K. B. Kim

Phase 3 study of docosahexaenoic acid–paclitaxel versus dacarbazine in patients with metastatic malignant melanoma

BACKGROUND Docosahexaenoic acid-paclitaxel (DHA-paclitaxel, Taxoprexin(®)) is made by covalently conjugating the essential fatty acid DHA to the paclitaxel molecule. Preclinical studies of DHA-paclitaxel have demonstrated increased activity relative to paclitaxel and the potential for an improved therapeutic ratio. In the present study, the efficacy and toxicity profiles of DHA-paclitaxel were compared with those of dacarbazine. METHODS In this study, 393 chemonaive patients with metastatic melanoma were randomly assigned to receive either DHA-paclitaxel at a starting dose of 900 mg/m(2) IV on day 1 every 3 weeks or dacarbazine at a starting dose of 1000 mg/m(2) IV on day 1 every 3 weeks. The primary end point of the study was the comparison of overall survival (OS). RESULTS No significant difference in OS was noted between patients in the DHA-paclitaxel and dacarbazine arms. Similarly, there were no significant differences in response rate, duration of response, time to progression, and time to treatment failure between the two drugs. Safety results of the two drugs were as predicted from prior studies. Myelosuppression was more common with DHA-paclitaxel. CONCLUSIONS DHA-paclitaxel was not superior to dacarbazine. We conclude that further studies with the drug on an every 3-week schedule in melanoma are not warranted.

Dose Selection, Pharmacokinetics, and Pharmacodynamics of BRAF-inhibitor Dabrafenib (GSK2118436)

PURPOSE Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship. EXPERIMENTAL DESIGN Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data. RESULTS One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation-positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma. CONCLUSION The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose-response relationship. A maximum tolerated dose for dabrafenib was not determined.

Association between melanoma and renal-cell carcinoma for sequential diagnoses: A single-center retrospective study

BACKGROUND Melanoma and renal-cell carcinoma (RCC) are known to be immunological neoplasms. Previous studies have shown increased risks in patients with melanoma of developing RCC and in those with RCC of developing melanoma. However, data regarding immunocompromised status in these patients are lacking. METHODS We conducted a retrospective review of patients who had a diagnosis of melanoma and/or RCC. Using summary statistics, we calculated total person-years at risk for developing melanoma among patients with RCC and for developing RCC among patients with melanoma, and compared the results with the SEER data. We also assessed medical history related to immune status and the use of immunosuppressive drugs. RESULTS Among 13,879 patients with melanoma and 7597 patients with RCC, 89 had diagnoses of both melanoma and RCC (0.6% and 1.2% of melanoma and RCC patients, respectively): eight were diagnosed with both cancers concurrently, 54 were diagnosed with melanoma first, and 27 were diagnosed with RCC first. Standardized incidence ratios (SIRs) were 2.87 (95%CI 2.16-3.74) for developing RCC among the melanoma patients and 2.31 (95%CI 1.52-3.37) for developing melanoma among the RCC patients, compared to age-, sex-, race-, and calendar-specific adjusted incidence rates of each cancer in the SEER registry. None of the 81 patients with sequential diagnoses had a history of immunocompromised disease, nor did they receive chronic immunosuppressive drugs. Only two received chemotherapy and/or radiotherapy. CONCLUSION We demonstrated a strong association between the diagnoses of melanoma and RCC. These increased risks could not be attributed to either immune status or previous antineoplastic treatment.

Clinical characterstics and outcomes of patients with BRAF-mutant advanced cancer in a phase I clinic: The University of Texas M. D. Anderson Cancer Center experience.

10535 Background: BRAF mutations are found in diverse malignancies. The current study assesses the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced malignancies. METHODS Chart review of 80 patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy. RESULTS mutBRAF patients had melanoma (N=56); colorectal (N=10); papillary thyroid (N=11); ovarian, (N=2); and esophageal cancer, N=1. Seventy-seven patients had a mutation in codon 600 (62, V600E; 13, V600K; 1, V600R; 1 unreported); two in codon 601; and one, in both codons 600 and 599. NRAS and KRAS mutations were more common in the wtBRAF group (P < 0.005). A trend to longer median survival in melanoma and shorter survival in colorectal cancer was observed in mutBRAF compared to wtBRAF. Patients harboring V600K+ melanoma had more frequent brain and lung metastases (p < 0.05), and a shorter time from diagnosis to metastases and to death (19 vs. 53 months, and 78 vs. 322 months, respectively [p< 0.05]) compared to melanoma patients with other BRAF-type mutations. In multivariate analysis, soft tissue, lung and retroperitoneal metastases were associated with wtBRAF whereas brain metastases were associated with mutBRAF (p < 0.05). Treatment with RAF/MEK targeting agents and any decrease in tumor size after referral correlated with longer survival in mutBRAF patients (p <0.05). CONCLUSIONS BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that may correlate with histology or site of mutation.

Frequency of radiologically confirmed brain metastasis from time of diagnosis of stage IV disease in patients with melanoma.

e19012 Background: Melanoma has a high rate of brain metastasis (BM) with grave prognosis. Up to 75% of patients (pts) with MM are found to have BMs in autopsy series. Early diagnosis (Dx) of BM al...

Management of venous thromboembolism (VTE) in melanoma patients with brain metastasis

9522 Background: Venous thromboembolism (VTE) is a frequent complication in melanoma pts with brain metastases (BM). Because these pts are at very high risk of intracranial bleeding, treating VTE i...