A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma.

Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest that temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab. We performed an open-label single-arm phase II study of ipilimumab plus temozolomide in the frontline setting for patients with metastatic melanoma and LDH ≤2× upper limit of normal. Ipilimumab was given at 10 mg/kg on day 1 and temozolomide 200 mg/m2 orally days 1-4 every 3 weeks for four doses followed by maintenance ipilimumab every 12 weeks plus temozolomide every 4 weeks. The primary objective of the study was 6-month PFS. A total of 64 patients were enrolled and the 6-month PFS was 45% with median OS of 24.5 months. There were 10 (15.6%) confirmed partial responses and 10 (15.6%) confirmed complete responses. Duration of response amongst responders is 35 months with 10 patients demonstrating an ongoing response at median follow-up of 20 months. There were no deaths or unexpected toxicities on study. The most common gastrointestinal side effects were nausea and constipation rather than diarrhea or colitis. These results suggest that the combination of induction ipilimumab plus temozolomide could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. These findings warrant further evaluation in a large prospective study.

Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma.

BACKGROUND: The high prevalence of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma v-ras oncogene homolog (NRAS) mutations in melanoma provides a strong rationale to test the clinical efficacy of mitogen-activated protein kinase kinase (MEK) inhibition in this disease. The authors hypothesized that the presence of BRAF or NRAS mutations would correlate with clinical benefit among patients who received treatment with combination regimens that included the MEK inhibitor selumetinib. METHODS: BRAF and NRAS mutation status was determined retrospectively in available tissue specimens from patients with melanoma who were enrolled in a phase 1 trial of selumetinib in combination with 1 of 4 drugs (dacarbazine, docetaxel, temsirolimus, or erlotinib). The clinical response rate and the time to progression (TTP) were assessed as a function of BRAF and NRAS mutation status. RESULTS: Among 18 patients analyzed, 9 patients (50%) harbored a BRAF mutation (8 had a valine-to-glutamic acid substitution at residue 600 [V600E]; 1 had an arginine nonsense mutation at residue 603 [R603]), 4 patients (22%) harbored an NRAS mutation (2 had a glutamine-to-arginine substitution at residue 61 [Q61R], 1 had a glutamine-to-lysine substitution at residue 61 [Q61K], and 1 had a glycine-to-lysine substitution at residue 12 [G12S]), and 5 patient (28%) had the wild type of both genes. These mutations were mutually exclusive. Among the 9 patients who had BRAF mutations, 5 patients (56%) achieved a partial response, and 4 patients (44%) achieved stable disease for at least 6 weeks. No patient with the wild-type BRAF gene achieved a clinical response (P = .01 vs patients with BRAF mutations). The presence of an NRAS mutation did not correlate with the clinical response rate. The presence of a BRAF mutation was correlated significantly with the TTP in a multivariate model (hazard ratio, 0.22; P = .02 vs wild-type BRAF). CONCLUSIONS: Higher response rates and longer TTP were observed with selumetinib-containing regimens in patients who had tumors that harbored a BRAF mutation compared with patients who had wild-type BRAF.

BRAF, NRAS and KIT sequencing analysis of spindle cell melanoma.

BACKGROUND: Spindle cell melanoma represents a rare but distinct subset of melanoma, and its genomic spectrum has not been fully defined. METHODS: We searched our institutional database for patients with a diagnosis of pure spindle cell-type melanoma whose tumors had been analyzed for BRAF, NRAS, and KIT mutations using pyrosequencing technique. RESULTS: We identified 24 patients with spindle cell melanoma, including 10 patients with desmoplastic melanoma, whose tumors had been analyzed for at least one of the three genes. The median Breslow thickness was 2.6 mm, and the most common site of the primary melanoma was the trunk, followed by the head and neck region. BRAF, NRAS and KIT genomic sequencing was performed successfully in 20, 18 and 14 patients, respectively. Among the 20 melanomas with completed BRAF-sequencing analysis, 6 (30%) harbored a mutation, of which 5 (83%) had a V600E mutation and 1 (17%) had a V600R mutation. None of the melanomas harbored NRAS or KIT mutations. CONCLUSION: As has been reported in other common types of melanoma, V600 BRAF mutation is the most common mutation of those tested in spindle cell melanoma. NRAS or KIT mutation appears to be rare, if not completely absent.

A phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresectable stage-III or IV melanoma.

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/m(2)/day x 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.

Prognostic factors that determine the long-term survival of patients with unresectable metastatic melanoma.

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-naive 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.

Phase I/II Study of Hepatic Arterial Infusion of Nab-paclitaxel in Patients With Metastatic Melanoma to the Liver.

OBJECTIVES: Hepatic arterial infusion (HAI) of cytotoxic chemotherapy is a strategy to deliver high dose of anticancer therapy to liver metastases that derive their blood supply from the hepatic artery. Metastatic melanoma (MM) has a high incidence of liver metastases, with uveal subtype in particular exhibiting a predilection for liver dissemination. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has demonstrated efficacy in MM and first-pass hepatic metabolism. Therefore, we hypothesized that HAI of nab-paclitaxel would deliver an effective dose of drug to the end organ of interest, with minimal systemic exposure. PATIENT AND METHODS: We performed a single-institution open-label phase I/II study of HAI of nab-paclitaxel in MM patients with liver metastasis. Patients received treatment every 21 days at 4 different dose levels. The primary objective of the phase I portion of the study was safety and determination of the maximum-tolerated dose. The primary objective of the phase II portion of the study was overall response rate per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0. RESULTS: A total of 30 patients were treated between 2009 and 2013, 16 of whom had uveal melanoma. The maximum-tolerated dose was 220 mg/m and 19 patients were treated at this dose. There was 1 patient (5%) with a partial response at this dose, and 8 patients (42%) with stable disease at this dose. CONCLUSIONS: HAI nab-paclitaxel demonstrates rare objective responses in melanoma patients with liver metastases. This treatment should be studied in combination with checkpoint blockade or other novel treatments to enhance meaningful responses but should not be considered effective monotherapy.

Sphincter-sparing local excision and adjuvant radiation for anal-rectal melanoma.

PURPOSE: To evaluate the outcome and toxicity of a sphincter-sparing treatment strategy in the management of patients with anal-rectal melanoma. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: Sphincter-sparing local excision and adjuvant radiation is well tolerated and can effectively control local-regional disease while avoiding the functional morbidity of APR.

Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial.

PURPOSE: The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b. PATIENTS AND METHODS: Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1 and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25). Biochemotherapy involved CVD with vinblastine reduced 25% plus interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20, and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days 5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks. RESULTS: Among 190 patients enrolled, 91 were assessable for biochemotherapy and 92 for chemotherapy. Ten percent of the patients were alive a median of 52 months from start of therapy. Response rates were 48% for biochemotherapy and 25% for chemotherapy (P =.001); six patients given biochemotherapy and two given chemotherapy had complete responses. Median time to progression (TTP) was 4.9 months for biochemotherapy and 2.4 months for chemotherapy (P =.008); median survival was 11.9 and 9.2 months, respectively (P =.06). The influence of treatment on TTP and survival was confirmed in multivariate analyses with other prognostic factors not included in the original stratification. Biochemotherapy produced substantially more constitutional, hemodynamic, and myelosuppressive toxic effects. CONCLUSION: Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.

Intrathecal Administration of Tumor-Infiltrating Lymphocytes Is Well Tolerated in a Patient with Leptomeningeal Disease from Metastatic Melanoma: A Case Report.

UNLABELLED: 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. TREATMENTS: 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.

Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma.

The management of melanoma has evolved owing to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next-generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-V600 (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent events in tumors with BRAFV600 and NRAS mutations. Melanomas with BRAFNon-V600mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAFV600 and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma.

Phase I trial of biochemotherapy with cisplatin, temozolomide, and dose escalation of nab-paclitaxel combined with interleukin-2 and interferon-α in patients with metastatic melanoma.

The primary objective of this study was to determine the safety, toxicity, and maximum tolerated dose of nanoparticle albumin-bound (nab)-paclitaxel as part of biochemotherapy for metastatic melanoma and to determine whether substituting nab-paclitaxel for less potent agents could increase response rates and duration. Treatment consisted of intravenous cisplatin (20 mg/m) on days 1-4, oral temozolomide (250 mg/m) on days 1-3, subcutaneous interferon-α (5×10 IU/m) on days 1-5, and continuous intravenous interleukin-2 (9×10 IU/m) for 96 h on days 1-4. A standard 3+3 dose escalation method was used; the nab-paclitaxel starting dose was 100 mg/m on day 1 and 70 mg/m on day 5. The treatment cycle was repeated every 3 weeks and toxicity was assessed weekly. Ten patients were enrolled. Dose-limiting toxicities included diarrhea, transaminasemia, and neutropenia. The maximum tolerated dose was not identified because the nab-paclitaxel dose on day 1 at the lowest planned dose (80 mg/m) caused dose-limiting toxicity in two of five patients. Of the nine patients who were evaluable for response, five had a partial response. The median time to disease progression was 5.30 months and the median overall survival was 8.73 months. Six patients developed central nervous system metastasis at a median of 5.33 months after treatment initiation. Biochemotherapy including nab-paclitaxel according to the doses and schedule regimen used in the present study has significant toxicity. Substituting dacarbazine with temozolomide did not prevent central nervous system metastasis in patients with metastatic melanoma.

Delayed systemic recurrence of uveal melanoma.

CONTEXT: Metastatic uveal melanoma recurrence after ≥10 years is not well studied in the clinical literature. This study describes the clinical characteristics and natural history of patients with delayed tumor recurrence. OBJECTIVE: To describe the characteristics of patients with delayed systemic recurrence of uveal melanoma and the natural history of the disease after recurrence. EVIDENCE ACQUISITION: This is a chart review of patients treated between 1994 and 2008 at The University of Texas, MD Anderson Cancer Center for uveal melanoma whose disease recurred ≥10 years after treatment of the primary tumor. RESULTS: Of 463 patients treated for metastatic uveal melanoma, 305 developed systemic recurrence within 5 years from the time of diagnosis of primary melanoma, 97 developed systemic recurrences between 5 and 10 years, whereas 61 patients developed metastasis after ≥10 years. The interval between primary to first systemic metastasis was a significant independent predictor of survival time from first systemic metastasis. The median survival time for patients with delayed metastatic recurrence after ≥10 years was significantly longer than for patients who had intermediate or early systemic recurrence. Levels of lactate dehydrogenase, serum alkaline phosphatase, serum albumin, age, M-stage, and performance status at time of recurrence, as well as sex were also independent predictors of survival time from systemic recurrence. CONCLUSIONS: Longer time interval between primary and first systemic metastasis is significantly correlated with prolonged survival. Patients who survive ≥10 years without tumor metastasis after treatment for primary uveal melanoma cannot be considered cured. Prognosis remains poor for patients with metastatic uveal melanoma.

Chemical castration of melanoma patients does not increase the frequency of tumor-specific CD4 and CD8 T cells after peptide vaccination.

Peptide vaccination against tumor-associated antigens remains one of the most common methods of immunization in cancer vaccine clinical trials. Although peptide vaccination has been reported to increase circulating antigen-specific T-cells, they have had limited clinical efficacy and there is a necessity to increase their capacity to generate strong antitumor responses. We sought to improve the clinical efficacy of peptide-based vaccines in cancer immunotherapy of metastatic melanoma using a LHRH agonist (leuprolide) as adjuvant. Seventy HLA-A*0201 stage IIb-IV melanoma patients were vaccinated with class I HLA-A*0201-restricted gp100209-2M peptide and stratified for HLA-DP4 restriction. HLA-DP4 patients were also vaccinated with class II HLA-DP4-restricted MAGE-3243-258 peptide. Patients from both groups were randomized to receive 2 doses of leuprolide or not. Here we report the increase in PBMC TREC levels at week 24 after peptide vaccination, which was independent of the leuprolide treatment. This change was mirrored by a small increase in the TREC-enriched CD8CD45RAROCD27CD103, but not the TREC-enriched CD4CD45RAROCD31 T-cell population. Serum concentration of 2 important factors for thymopoiesis was measured: insulin growth factor 1 (IGF-1) levels were not changed, whereas a moderate increase in IL-7 levels was noted in the sera of all patients 6 weeks after vaccination. Increased expression of CD127 (IL-7 receptor-α) at week 24, compared with baseline, was only seen in the CD8CD45RAROCD27CD103 T-cell population. Our results suggest that leuprolide has no effect on thymic output when used as peptide vaccine adjuvant, but IFA-based peptide vaccination may unexpectedly affect the thymus by increasing thymic output of new T cells.

Topical treatment of recurrent vaginal melanoma in situ with imiquimod: A case report.

► Vaginal melanoma in situ is a rare neoplasm with a paucity of data regarding the optimal management. ► More conservative approaches are needed to avoid the disfigurement, pain and postoperative complications associated with repeated surgical interventions. ► Imiquimod may prove to be a useful treatment modality for patients with vulvar or vaginal melanoma in situ.

Risk of intracranial hemorrhage with anticoagulation therapy in melanoma patients with brain metastases.

Venous thromboembolism (VTE) is a frequent complication in melanoma patients with brain metastases (BM). The management of these patients is challenging because of the high risk of intracranial hemorrhage (ICH) and the limited data available on the safety of anticoagulation in this scenario. We reviewed the treatments and outcomes among melanoma patients with BM and VTE at our institution to determine the safety of anticoagulation in these patients. A retrospective chart review was performed to identify melanoma patients with BM who were diagnosed with VTE. The clinical characteristics of the BM and the VTE, the treatments given for VTE, subsequent ICH, and overall survival (OS) were determined. The characteristics and outcomes were compared between patients who received systemic anticoagulation and those who did not. A total of 74 evaluable melanoma patients with BM and VTE were identified. Fifty-seven (77%) patients received systemic anticoagulation. There was no significant difference in the number (P=0.40) or the maximum diameter (P=0.55) of brain metastasis between the patients who received anticoagulation and those who did not. Two (4%) patients who received anticoagulation developed ICH, which was not statistically different from the patients who did not receive anticoagulation (0%, P=1.00). There was a trend toward longer OS from VTE among patients who received systemic anticoagulation (median OS: 4.2 vs. 1.2 months, P=0.06). Anticoagulation for VTE did not significantly increase the risk of ICH or decrease OS in patients with melanoma BM. These data support the safety of systemic anticoagulation for VTE in these patients.

Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma.

PURPOSE: 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 AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 randomized phase II study of cilengitide (EMD 121974) in patients with metastatic melanoma.

Cilengitide (EMD 121974) is a selective inhibitor of integrins αvß3 and αvß5. The αvß3 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 αvß3 expression at baseline. Overall, αvß3 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 αvß3 expression.

The left ventricle as the first site of uveal melanoma metastasis 13 years after treatment of the primary tumor.

Treatment of patients with metastatic uveal melanoma is very challenging because the tumor commonly spreads to the liver, surgical resection of metastases is rarely possible, and there is no standard effective systemic therapy. We report the case of a 38-year-old man, who presented with metastatic involvement of the left ventricle as the first site of uveal melanoma recurrence 13 years after treatment of his primary tumor. The metastatic tumor was considered unresectable. We describe the patient's medical management over the next 3 years, the course of his disease, and the results of our review of the literature.

Pharmacokinetics and safety of Marqibo (vincristine sulfate liposomes injection) in cancer patients with impaired liver function.

Marqibo (vincristine sulfate liposome injection, VSLI) is a novel liposomal formulation of vincristine sulfate (VCR) being developed for the systemic treatment of cancer. This study evaluated the pharmacokinetics (PK) of Marqibo in subjects with melanoma and impaired hepatic function. Calculated PK parameters were similar in subjects with impaired liver function compared with those in subjects with adequate liver function. Subjects with impaired liver function universally had a monoexponential total plasma VCR concentration versus time decline, whereas two thirds of subjects with adequate liver function had a biexponential decline profile. Because one third of subjects with normal hepatic function demonstrated monoexponential disposition, lack of biexponential disposition in the hepatically impaired subjects cannot be clearly attributed to liver impairment. VSLI was generally well tolerated in all subjects.

Predictive factors for the development of brain metastasis in advanced unresectable metastatic melanoma.

BACKGROUND: Melanoma that metastasizes to distant sites is associated with a grave prognosis. The objectives of the study were (1) to identify predictive factors for the development of brain metastases from the time of diagnosis of stage III/IV disease, (2) to identify predictive factors for the development of central nervous system (CNS) metastases from the time of diagnosis of primary melanoma, and (3) to assess whether the incidence of brain metastasis is more frequent in patients who had no tumor response to systemic therapy for stage III/IV disease compared with those who had partial or complete response. PATIENTS AND METHODS: We collected and retrospectively analyzed information of 740 patients with advanced metastatic melanoma treated at MD Anderson Cancer Center over 15 years. Three hundred and twenty-nine patients had CNS metastases. The characteristics of these patients in terms of median age, sex, primary site, Breslow thickness, stage at first visit, baseline serum parameters, and response to systemic therapy were compared with those of patients who did not develop CNS metastasis. Cox proportional hazards models were used to analyze the cause-specific hazard function for CNS metastasis and deaths without CNS metastasis. RESULTS: We identified that M-stage [stage M1b vs. stage III or M1a, hazard ratio (HR)=2.64; stage M1c vs. stage III or M1a, HR=2.13, P<0.0001] and lactic acid dehydrogenase (LDH) (elevated vs. normal LDH, HR=1.51, P<0.001) at diagnosis of unresectable stage III/IV disease can independently predict the risk of developing CNS metastasis from the time of diagnosis of stage III/IV disease. Older age (HR=1.01, P=0.076), chemoresistance (stable disease+progressive disease vs. complete response+partial response HR=2.91, P<0.0001), low level of albumin (vs. normal HR=2.87, P<0.0001), elevated LDH (vs. normal HR=1.55, P=0.0004), and M-stage (M1c disease vs. stage III or M1a HR=1.89, P<0.0001) can independently predict shorter time to death without CNS metastasis from the diagnosis of stage III/IV disease. The location (head and neck vs. limbs HR=1.56, P=0.028; trunk and abdomen vs. limbs HR=1.45, P=0.029; unknown site vs. limbs HR=8.43, P=0.036) and pathology [Clark level (CL)=3 and/or BR2 to 4 mm vs. CL≤2 and/or BR<2 mm HR=1.60, P=0.037; CL>3 and/or BR> 4 mm vs. CL≤2 and/or BR<2 mm HR=2.03, P=0.001) of the primary melanoma can independently predict CNS metastasis-free interval from the time of diagnosis of primaries. Age (HR=1.012, P=0.034) and pathology of the primary melanoma (CL>3 and/or BR>4 mm vs. CL≤2 and/or BR<2 mm HR=1.54, P=0.024) can independently predict time to death without CNS metastasis from primaries. CONCLUSION: We identified the predictive factors associated with the development of CNS metastasis in patients with unresectable metastatic melanoma.