A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma.

OBJECTIVE: Ipilimumab is a fully human, anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma. METHODS: Chemotherapy-naïve patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg/m(2)/day. The primary efficacy endpoint was objective response rate. RESULTS: Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8-30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7-18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2-18.8) and 11.4 months (95% CI, 6.1-15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively. CONCLUSION: Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.

A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin's lymphoma.

PURPOSE: The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)-bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted. EXPERIMENTAL DESIGN: The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m(2) (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9). RESULTS: Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcgammaR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy. CONCLUSIONS: rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.

Phase II study of SU5416--a small-molecule, vascular endothelial growth factor tyrosine-kinase receptor inhibitor--in patients with refractory myeloproliferative diseases.

BACKGROUND: Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with myeloproliferative disorders (MPD), including agnogenic myeloid metaplasia (AMM), chronic myeloid leukemia in blastic phase (CML-BP), and chronic myelomonocytic leukemia (CMML). VEGF is a soluble, circulating, angiogenic molecule that acts through receptor tyrosine kinases (RTK), including VEGF receptor 2 (VEGFR-2). SU5416 is a small-molecule RTK inhibitor (RTKI) that targets VEGFR-2, c-kit, and fms-related tyrosine kinase Flk2. METHODS: Adult patients with advanced CMML, AMM, CML-BP, or other BCR-ABL negative MPD were entered on a multicenter, Phase II study. RESULTS: Thirty-two patients (19 patients with BCR-ABL negative MPD, 6 patients with CMML, 4 patients with CML-BP, and 3 patients with AMM) with a median age of 66 years (range, 29-85 years) received SU5416 145 mg/m(2) twice weekly intravenously for a median of three 4-week cycles (maximum, 12 cycles). Drug-related Grade 3-4 toxicities included acute abdominal pain (13%), bone pain (9%), infusion-related dyspnea (9%) or headache (6%), fatigue (6%), diarrhea (3%), and catheter site reactions (3%). Eleven patients (34%) did not receive a second cycle of therapy (6 patients had progressive disease, 3 because of adverse events; 2 patients withdrew due to lack of response). One patient with AMM achieved a partial response. Eight patients received more than 6 months of therapy. CONCLUSIONS: SU5416 had minimal clinical activity in patients with MPD. Long-term administration of a twice-weekly, hyperosmolar, intravenous solution containing polyoxyl 35 castor oil was difficult. More tolerable RTKI may be worthy of further investigation in patients with MPD.