Showing papers by "Christopher D. Lao published in 2012"
TL;DR: The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use, but newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates.
Abstract: Purpose: Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by intrinsic and acquired resistance. The mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate 2 molecularly targeted drug combinations in patients with untreated metastatic melanoma. Experimental Design: This randomized phase II study enrolled patients between May 2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400 mg every morning, 200 mg every night daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate, and toxicity for the 2 regimens. Results: On arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) was 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS was 7 months, with 1 patient achieving PR. Conclusions: The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates. Clin Cancer Res; 18(4); 1129–37. ©2012 AACR .
75 citations
TL;DR: The overall efficacy of CP plus sorafenib in metastatic uveal melanoma did not warrant further clinical testing when assessed by ORR, although minor tumor responses and stable disease were observed in some patients.
Abstract: Author(s): Bhatia, Shailender; Moon, James; Margolin, Kim A; Weber, Jeffrey S; Lao, Christopher D; Othus, Megan; Aparicio, Ana M; Ribas, Antoni; Sondak, Vernon K | Abstract: BackgroundSorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, inhibits the mitogen-activated protein kinase pathway that is activated in most uveal melanoma tumors. This phase II study was conducted by the SWOG cooperative group to evaluate the efficacy of sorafenib in combination with carboplatin and paclitaxel (CP) in metastatic uveal melanoma.MethodsTwenty-five patients with stage IV uveal melanoma who had received 0-1 prior systemic therapy were enrolled. Treatment included up to 6 cycles of carboplatin (AUC = 6) and paclitaxel (225 mg/m(2)) administered IV on day 1 plus sorafenib (400 mg PO twice daily), followed by sorafenib monotherapy until disease progression. The primary endpoint was objective response rate (ORR); a two-stage design was used with the study to be terminated if no confirmed responses were observed in the first 20 evaluable patients. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS).ResultsNo confirmed objective responses occurred among the 24 evaluable patients (ORR = 0% [95% CI: 0-14%]) and the study was terminated at the first stage. Minor responses (tumor regression less than 30%) were seen in eleven of 24 (45%) patients. The median PFS was 4 months [95% CI: 1-6 months] and the 6-month PFS was 29% [95% CI: 13%-48%]. The median OS was 11 months [95% CI: 7-14 months].ConclusionIn this study, the overall efficacy of CP plus sorafenib in metastatic uveal melanoma did not warrant further clinical testing when assessed by ORR, although minor tumor responses and stable disease were observed in some patients.Trial registrationClinicalTrials.govNCT00329641.
69 citations
TL;DR: Results of BRAF mutational analysis were concordant in all 34 FNA smear/tissue excision pairs and represents a rapid, minimally invasive, and effective management strategy in this era of precision medicine.
Abstract: Patients with advanced-stage melanoma harboring a BRAF mutation are candidates for BRAF inhibition as a therapeutic strategy. The use of fine-needle aspiration (FNA) to diagnose metastatic melanoma is increasing. Studies examining the predictive value of BRAF mutation analysis on melanoma FNAs via correlation with follow-up excision findings are lacking. We examined 37 consecutive FNA cases of metastatic melanoma in which the aspirated lesion was subsequently excised. DNA was purified from Diff-Quik-stained FNA smears and tissue blocks from corresponding excisions in parallel. BRAF mutation status was successfully obtained from both specimen types in 34 (92%) of 37 cases. BRAF mutations were detected in 12 (35%) of 34 cases-11 V600E and 1 V600K. Results of BRAF mutational analysis were concordant in all 34 FNA smear/tissue excision pairs. Thus, melanoma FNA for molecular diagnostics represents a rapid, minimally invasive, and effective management strategy in this era of precision medicine.
27 citations
TL;DR: A multicenter, single-arm phase II trial of the cdk inhibitor SCH 727965 in patients with metastatic melanoma of cutaneous or mucosal origin found that selective inhibition of cdk2 may be of therapeutic value in a subset of patients with melanoma.
Abstract: 8521 Background: Cyclin-dependent kinases (cdks) function to regulate cell cycle control and agents that can target cdks in malignant progression remain viable therapeutic strategies. Selective inhibition of cdk2, in particular, may be of therapeutic value in a subset of patients with melanoma. Methods: 60 patients with metastatic melanoma of cutaneous or mucosal origin were planned to be recruited to a multicenter, single-arm phase II trial of the cdk inhibitor, SCH 727965 (NSC747135). Patients were potentially eligible if they had 0-1 previous treatments, PS of 0-1, and adequate organ function. Ocular melanoma patients and patients with a history of brain metastases were excluded. SCH 727965 50 mg IV every 3 weeks was given until progression with disease assessment occurring every 2 cycles. Co-primary endpoints were 1-year overall survival (OS) and 6-month progression free survival (PFS). Results: 72 patients were enrolled from July 1, 2009 to November 1, 2010 at 24 institutions. 68% of patients had...
7 citations