Repeated Cycles with 72-Hour Continuous Infusion Interleukin-2 in Kidney Cancer and Melanoma

Abstract

While high-dose bolus inpatient interleukin-2 is generally given on 8-week cycles, continuous infusion interleukin-2 could potentially allow for more rapidly repeated cycles. Fourteen (14) patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, having either kidney cancer (6) or melanoma (8), have been treated with continuous infusion (CIV) interleukin-2 (IL-2) 18 MIU/m(2)/24 hours for 72 hours. Cycles were repeated every 3 weeks up to 4 cycles, then every 3-4 weeks for 2 cycles, then every 6-8 weeks, until progression or intolerable toxicity. All patients received famotidine 20 mg intravenously (i.v.) twice per day during the 72-hour infusions. Patient characteristics included a median ECOG performance status of 1; median age = 63 (range: 25-79); most common metastatic sites: lung (9), bone (5), lymph nodes (5), and the liver (3). No patients with metastatic kidney cancer underwent a nephrectomy prior to interleukin-2. Median number of cycles received = 5 (1-9). No patients required Intensive Care Unit (ICU) admission. There have been no treatment-related deaths. Most common toxicities have been rigors, fever, nausea/emesis, and the reversible elevation of creatinine. One complete response and three partial responses (67% response rate; 95% confidence interval: 30%-90%) have been seen in kidney cancer, and two partial responses (25% response rate; 95% confidence interval: 7%-60%) have occurred in melanoma. Median survival has not been reached at >9+ months. Responding sites include the liver, bone, lung, lymph node and subcutaneous sites. Inpatient 72-hour continuous infusion interleukin-2 at this dose and schedule is well tolerated by patients with an ECOG performance status of 0 or 1 and has activity in kidney cancer and melanoma.

Therapeutic Agents for Advanced Melanoma

“…Although the optimal dosing schedule resulting in the best clinical response is currently unknown, previous data would suggest that the higher dose regimens as well as the number of total doses received correlates best with clinical response. Thus, several groups have begun to look at alternative dosing strategies to achieve an increased drug tolerance and tolerability profile, such as the continuous infusion of IL-2 (18 mIU/m 2 /day) over an extended period of 72 h [33]. But the multiorgan toxicity of many IL-2 regimens limits its use.…”

Outpatient Intravenous Interleukin-2 with Famotidine Has Activity in Metastatic Melanoma

“…12 Repeated grade III toxicity resulted in patients being treated using a 50% reduction of their daily IL-2 dose.…”

TDiscovery and Development of Novel Therapeutic Agents for Advanced Melanoma

“…This experiment was performed by my colleague Mr. Chien-Ming Li. He demonstrated that SMART-100 inhibited tubulin polymerization in a doseresponse manner in the previous study (15). In the current study, 10 M of SMARTs were used to examine the inhibition of tubulin polymerization.…”

“…Although the optimal dosing schedule resulting in the best clinical response is currently unknown, previous data would suggest that the higher dose regimens as well as the number of total doses received correlates best with clinical response. Thus, several groups have begun to look at alternative dosing strategies to achieve an increased drug tolerance and tolerability profile, such as the continuous infusion of IL-2 (18 mIU/m 2 /day) over an extended period of 72 h (15). But the multiorgan toxicity of many IL-2 regimens limits its use.…”

“…Although they do not contain any chiral centers, analogs containing an imidazole ring (compounds 5-11) did not have activity at concentrations below 10 M. Replacing the imidazole ring with an imidazoline ring slightly improved the activity in general (compounds [15][16][17][18][19], with substantial improvement when trimethoxyl or amino acetyl substitutions were added (compounds 20-21). The structure activity for the side chain was similar to that of the thiazolidine analogs, with a saturated C14~C16 chain or an unsaturated C18 chain to be optimal for activity against melanoma cells.…”