Phase I study of subcutaneously administered interleukin-2 in combination with interferon alfa-2a in patients with advanced cancer.
OBJECTIVE
Although high-dose interleukin-2 (IL-2) can produce durable remissions in a subset of responding patients with renal cell carcinoma (RCC), this occurs in the setting of significant toxicity. The purpose of this study is to define the maximum-tolerated dosage (MTD) of IL-2 and interferon alfa-2a (IFN alpha-2a) that can be administered chronically on an outpatient basis.


METHODS
Fifty-three patients with advanced cancer of variable histology with good prognostic features were treated in six cohorts. Patients in cohorts one through five received IL-2 (1.5 or 3.0 x 10(6) million units (mU)/m2) Monday through Friday and IFN alpha-2a (1.5 or 3 x 10(6) mU/m2) daily for a 4-week cycle. In cohort six, IFN alpha-2a was given three times a week. Immunologic monitoring, including serum levels of soluble IL-2 receptor (sIL-2R) and neopterin, flow cytometry, and natural killer cell (NK) activity, were measured. Patients were evaluated for toxicity, response, and survival.


RESULTS
Almost all patients developed grade I/II toxicities commonly associated with cytokine therapy. Symptoms were most severe with the first treatment of each week. Dose-limiting toxicities included grade III fatigue, hypotension, and creatinine elevations. The MTD was 1.5 mU/m2 daily x 5 given subcutaneously repeated weekly for IL-2 and 1.5 mU/m2 daily subcutaneously (dose level 3) for IFN. Six of 25 assessable patients with RCC (24%) achieved a partial response (PR), including four of eight patients who were previously untreated. There were no objective responses in patients with other tumors, including 12 melanoma patients.


CONCLUSIONS
IL-2 and IFN alpha-2a can be given with tolerable toxicities on an outpatient basis and shows significant activity in patients with metastatic RCC.
Gause
B L
BL
Division of Cancer Treatment, National Cancer Institute, Bethesda, MD, USA. bgause@mail.ncifcrf.gov
Sznol
M
M
Kopp
W C
WC
Janik
J E
JE
Smith
J W
JW
Steis
R G
RG
Urba
W J
WJ
Sharfman
W
W
Fenton
R G
RG
Creekmore
S P
SP
Holmlund
J
J
Conlon
K C
KC
VanderMolen
L A
LA
Longo
D L
DL
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001708:Biopterins / Q000031:analogs & derivatives / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D019798:Neopterin; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011994:Recombinant Proteins; D012074:Remission Induction
D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D001708:Biopterins; D019798:Neopterin