Outpatient intravenous interleukin-2 with famotidine has activity in metastatic melanoma.

UNLABELLED: Daily short intravenous interleukin-2 (IL-2) infusions have been developed to decrease toxicity while maintaining the anticancer activity of this agent against melanoma. Such IL-2 schedules have previously been shown to promote lymphokine-activated killer cell (LAK) activity. Famotidine may increase LAK activity by increasing IL-2 internalization by the IL-2 receptor on lymphocytes. Twenty-one patients with metastatic melanoma were treated with IL-2 18 million IU/m² intravenously (i.v.) over 15-30 minutes and famotidine 20 mg i.v. daily for 3 days for 6 consecutive weeks on an outpatient basis. Cycles were repeated every 8 weeks. PATIENT CHARACTERISTICS: 13 males/8 females, median age, 51 (range: 26-79), and median Eastern Cooperative Oncology Group performance status, 1; common metastatic sites: lymph nodes (16), lungs (14), subcutaneous (8), liver (7), and bone (7). Prior systemic therapy: chemotherapy (7); IL-2 (7); and interferon (5). Most common toxicities were myalgia/arthralgia, rigors, nausea/emesis, and mild elevation of liver function tests. No patients required hospitalization for toxicity of therapy. One patient (5%) has had a complete response (ongoing at 29+ months), while 4 other patients (19%) had partial responses (total response rate: 24%; 95% confidence interval: 9%-48%). Responses occurred in lung, spleen, bones, lymph nodes, and subcutaneous sites. Median response duration=20+ months. Outpatient intravenous IL-2 and famotidine has activity in melanoma.

Pulse interleukin-2 with famotidine induces CD56+ lymphocytes in the peripheral blood of patients with metastatic melanoma or kidney cancer.

Increased lymphokine-activated killer (LAK) cell numbers and cytotoxicity against tumor cell lines have been seen in patients receiving high-dose continuous and bolus infusion interleukin-2 (IL-2) regimens. LAK are CD56 positive on flow cytometry. Daily intravenous doses of IL-2 of 18-21.6 MIU/m(2) over 15-30 minutes ("pulses") have been developed to attempt to lessen the toxicity of this therapy. It has been previously shown that the patients with metastatic melanoma or kidney cancer may be treated safely with pulse IL-2 daily for 5 days preceded by intravenous famotidine. Cycles were repeated every 21 days. Because LAK numbers have not been previously described with this regimen, the present study has examined CD56 numbers via peripheral blood flow cytometry in 11 patients with samples scheduled at baseline, after two cycles, and after four cycles. Eight (8) patients had melanoma and 3 had kidney cancer. Median CD56 counts after two cycles was significantly higher than baseline (p = 0.001). Similarly, CD56 counts at 2 months later were also greater than baseline (p = 0.009). There was no difference between median values after two cycles versus after four cycles. Patients who were clinical responders had a median CD56 count of 650 after two cycles when compared with nonresponders who had a median CD56 count of 290 (p = 0.005). CD56 counts are significantly elevated in patients treated with pulse IL-2 with famotidine and clinical responders have significantly higher CD56 than nonresponders.

High-dose intensity pulse interleukin-2 with famotidine in metastatic kidney cancer.

Lymphokine-activated killer cell (LAK) activity against tumor cell lines may be induced by intravenous (i.v.) interleukin-2 (IL-2). Daily short infusions (pulses) have been developed to decrease toxicity while maintaining the anticancer activity of this agent against kidney cancer. The anthihistamine, famotidine, may increase IL-2 uptake by the IL-2 receptor on lymphocytes. We have treated 12 patients with metastatic kidney cancer, using pulse IL-2 (18 million IU/M(2) i.v.) over 15-30 minutes, preceded by famotidine (20 mg I.V. daily for 5 days) on an oncology inpatient unit. Cycles were repeated every 3 weeks until disease progression. Patient characteristics were as follows: 9 males with a median age of 66 years (range, 48-74), and median Eastern Cooperative Oncology Group performance status of 1; common metastatic sites included in the lungs 9 and lymph nodes 3. Median number of cycles received was 2 (range, 1-5). The most common toxicities were fever, rigors, and hypomagnesemia. Two (2) patients had partial responses (17% response rate). Responses occurred in the liver (11.5 months) and lung, pleura, and lymph nodes (3 months). Pulse IL-2 with famotidine shows activity in kidney cancer.

Activity of continuous infusion + pulse interleukin-2 with famotidine in metastatic melanoma.

High-dose interleukin-2 (IL-2), given via continuous intravenous (i.v.) infusion, induces lymphokine-activated killer (LAK) cell cytotoxicity against tumor cells. These LAKs exhibit enhanced cytotoxicity against tumor cells in vitro when they are subsequently pulsed with additional IL-2. Famotidine may increase LAK cytotoxicity against neoplastic cells by allowing for greater IL-2 uptake at the IL-2 receptor on lymphocytes. Twenty-three (23) patients received famotidine 20 mg i.v. twice per day and continuous-infusion IL-2 (18 MIU/m(2)/24 hours) for 72 hours, followed by a 24-hour rest, then 1-3 daily-pulse IL-2 doses of 18 MIU/m(2) over 15-30 minutes preceded by famotidine 20 mg i.v. Cycles were repeated every 3 weeks. The most common metastatic sites were lung, lymph node, and subcutaneous/soft tissue. The most common toxicities were fever, rigor, nausea/emesis, hypophosphatemia, hypotension, elevated creatinine, and pulmonary edema. There were no treatment-related deaths. One (1) complete (4%) and 9 partial responses (39%) were seen (43% total response rate; 95% confidence interval: 22%-65%). Median survival for all patients is 13 months. The combination of famotidine and high-dose continuous infusion + pulse IL-2 is active in metastatic melanoma.

High-dose intensity pulse interleukin-2 with famotidine has activity in metastatic melanoma.

Daily short intravenous (i.v.) infusions (pulses) of interleukin-2 (IL-2) have been developed to decrease toxicity while maintaining anticancer activity of this agent against melanoma. Such IL-2 schedules have previously been shown to promote lymphokine-activated killer (LAK) cell activity. Famotidine may increase LAK activity by increasing IL-2 internalization by the IL-2 receptor on lymphocytes. We treated 16 patients with metastatic melanoma using pulse IL-2 18 (15 patients) or 9 million IU/M2 (1 patient) i.v. over 15-30 minutes preceded by famotidine 20 mg i.v. daily for 5 days on an oncology inpatient unit. Cycles were repeated every 3 weeks until disease progression. Patient characteristics were as follows: 11 males, median age, 66, median ECOG performance status, 1; common metastatic sites: lymph nodes, lungs, subcutaneous, liver, and bone. Median number of cycles received was 3. Overall, 93% of planned doses were delivered. Most common toxicities were hypomagnesemia, fever, rigors, hypophosphatemia, and nausea/emesis. Three (3) patients had partial responses (19% response rate; 95% confidence interval: 6%-44%). A fourth patient, after resection of residual disease, remains a surgical complete responder at > 12 months. Responses occurred in lung, liver, lymph nodes, bone, and subcutaneous sites. Median response duration was 7 months. Pulse IL-2 with famotidine has activity in melanoma.

Low-dose cyclophosphamide and continuous-infusion interleukin-2 with famotidine in previously treated metastatic melanoma or kidney cancer.

UNLABELLED: The cytotoxic ability of T-cells against tumor cells may be increased by interleukin (IL)-2. The infiltration of tumors by these cytotoxic T-cells may be enhanced by low-dose cyclophosphamide, which may also serve to deplete regulatory T-cells. Famotidine may increase IL-2 internalization by the IL-2 receptor on T-lymphocytes. We have treated 14 patients with either metastatic melanoma or kidney cancer, using CY 350 mg/M(2) intravenously (i.v.) over 1 hour followed by a continuous infusion IL-2 9 MIU/M(2)/24 hours for 72 hours and famotidine 20 mg i.v. twice per day. All patients had received prior systemic therapy. Cycles were repeated every 4 weeks until disease progression. PATIENT CHARACTERISTICS: 8 with melanoma, 8 males, median age, 64, median Eastern Cooperative Oncology Group performance status, 1; most common metastatic sites: lungs, lymph nodes, bone, and liver. Median number of cycles received=2 (range, 2-4). Most common toxicities were fever, nausea/emesis, hypomagnesemia, hypophosphatemia, hyponatremia, and rigors. All patients were treated on an oncology inpatient unit. One (1) patient with kidney cancer has had a partial response in lung and lymph nodes for 5 months, while 1 patient with melanoma had a partial response in pulmonary metastases. Cyclophosphamide and IL-2 with famotidine has evidence of antitumor activity in previously treated kidney cancer and melanoma.

Activity of continuous infusion plus pulse interleukin-2 with famotidine in patients with metastatic kidney cancer or melanoma previously treated with interleukin-2.

Lymphokine-activated killer (LAK) cells generated by high-dose continuous infusion interleukin-2 (IL-2) are able to nonspecifically lyse melanoma and kidney cancer cells. In vitro famotidine enhances cytotoxicity of LAK against tumor cells, possibly by increasing IL-2 uptake at the IL-2 receptor on lymphocytes. Outpatient IL-2 regimens typically have response rates of 15% or less, with most patients eventually experiencing progressive disease. Second-line therapy is, therefore, needed. We treated 11 patients (6 with metastatic melanoma; 5 having metastatic kidney cancer) who had previously experienced progressive disease on prior IL-2 regimens, with a combination of famotidine 20 mg intravenously (i.v.) twice per day and continuous-infusion IL-2 18 MIU/M2/24 hours x 72 hours, followed 24 hours later by a pulse IL-2 dose (18 MIU/M2 over 15 minutes). Cycles were repeated every 3 weeks. Patient characteristics were: 9 males, median age 63 years (range, 57-75), median Eastern Cooperative Oncology Group (ECOG) performance status: 1; most common metastatic sites: lungs, lymph nodes, and soft tissue/subcutaneous (s.c.); median number of cycles received: 4; most common toxicities were fever, nausea/emesis, hypophosphatemia, and hypomagnesemia. Five (5) patients (3 with melanoma, 2 with kidney cancer) have had partial responses. Two (2) patients with kidney cancer have been converted to complete responders with resection of residual disease, remaining without relapse at 5+ and 20+ months. Responding sites are lungs, lymph nodes, abdominal mass, and s.c. Median duration of response was 9.5 months. Median survival was 12 months. This combination has activity in patients with metastatic kidney cancer or melanoma who have received prior IL-2.

Continuous infusion interleukin-2 and famotidine in metastatic kidney cancer.

Infusional interleukin-2 (IL-2) is able to elicit lymphokine-activated killer cell (LAK) cytotoxicity against kidney cancer in vitro and in vivo. Famotidine may be able to augment LAK cytotoxicity against neoplastic cells. Fifteen (15) patients were treated with continuous-infusion IL-2 (9-18 MIU/m2/24 hours) for 72 hours and famotidine 20 mg intravenously twice per day. Cycles were repeated every 3 weeks. These patients had a median age of 60 years (range, 29-72), had a median performance status of 1 (range, 0-1), and had metastatic sites, including lung, bone, lymph node, and liver. The most common toxicities of this regimen were hypophosphatemia, fever, nausea/emesis, rigors, elevated creatinine, and hypomagnesemia. One (1) complete and 6 partial responses have been seen (47% response rate). The median duration of response is 9 months. The median survival for all patients is 20 months. Five (5) patients are alive at a median of 36+ months. This combination of infusional IL-2 with famotidine is active in metastatic kidney cancer.

Continuous infusion interleukin-2 and intravenous famotidine in metastatic melanoma.

Lymphokine-activated killer cell (LAK) cytotoxicity against tumor cells is induced by the use of high-dose infusional interleukin-2 (IL-2). LAK cytotoxicity against neoplastic cells may be augmented by famotidine. Twelve (12) patients have been treated with continuous infusion IL-2 (18 MIU/m2/24 hours) for 72 hours and famotidine 20 mg IVPB twice per day. Cycles were repeated every 3 weeks. These patients were of median age--67 years (range, 25-79), had a median performance status of 1 (range, 0-1), and had metastatic sites, including lung, lymph node, subcutaneous/soft tissue, and liver. The most common toxicities of this regimen were fever, rigors, nausea/emesis, hypophosphatemia, and hypomagnesemia. Three (3) partial responses have been seen (25% response rate). One (1) of these responders has undergone complete surgical resection and is disease-free at 15+ months. Four (4) patients are alive at a median of > 25 months. The median survival for all patients is 13 months. This combination of infusional IL-2 with famotidine is active in metastatic melanoma.

Bolus followed by continuous infusion interleukin-2 in patients with metastatic malignant melanoma and kidney cancer previously treated with interleukin-2.

Six patients with either melanoma (3) or kidney cancer (3) who had experienced disease progression on outpatient interleukin-2 regimens were subsequently treated with inpatient bolus Interleukin-2 (IL-2) 36 MIU/m(2) followed by continuous infusion IL-2 18 MIU/m(2)/day for 3 days. Cycles were repeated every 2 weeks up to four times, then every 3-4 weeks if tolerated and in the absence of disease progression. Two patients (one each with kidney cancer and melanoma) have achieved partial responses. One patient with kidney cancer and hepatic metastases has had a minor response. Interleukin-2 given at this dose and schedule shows some evidence of activity in patients who have received prior outpatient IL-2.

Outpatient experience with moderate dose bolus interleukin-2 in metastatic malignant melanoma and kidney cancer.

Twenty patients with either melanoma ( 7) or kidney cancer ( 13) were treated with outpatient bolus interleukin (IL)-2 18-22 MIU/m2 IVPB for 3 consecutive days for 6 consecutive weeks followed by a 2-week rest break (on an 8-week cycle). Patient characteristics included 16 males/4 females, eleven patients had received no prior systemic therapy, median ECOG performance status = 1, and most common disease sites being lung, lymph node, subcutaneous, bone, and liver. Two patients with melanoma (29% response rate) (95% CI: 8-64%) and two with kidney cancer (15%) (95% CI: 3-43%) have achieved partial responses. Two minor responses in kidney cancer were also seen. The most common toxicities were nausea, fatigue, rigors, fever, and myalgias/arthralgias. No cardiac events occurred, and no patients required hospitalization due to toxicity. IL-2 at this outpatient dose and schedule is well tolerated and displays some evidence of activity in melanoma and kidney cancer. Larger patient numbers are required to corroborate these response rates and to determine whether complete responses are possible.