Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response.
The aim of this study was to examine the tolerability, antitumor activity, and biological effects of a new schedule of i.v. recombinant human interleukin 12 (rhIL-12). Twenty-eight patients were enrolled in a Phase I trial in which rhIL-12 was administered twice weekly as an i.v. bolus for 6 weeks. Stable or responding patients were eligible to receive additional 6-week cycles until there was no evidence of disease or until tumor progression. Patient cohorts were treated with escalating doses of rhIL-12 (30-700 ng/kg). The maximum tolerated dose (MTD) was 500 ng/kg, with dose-limiting toxicities consisting of elevated hepatic transaminases and cytopenias. At the MTD (n = 14), there was one partial response occurring after 6 cycles of rhIL-12 in a patient with renal cell cancer. Two additional renal cell cancer patients treated at the MTD had prolonged disease stabilization, with one of these exhibiting tumor regression after 8 cycles of rhIL-12. IFN-gamma, IL-15, and IL-18 were induced in patients treated with rhIL-12. Whereas IFN-gamma and IL-15 induction were attenuated midway through the first cycle in patients with disease progression, those patients with tumor regression or prolonged disease stabilization were able to maintain IFN-gamma, IL-15, and IL-18 induction. The down-modulation of IFN-gamma induction during rhIL-12 treatment did not relate to IL-10 production or alterations in rhIL-12 bioavailability but was associated with an acquired defect in lymphocyte IFN-gamma production in response to IL-12, IL-2, or IL-15. This defect could be partially overcome in vitro through combined stimulation with IL-12 plus IL-2. These findings show that the chronic administration of twice-weekly i.v. rhIL-12 is well-tolerated, stimulates the production of IL-12 costimulatory cytokines and IFN-gamma, and can induce delayed tumor regression. Strategies aimed at maintaining IFN-gamma induction, such as the addition of IL-2, may further augment the response rate to this schedule of rhIL-12.
Gollob
J A
JA
Beth Israel Deaconess Medical Center, Division of Hematology/Oncology, Boston, Massachusetts 02215, USA.
Mier
J W
JW
Veenstra
K
K
McDermott
D F
DF
Clancy
D
D
Clancy
M
M
Atkins
M B
MB
D000328:Adult; D000368:Aged; D018771:Arthralgia / Q000139:chemically induced; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005334:Fever / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D018664:Interleukin-12 / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019409:Interleukin-15 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009061:Mouth Mucosa; D009362:Neoplasm Metastasis; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013280:Stomatitis / Q000139:chemically induced; D013997:Time Factors
D019409:Interleukin-15; D020382:Interleukin-18; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma