadelphia chromosome-positive chronic myelocytic leukemia.

The therapeutic efficacy and toxicity of alpha-interferon (alpha-IFN) (Roferon, Hoffmann-La Roche, Inc., Nutley, NJ) were determined in 15 children (age range, 6 to 20 years) with Philadelphia chromosome-positive chronic myelocytic leukemia (Ph+ CML). All patients had received cytoreductive therapy with either hydroxyurea (n = 13) or busulfan (n = 1) or both (n = 1) for 6 weeks to 46 months (median, 7 months) before beginning alpha-IFN therapy at a dose of 5 x 10(6) U/m2/d intramuscularly. This dose was escalated to 10 x 10(6) U/m2/d if leukemia was inadequately controlled. Ten children had a hematologic response, with nine showing a reduction in the percentage of Ph+ marrow cells, including four who had no detectable Ph+ cells in marrow samples collected 48 to 204 weeks after the initiation of therapy. Two of 15 patients remain free of Ph+ cells. Therapy was discontinued before week 104 in ten patients because of the following: (1) early hematologic responses without a decrease in Ph+ cells (three patients); (2) early resistant disease (one patient); (3) blast crisis (one patient); (4) progressive disease (two patients); (5) seizure attributed to high-dose alpha-IFN (one patient); or (6) an inadequate trial of alpha-IFN caused by aseptic necrosis or poor compliance (two patients). The most common side effects were mild and have included fever, malaise, headache, myalgias, and pain at the injection site. Adverse events causing interruption of therapy were seizures, aseptic necrosis, and myelofibrosis. alpha-IFN stabilizes the chronic phase of Ph+ CML in some children, is adequately tolerated when administered at a dose of 2.5 to 5 x 10(6) U/m2/d intramuscularly, and results in a significant decrease in the proportion of Ph+ metaphases in some patients. alpha-IFN in combination with an effective cytoreductive agent or agents appears worthy of further clinical testing in this disease.     

Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer

We performed an escalating dose study of the combined administration of interleukin-2 (IL-2) and alpha-interferon (alpha-IFN) in 94 patients with metastatic cancer. Patients received alpha-IFN at a dose of 3 x 10(6) U/m2 in conjunction with IL-2 at doses of either 1 x 10(6) U/m2 (six patients), 3 x 10(6) U/m2 (32 patients), or 4.5 x 10(6) U/m2 (26 patients). Thirty patients received alpha-IFN at 6 x 10(6) U/m2 plus IL-2 at 4.5 x 10(6) U/m2. Patients each received cytokine as an intravenous bolus infusion every 8 hours for up to 5 consecutive days and after a 10-day rest received a second cycle of combination cytokines. Of the 91 patients evaluable for response, seven patients had a complete regression of cancer, and 18 had a partial regression. At the four increasing dose levels used in patients with renal cell cancer (35 patients) or melanoma (39 patients), objective responses were seen in 17% (of six patients), 24% (of 25 patients), 38% (of 16 patients), and 41% (of 27 patients), respectively. Of the 25 total responding patients, 16 are still responding 5 to 14 months after treatment. The toxicities associated with the combined administration of IL-2 and alpha-IFN were similar to those expected from each agent alone. There was one treatment-related death in the 94 patients treated in this study. Thus, using increasing doses of the combination of IL-2 and alpha-IFN, it appears that response rates may be related to the doses of the cytokines used, and that at the highest doses of these combination cytokines, response rates may be higher than those for either cytokine alone. A prospective randomized trial comparing the cytokine combinations with each cytokine administered alone is necessary as is the extension of this combination cytokine treatment to patients with other types of solid cancer.     

Phase I trial of high-dose bolus interleukin-2 and interferon alfa-2a in patients with metastatic malignancy.

PURPOSE: Based on preclinical evidence that the antitumor effects of the combination of interleukin-2 (IL-2) and interferon alfa (IFN alpha) are greater than those of either cytokine alone, we have performed a phase I trial of recombinant IL-2 (rIL-2) and recombinant human IFN alpha 2a (rHuIFN alpha 2a) in patients with refractory malignancies. This study was an extension of an earlier trial that identified reversible myelosuppression as the dose-limiting toxicity of this combination. The present trial used modified definitions of unacceptable toxicity to allow exploration of higher doses of rIL-2. PATIENTS AND METHODS: Both rHuIFN alpha 2a 10.0 x 10(6) U/m2 intramuscularly (IM) and rIL-2 were administered three times weekly for 4 consecutive weeks. IL-2 was given by intravenous (IV) bolus injection at doses that were escalated in successive cohorts of four to six patients, provided that toxicity at the preceding dose level was acceptable. Unacceptable toxicity was defined as an elevation of the serum creatinine level to greater than 5 mg/dL, an elevation of the serum bilirubin level to greater than 5 mg/dL, dyspnea at rest, hypotension refractory to pressors, altered mental status, or other toxicities of grade 3 to 4, using the National Cancer Institute (NCI) Common Toxicity Criteria. The doses of rIL-2 administered were 4.0 x 10(6), 6.0 x 10(6), 8.0 x 10(6), 10.0 x 10(6), 12.0 x 10(6), 14.0 x 10(6), 18.0 x 10(6), 22.0 x 10(6), and 26.0 x 10(6) BRMP (Hoffman-LaRoche) U/m2. At a dose of rIL-2 10.0 x 10(6) BRMP U/m2, patients were also treated with doses of rHuIFN alpha 2a of 1.0 x 10(6) and 0.1 x 10(6) U/m2. RESULTS: A total of 57 patients were treated. Intolerable side effects (hypotension, pulmonary, and CNS toxicity) were produced by rIL-2 26.0 x 10(6) BRMP U/m2 and rHuIFN alpha 2a 10.0 x 10(6) U/m2. Two of 21 patients with renal cell carcinoma showed objective responses, and five of 17 patients with malignant melanoma responded. Two of these responses in melanoma were complete and continue to be longlasting. CONCLUSIONS: When given with rHuIFN alpha 2a 10.0 x 10(6) U/m2 as described above, the maximum-tolerated dose of rIL-2 is 22.0 x 10(6) BRMP U/m2. This dose of rIL-2 is equivalent to 50 to 60 MIU/m2, depending on the conversion factor used. Based on this experience and other trials, we favor phase II trials in renal cell carcinoma using an alternative dose schedule of this cytokine combination, in which rIL-2 is administered by continuous infusion. We suggest that phase II trials of this combination in patients with melanoma use an rIL-2 dose of 8.0 x 10(6) BRMP U/m2 by IV bolus injection three times weekly in combination with rHuIFN alpha 2a 10.0 x 10(6) U/m2 IM three times weekly.     

A phase I study of an outpatient regimen of recombinant human interleukin-2 and alpha-2a-interferon in patients with solid tumors

This study was undertaken to define the maximum tolerated dose (MTD) of recombinant interleukin-2 (IL-2) that could be combined with a fixed dose of alpha-2a-interferon (alpha-IFN) in an outpatient setting. The schedule called for IL-2 to be given by a 2-hour intravenous infusion 5 days a week for 4 weeks. The alpha-IFN was given at a dose of 6 x 10(6) U/m2/d intramuscularly 3 days per week (Monday, Wednesday, and Friday). The IL-2 dose was escalated in four dose levels from 1 to 4 x 10(6) U/m2/d. The MTD in this study of 17 patients was at the fourth dose level of IL-2 (4 x 10(6) U/m2/d). In addition to the usual IL-2 toxicities, debilitating fatigue limited outpatient administration of this dose. Although the response rate was low, with partial responses seen in only 1 of 15 patients, 2 of 5 patients with melanoma treated at the higher dose levels had objective tumor shrinkage with one partial and one minor response. Thus, an IL-2 dose of 3 x 10(6) U/m2/d combined with a recombinant alpha-2a-IFN dose of 6 x 10(6) U/m2/d is recommended for Phase II studies.     

Studies on the optimal dose and the mode of action of alpha-interferon in the treatment of hairy cell leukemia

The therapeutic efficacy and side effects of alpha-2c-interferon (IFN-alpha 2c) treatment of hairy cell leukemia were compared between two different dose regimen: 10 patients received maximum tolerable doses of IFN-alpha 2c for 1 year (group A), and 11 patients received minimum doses of IFN-alpha 2c, which induced an optimal biological response (group B). Induction of neopterin excretion was chosen as the marker to define biological response and the dose of IFN-alpha 2c applied was on average only one tenth of that in group A cases. Average time of treatment in group B was 42 weeks. The data indicate that both dose levels are effective in the treatment of advanced hairy cell leukemia but that the low dose regimen is free of toxicity. Laboratory investigations on the mechanism of IFN-mediated remission in HCL further revealed that hairy cells are resistant to lysis by IFN-alpha activated large granular lymphocytes and that improved natural killer function subsequent to IFN-alpha treatment in vivo is primarily due to the disappearance of leukemic hairy cells which dilute the natural killer effector cells. These findings support the view of a direct antitumor activity of IFN-alpha as the main therapeutic principle.     

Proliferative response of hairy cells to B cell growth factor (BCGF): in vivo inhibition by interferon-alpha and in vitro effects of interferon-alpha, -beta, and -gamma

Hairy cell leukemia (HCL) is a pre-plasma B cell tumor which responds to interferon (IFN)-alpha therapy. In vitro, B cell growth factor (BCGF) can induce proliferation of hairy cells. We have investigated the effect of in vitro and in vivo treatments with different recombinant IFN on the capacity of hairy cells to proliferate in response to human BCGF. In vitro treatment of leukemic cells from HCL patients with recombinant IFN-alpha-2 (5/5 cases) or IFN-beta (4/5 cases) resulted in a marked inhibition of the BCGF-dependent response. This suppressive effect was obtained with IFN concentrations of 1000, 100 IU/ml, and even occasionally 10 IU/ml. In contrast, no such inhibition was observed with IFN-gamma, despite the presence of specific IFN-gamma receptors on hairy cells at densities similar to receptors for IFN-alpha/beta. The IFN-alpha-induced suppression of the proliferative response of hairy cells to BCGF was also observed in vivo in two patients within 6-12 hr after administration of single doses of IFN-alpha. When hairy cells were maintained in culture for 1 week, they recovered their capacity to be stimulated by BCGF. This reversion was also shown in vivo in hairy cells isolated 1 week after IFN administration. Since in vivo growth of hairy cells could possibly result from the autocrine secretion of BCGF, we propose that the therapeutic effect of IFN-alpha on HCL may be due in part to an inhibition of such autocrine loop.     

Human recombinant interferon-alpha-2 in the treatment of patients with hairy cell leukemia

During the last 2 years, we have treated 14 hairy cell leukemia (HCL) patients with human recombinant interferon-2 alpha (Boehringer Ingelheim). The above group consisted of eight nonsplenectomized and six previously splenectomized progressive HCL patients. The patients received daily doses of 5 x 10(6) units of IFN for 3 months and two doses per week for the next 3 months thereafter by i.m. route. The therapy resulted in the complete (nine cases, = 64.3%) or partial (two cases = 14.3%) clinical and hematological remission (response rate 78.6%), with either disappearance or marked reduction in circulating and bone marrow hairy cells, decreased spleen size, and recovery of normal hemopoiesis. Apart from a transient flulike syndrome during the first 2 weeks of therapy, no other side effects were observed.     

A phase II trial of intra-cerebrospinal fluid alpha interferon in the treatment of neoplastic meningitis

BACKGROUND: Neoplastic meningitis (NM), a metastatic complication of both primary central nervous system and systemic cancer, occurs in 1-5% of patients with known cancer. Currently available treatment options are limited and provide only modest benefit. The current study was performed to determine the toxicity and response rate of intra-cerebrospinal fluid (CSF) alpha interferon (alpha-IFN) in the treatment of patients with NM. METHODS: Twenty two patients (median age, 56 years) with clinical and cytologically documented NM received intra-CSF alpha-IFN. Tumor histologies included: lung (five patients); brain (five patients); non-Hodgkin lymphoma (three patients); breast (three patients); melanoma (two patients); chronic myelogenous leukemia (two patients); colon (one patient); and prostate (one patient). Concurrent involved-field radiotherapy (12 out of 22 patients) or systemic chemotherapy (11 out of 22) was administered based on clinical indications. -alpha-IFN was administered at a fixed dose (1 x 10(6) IU every other day given three times per week for four weeks by induction). Patients were evaluated by CSF cytology and neurologic examination at the conclusion of induction therapy. Responding patients continued to receive alpha-IFN with monthly evaluations. RESULTS: Ten out of 22 patients (45%) treated with alpha-IFN had a cytologic response and either stable or improved neurologic status at the conclusion of induction. Duration of response ranged from 8 to 40 weeks (median, 16 weeks). Toxicity was manifested as transient chemical arachnoiditis (16 out of 22 patients; 60% of all treatment cycles) and chronic fatigue (20 out of 22 patients). No treatment-related hospitalizations or deaths were seen. CONCLUSIONS: alpha-IFN has modest activity against NM. However, it is associated with considerable toxicity at the dose and schedule used in the current study and, as a result, may prove difficult to administer.     

Recombinant interferon-alpha combined with prednisone in metastatic renal cell carcinoma. Reduced toxicity without reduction of the response rate--a phase II study

Five responses (lung metastases, three; lymph node metastases, two) were observed in 23 patients with metastatic renal cell carcinoma who received recombinant interferon-alpha-2A (IFN) 18 X 10(6) U in three intramuscular doses each week combined with oral prednisone (10 to 20 mg daily). The response duration was 4+, 4+, 9, 11+, and 15+ months. In general, the combination treatment of interferon and prednisone lead to a significant reduction of the subjective side effects (flu-like symptoms) as compared to a previous experience in patients treated with interferon only. Reduction of the interferon dose or discontinuation of IFN treatment was necessary in only two of 23 patients receiving IFN plus prednisone. Prednisone, however, had little effect on the hepatic toxicity often associated with high-dose IFN treatment. The subjective tolerability of a high dose of IFN is significantly increased if oral prednisone (10-20 mg) is given concomitantly in patients with metastatic renal cell carcinoma without reducing the response rate. Randomized trials will be necessary to confirm the efficacy of the IFN and prednisone combination. In addition, higher doses of IFN combined with prednisone should be evaluated in this malignancy.     

Recombinant interleukin-2 and interferon-alpha-2a in pretreated advanced soft-tissue sarcomas

Fourteen patients with advanced soft tissue sarcomas (STS), all pre-treated with one or more chemotherapy (CT) lines, entered an outpatient phase 11 study in which subcutaneous recombinant Interleukin-2 (rIL-2) and intramuscular recombinant alpha-2a-interferon (r-alphaIFN) were concomitantly administered. Both the cytokines were given for 5 days/week for 3 consecutive weeks followed by a 2 weeks period during which only r-alphaIFN was administered. r-alphaIFN was provided at a dose of 3 x 10(6) International Units (IU), while rIL-2 was given at a dosage of 6 x 10(6)/m2/day IU (in 2 subcutaneous injections), starting from 2 x 10(6)/m2/day IU in the first week and progressively increasing to 4 and 6 x 10(6)/m2/day IU in the second and third weeks; in 4 patients the dose of 8 x 10(6)/m2/day IU was reached. Toxicity was moderate and correlated with rIL-2 dose; main side effects included changes in liver functionality tests (14/14), fever (13/14), fatigue (13/14), nausea and vomiting (9/14). In all 11 patients evaluable for response, stable disease (SD) was observed (duration 4-43 weeks; median 9 weeks); the median survival from the starting treatment was 18 weeks (range 10-52). In all treated patients, an immunological monitoring was performed: an increase in percentage (from 10 to 74%) and in absolute number (from 400 to 4.500 cells/mm3) of CD16+ lymphocytes (NK cells) was observed in the majority of cases. Our data indicate that this regimen can be administered in pre-treated and severely immunocompromised patients with minimal to moderate toxicity on ambulatory and home bases, with acceptable clinical results.     

Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies.

PURPOSE: To evaluate the toxicity, pharmacokinetics, immunogenicity, and antitumor activity of anti-Tac(Fv)-PE38 (LMB-2), an anti-CD25 recombinant immunotoxin that contains an antibody Fv fragment fused to truncated Pseudomonas exotoxin. PATIENTS AND METHODS: Patients with CD25(+) hematologic malignancies for whom standard and salvage therapies failed were treated with LMB-2 at dose levels that ranged from 2 to 63 microg/kg administered intravenously over 30 minutes on alternate days for three doses (QOD x 3). RESULTS: LMB-2 was administered to 35 patients for a total of 59 cycles. Dose-limiting toxicity at the 63 microg/kg level was reversible and included transaminase elevations in one patient and diarrhea and cardiomyopathy in another. LMB-2 was well tolerated in nine patients at the maximum-tolerated dose (40 microg/kg QOD x 3); toxicity was transient and most commonly included transaminase elevations (eight patients) and fever (seven patients). Only six of 35 patients developed significant neutralizing antibodies after the first cycle. The median half-life was 4 hours. One hairy cell leukemia (HCL) patient achieved a complete remission, which is ongoing at 20 months. Seven partial responses were observed in cutaneous T-cell lymphoma (one patient), HCL (three patients), chronic lymphocytic leukemia (one patient), Hodgkin's disease (one patient), and adult T-cell leukemia (one patient). Responding patients had 2 to 5 log reductions of circulating malignant cells, improvement in skin lesions, and regression of lymphomatous masses and splenomegaly. All four patients with HCL responded to treatment. CONCLUSION: LMB-2 has clinical activity in CD25(+) hematologic malignancies and is relatively nonimmunogenic. It is the first recombinant immunotoxin to induce major responses in cancer. LMB-2 and similar agents that target other cancer antigens merit further clinical development.     

Results of the association of intralesional recombinant alpha-interferon-2a (alpha-IFN) plus 13-cis-retinoic Acid (13cra) in the treatment of Basal-cell carcinomas (bcc) of the skin

In this phase II study, twenty-four patients (median age 72 years) with BCC of the skin were treated with intralesional alpha-IFN plus 13cRA. Alpha-IFN was administered intralesionally at the dose of 3x10(6) I.U. for injection, 3 times/week for 4 weeks (total dose 12x10(6) I.U./cycle); concomitantly, 13cRA was given per os at a 0.2-0.4 mg/kg/day dose. The 4-week cycles were repeated after a one week interval, in which only 13cRA was administered. Patients were evaluated after at least 2 cycles of treatment. Sixteen of the 20 assessable patients (80%) showed an objective response (OR), 12 of whom (60%) had a complete response (CR). The overall OR rate was 75% (12/16) in patients treated with 0.2 mg/kg/day of 13cRA, and 100% (4/4) in patients who received 0.4 mg/kg/day of the drug. The median response duration was 12 months (range, 6 to 20). Toxicity was mild and reversible in all cases; major side effects observed were fever, nausea, skin erythema, hypertriglyceridemia and hypercholesteremia. These results show the efficacy and the feasibility of alpha-IFN and 13cRA acid association in BCC treatment, with good compliance even in elderly patients; this medical approach could be a valid choice of therapy in addition to the traditional surgical modalities, as it also produces satisfactory aesthetical results.     

Phase II trial of interferon-beta-serine in metastatic renal cell carcinoma

Interferon-beta-serine (IFN-beta-ser) is a muteine, recombinant IFN that is tolerated at a dose fivefold to 10-fold higher than IFN-alfa and interacts with the same cell membrane receptor as IFN-alfa. We hypothesized that at high doses IFN-beta-ser might induce a higher response rate than IFN-alfa in metastatic renal cell carcinoma. We undertook a phase II trial of IFN-beta-ser in patients with metastatic renal cell carcinoma. Patients were treated three times each week by a 2-hour intravenous infusion. Doses were escalated weekly (.25 to 5.5 mg, 1 mg = 180,000,000 U) until the maximum-tolerated treatment dose (MTTD) was determined. The MTTD is defined as one dose level less than that which caused grade 3 toxicity and was subsequently administered three times weekly for at least 4 weeks. Twenty-nine patients were entered, and 25 were assessable for response and toxicity. The performance status was 0-1 in all patients and only one patient received previous chemotherapy. The MTTD dose was 2.5 mg (range, 0.5 to 5.5 mg per treatment), although in 10 patients, doses were later deescalated because of cumulative toxicity. Initial dose-limiting toxicity and cumulative toxicity were fatigue, malaise, and fever in most patients. Hepatic transaminitis, neutropenia, and elevation of serum creatinine were also observed but were not dose-limiting. There was one complete response (CR) and four partial responses (PRs). All responses but one occurred in pulmonary metastases. The median time to response was 26 days (range, 17 to 102 days). These data demonstrate that IFN-beta-ser given in high doses exhibits significant antitumor activity in renal cell carcinoma; however, the objective response rate is 20%. This is no higher than previous IFN studies; therefore, we reject the hypothesis than IFN-beta-ser at high doses may induce a greater response rate than IFN-alfa. However, we did observe more responses than were seen in a similar trial undertaken with lower dose IFN-beta serine in renal cell carcinoma.     

Combined treatment with pegylated interferon-alpha-2a and dacarbazine in patients with advanced metastatic melanoma: a phase 2 study

BACKGROUND.: Dacarbazine (DTIC) and pegylated interferon (IFN)-alpha-2a have both demonstrated some efficacy as single agents in metastatic melanoma. To the authors' knowledge, the current study is the first to test a combination of these 2 agents in a phase 2 trial. METHODS.: Twenty-eight patients with stage IV melanoma without brain metastases were treated with DTIC (at a dose of 850 mg/m(2) every 3 weeks) combined with weekly pegylated IFN-alpha-2a at a dose of 180 mug. The study was initiated to evaluate the efficacy and tolerability of the combination. The primary study endpoint was objective response. RESULTS.: Twenty-five patients were evaluable for response. Two patients (8.0%) achieved a complete response that continued for >480 days and 746 days, respectively. Four patients (16.0%) demonstrated a partial response, and another patient experienced stable disease. Six of 7 nonprogressive patients had either not received treatment or had not developed disease progression during adjuvant IFN treatment for stage II/III disease. The median duration of response was 236 days, the median progression-free survival was 56 days, and the overall survival time was 403 days. Few grade 3 toxicities and only 1 grade 4 toxicity were observed (according to National Cancer Institute Common Toxicity Criteria). CONCLUSIONS.: The combination of DTIC and pegylated IFN-alpha-2a was found to be well tolerated in patients with metastatic melanoma. The response rate of 24%, including 2 long-lasting complete responses, is encouraging, but must be confirmed in larger trials. Cancer 2008. (c) 2008 American Cancer Society.