Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma

Abstract

Background: We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.

Methods: In a single-center, phase II trial, DAB/IL2 (12 μg/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[(18)F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging.

Results: After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; p value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.

Conclusions: These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma.

Trial registration: NCT00299689.

Figure 1

Examples of partial and mixed responses after DAB/IL2 administration. A. Anterior/posterior and lateral views of PET imaging reveal a large duodenal mass (arrow) and several hepatic metastases (box) at baseline and 1 month after the final cycle of DAB/IL2. PET imaging confirmed regression of the hepatic metastases (right panels) and a modest reduction in the duodenal mass. The increased ¹⁸ F-fluorodeoxyglucose uptake in the left kidney is due to hydronephrosis which is unrelated to melanoma. B. After 3 cycles of DAB/IL2, this patient experienced the marked regression of a large subcutaneous and a pelvic mass (see bottom 2 horizontal red arrows just above the bladder [which normally contains tracer]) and a peritoneal mass (right vertical arrow). Simultaneously, enlarged paratracheal lymph nodes worsened (upper arrows), a large conglomeration of left axillary masses expanded (dashed circle). An inferior peritoneal mass appeared and expanded (left vertical arrow) and a superior peritoneal mass expanded and then regressed with treatment (upper horizontal arrow).

Figure 2

Durable responses after DAB/IL2 administration. On the left, baseline anterior/posterior views of FDG-PET imaging reveal multiple FDG-avid melanoma metastases in three clinical examples: A, 78 year-old female; B, 47 year-old male; and C, 62 year-old male. After DAB/IL2 administration, we observed a clinically significant and durable reduction in tumor burden, including hepatic metastases, pulmonary nodules, metatastic lymph nodes and subcutaneous nodules in all three patient examples.

Figure 3

A. Increased partial responses to DAB/IL2 noted in chemo/immuno-naïve and stage M1A melanoma patients. Sixty stage IV melanoma patients were administered DAB/IL2 and the objective response rates were determined using qualitative radiological assessments of FDG-PET and CT imaging. Whereas 16.7% of all treated patients experienced partial responses, 45.5% of the chemo/immuno-naïve patients experienced partial responses (A). Response rates were calculated based on sub-stage of melanoma. Whereas stage M1A (lymph node, skin and subcutaneous) (B) melanoma patients experienced the highest total objective response rate, stage M1B patients had no partial responses (C) and chemo/immuno-naïve patients with visceral metastases (stage M1C) had a > 60% partial response rate (D).

Figure 4

High overall survival in chemo/immuno-naïve, stage M1A and partial responders to DAB/IL2. Median overall survival of these patients was determined using the Kaplan-Meier method and stratified based on prior treatment exposure (A), stage (M1A-C) (B) and response rate (C).