Docosahexaenoic acid (DHA)-paclitaxel is a taxane with a unique pharmacokinetic profile. We investigated the safety and response rate of DHA-paclitaxel weekly in patients with metastatic uveal ...melanoma. Chemotherapy-naive and previously treated patients were eligible for this open-label phase II study. DHA-paclitaxel (500 mg/m²/week) was administered by a 1-hour intravenous infusion for five consecutive weeks in a 6-weeks cycle. Response was assessed using the Response Evaluation Criteria in Solid Tumors every 6 weeks. Twenty-two patients were enrolled. The patients' median age was 56 years (range: 33-79 years). Nine patients had a systemic therapy for metastatic disease earlier. The median number of treatment cycles was 1 (range 1-7 cycles). One chemonaive patient with liver metastases had partial response lasting for 5 months. Seven patients (32%) had stable disease with a median duration of 3 months (range: 3-7 months). The median overall survival was 9.8 months. Neutropenia (23%) and musculoskeletal pain (10%) were the most common grade 3 and grade 4 toxicities. As a single-agent therapy, DHA-paclitaxel is safe and well-tolerated in metastatic uveal melanoma patients. Its efficacy in this disease is limited with 32% of patients achieving stable disease. Further evaluation of DHA-paclitaxel in combination with other chemotherapeutic agents and/or targeted agents may improve its antitumor activity.
This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma.
Patients with stage IV or ...unresectable or recurrent stage III melanoma and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given i.v. weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per Response Evaluation Criteria in Solid Tumors criteria. Consenting patients with accessible tumors underwent optional tumor biopsies before treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-extracellular signal-regulated kinase (P-ERK) and P-S6 proteins.
A total of 25 patients were accrued to the study. The maximum tolerated doses were sorafenib 400 mg every morning and 200 mg every evening and temsirolimus 25 mg i.v. weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome, serum transaminase elevation, and hypertriglyceridemia. There were no complete or partial responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival was 2.1 months. Matching pretreatment and day 15 tumor biopsies showed marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK.
Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK.
A 42-year-old white woman with a diagnosis of metastatic melanoma developed severe neutropenia during treatment with ipilimumab (anticytotoxic T-lymphocyte-associated antigen-4 antibody). Bone marrow ...aspiration and biopsy specimens revealed marked myeloid hypoplasia, with unremarkable erythropoiesis and megakaryopoiesis. The patient's neutropenia did not respond to therapy with a combination of colony stimulating factors and steroids; however, it rapidly improved after administration of intravenous immunoglobulin. Treatment with ipilimumab has not been reported to be associated with hematologic toxicities, and to our knowledge, no case of neutropenia has previously been reported. This report of acute grade 4 neutropenia associated with ipilimumab and clinically consistent with an autoimmune process emphasizes the importance of monitoring complete blood count during treatment with this new monoclonal antibody.
Cilengitide (EMD 121974) is a selective inhibitor of integrins αvβ3 and αvβ5. The αvβ3 promotes the proliferation of tumor-associated endothelial cells and potentially the survival of melanoma cells. ...We conducted a randomized phase II trial in patients with metastatic melanoma to evaluate the clinical efficacy of cilengitide. Patients with stage IV or unresectable stage III melanoma who were either chemonaive or who had previously received one systemic therapy were enrolled. Patients were randomly assigned to either 500 or 2000 mg of cilengitide administered intravenously twice weekly. The primary aim of this study was to determine the progression-free survival rate at 8 weeks. Tumor samples and blood samples were collected for pharmacodynamic and pharmacokinetic studies. Twenty-nine patients were enrolled, of whom 26 were treated (14 at 500 mg and 12 at 2000 mg). Among those treated, only three were progression free at 8 weeks: two in the 500 mg arm and one in the 2000 mg arm. One patient in the 2000 mg arm showed a prolonged partial response after an initial 28% enlargement of her target lesions. The treatment was well tolerated without clinically significant adverse events. The sole responder and one of two patients with stable disease had no αvβ3 expression at baseline. Overall, αvβ3 expression was decreased by day 8 of the treatment (P=0.05). Cilengitide was well tolerated by patients in both the treatment arms but had minimal clinical efficacy as a single-agent therapy for metastatic melanoma, and the efficacy was not related to baseline αvβ3 expression.
INO-1001 is a PARP-1 inhibitor that interrupts the repair process of N-methylpurines generated by temozolomide. We evaluated the pharmacokinetics of INO-1001 and determined its safety when used with ...temozolomide at 200 mg/m2/day × 5 days every 4 weeks. We enrolled 12 adult patients, in cohorts of 3-6 patients, into the study. INO-1001 at doses of 100, 200 and 400 mg was given intravenous for 1 hr q 12 hr for 10 doses. INO-1001 had a moderate clearance, volume of distribution and a relatively short terminal half-life. Myelosuppression and elevation of liver transaminases were dose-limiting toxicities (DLTs) of INO-1001 at 400 mg.
Patients with leptomeningeal disease (LMD) from melanoma have very poor outcomes and few treatment options. We present a case of intrathecal (i.t.) administration of autologous tumor-infiltrating ...lymphocytes (TIL) in a patient with LMD from metastatic melanoma. The patient developed LMD after previous treatments with surgery, high-dose bolus interleukin-2 (HD IL2), and systemic TIL infusion and experienced radiographic progression after intrathecal IL2 (i.t. IL2) therapy. The patient received weekly treatment with increasing numbers of i.t. TIL followed by twice-weekly i.t. IL2. The patient received three i.t. TIL infusions and did not experience any toxicities beyond those expected with i.t. IL2 therapy. Analysis of cerebrospinal fluid demonstrated increased inflammatory cytokines following the i.t.
Subsequent imaging demonstrated disease stabilization, and neurological deficits also remained stable. The patient expired 5 months after the initiation of i.t. TIL therapy with disease progression in the brain, liver, lung, and peritoneal and retroperitoneal lymph nodes, but without LMD progression. These results demonstrate the safety of i.t. administration of TIL in melanoma patients with LMD and support the feasibility of conducting a prospective clinical trial to determine this therapy's clinical benefit among these patients.
To evaluate the outcome and toxicity of a sphincter-sparing treatment strategy in the management of patients with anal-rectal melanoma.
Between 1989 and 2000, 23 patients with invasive anal-rectal ...melanoma were managed with sphincter-sparing surgical resection and adjuvant radiation. Surgery consisted of primary local excision, as well as dissection for patients with documented regional nodal disease. Adjuvant radiation was delivered using a hypofractionated regimen of 30 Gy in five fractions over 2.5 weeks. Adjuvant systemic therapy was delivered to nine patients: cytotoxic chemotherapy in seven and immunotherapy in two.
After a median follow-up of 32 months, 15 patients had relapsed and 15 patients had died. The actuarial 5-year overall, disease-specific, disease-free, and distant metastasis-free survival rates were 31%, 36%, 37%, and 35%, respectively. The actuarial 5-year local and regional nodal control rates were 74% and 84%, respectively. No patient had locoregional failure as the sole site of failure and no patient required salvage abdominoperineal resection (APR). By univariate analysis, patients with nodal disease at presentation had a decreased actuarial 5-year disease-specific (0% v 45%, P =.004), disease-free (0% v 45%, P <.001), and distant metastasis-free survival (0% v 42%, P <.001). The actuarial complication-free survival rate was 71%. Two patients developed mild scrotal edema (grade 1), and four patients developed moderate proctitis requiring prolonged medical management (grade 2).
Sphincter-sparing local excision and adjuvant radiation is well tolerated and can effectively control local-regional disease while avoiding the functional morbidity of APR.
Early in development, endothelial cells proliferate, coalesce, and sprout to form a primitive plexus of undifferentiated microvessels. Subsequently, this plexus remodels into a hierarchical network ...of different-sized vessels. Although the processes of proliferation and sprouting are well studied and are dependent on the angiogenic growth factor VEGF, the factors involved in subsequent vessel remodeling are poorly understood. Here, we show that angiopoietin 1 can induce circumferential vessel enlargement, specifically on the venous side of the circulation. This action is due to the ability of angiopoietin 1 to promote endothelial cell proliferation in the absence of angiogenic sprouting; vessel growth without sprouting has not been ascribed to other vascular growth factors, nor has specificity for a particular segment of the vasculature. Moreover, angiopoietin 1 potently mediates widespread vessel enlargement only during a brief postnatal period, in particular, prior to the fourth postnatal week, corresponding to stages in which VEGF inhibition causes widespread vessel regression. These findings show that angiopoietin 1 has a potentially unique role among the vascular growth factors by acting to enlarge blood vessels without inducing sprouting, and also define a critical window of vascular plasticity in neonatal development. Finding the key molecular factors that regulate this plasticity may prove crucial to the further development of pro- and anti-angiogenic therapies.
This retrospective analysis aimed to identify the prognostic factors that influenced long-term survival of patients with metastatic melanoma. The medical records for 616 chemo-naïve patients who were ...treated with systemic therapy on eight phase II/III clinical trials were reviewed. Clinical characteristics, disease stage, metastatic sites, baseline serum albumin, LDH, and response to treatment were compared between the treatment groups and significant prognostic factors were identified. Cox proportional-hazards regression analysis identified treatment with biochemotherapy, younger age, normal baseline serum albumin and LDH levels, ECOG P.S. < 2 and absence of visceral metastasis as favorable prognostic factors for long-term survival.
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