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1.
J Clin Oncol ; 31(14): 1767-74, 2013 May 10.
Article in English | MEDLINE | ID: mdl-23569304

ABSTRACT

PURPOSE To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF(V600)-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy. METHODS In the phase II clinical study NP22657 (BRIM-2), patients received oral doses of vemurafenib (960 mg twice per day). Serial biopsies were collected to study changes in mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, and factors causing intrinsic or acquired resistance by immunohistochemistry, DNA sequencing, or somatic mutation profiling. Results Vemurafenib inhibited MAPK signaling and cell-cycle progression. An association between the decrease in extracellular signal-related kinase (ERK) phosphorylation and objective response was observed in paired biopsies (n = 22; P = .013). Low expression of phosphatase and tensin homolog showed a modest association with lower response. Baseline mutations in MEK1(P124) coexisting with BRAF(V600) were noted in seven of 92 samples; their presence did not preclude objective tumor responses. Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRAS(Q61) mutations or MEK1(Q56P) or MEK1(E203K) mutations. These two activating MEK1 mutations had not previously been observed in vivo in biopsies of progressive melanoma tumors. CONCLUSION Vemurafenib inhibits tumor proliferation and oncogenic BRAF signaling through the MAPK pathway. Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients. The data suggest that inhibition downstream of BRAF should help to overcome acquired resistance.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm , Indoles/pharmacology , MAP Kinase Signaling System/drug effects , Melanoma/drug therapy , Mitogen-Activated Protein Kinase Kinases/metabolism , Proto-Oncogene Proteins B-raf/metabolism , Skin Neoplasms/drug therapy , Sulfonamides/pharmacology , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Disease Progression , Female , GTP Phosphohydrolases/genetics , Humans , Immunohistochemistry , Indoles/administration & dosage , MAP Kinase Kinase 1/genetics , Male , Melanoma/secondary , Membrane Proteins/genetics , Middle Aged , Point Mutation , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/pathology , Sulfonamides/administration & dosage , Tumor Cells, Cultured , Vemurafenib
2.
Contemp Clin Trials ; 29(6): 896-904, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18703164

ABSTRACT

A common approach to the design of phase II clinical trials in oncology is to conduct a two-stage trial so as to control type I and type II error rates. A number of researchers have proposed methods for the design of such trials when the response can take one of a number of ordered values such as tumor response, stable disease or progressive disease. In this case, the problem may be formulated as that of testing a complex null hypothesis. Control of the type I error rate thus requires specification of the null region and construction of a test that limits the maximum error rate over this region. In this paper we propose that the null region should be bounded by a line in the two-dimensional parameter space for the setting with a response with three levels and more generally by a plane or hyperplane. We then propose a test based on the likelihood ratio statistic and show how this may be calculated in this case for a three-level response. The method is illustrated using an example of a clinical trial to evaluate a new treatment for breast cancer.


Subject(s)
Breast Neoplasms/drug therapy , Clinical Trials, Phase II as Topic , Data Interpretation, Statistical , Research Design , Female , Humans , Likelihood Functions , Models, Statistical , Multivariate Analysis
3.
J Clin Oncol ; 25(3): 257-62, 2007 Jan 20.
Article in English | MEDLINE | ID: mdl-17235043

ABSTRACT

PURPOSE: To determine the prostate-specific antigen (PSA) 50% decline rate within 24 weeks of starting treatment with single-agent pertuzumab in castrate patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Two independent Simon's two-stage designs were used to evaluate two doses of pertuzumab administered intravenously once every 3 weeks. An interim analysis of the first 23 assessable patients in the first cohort treated at 420 mg (loading dose of 840 mg) allowed termination of additional enrollment if three patients had a 50% decline in PSA after all patients had completed at least three cycles of therapy or withdrew due to insufficient therapeutic response, death, or study-related toxicity before completing three cycles. A second cohort of patients treated at 1,050 mg could be enrolled with the same design, and if more than three patients had a 50% decline in PSA, 27 more patients would be treated at 1,050 mg. RESULTS: Sixty-eight castrate, chemotherapy-naive men with HRPC were enrolled. A total of 35 patients were treated at 420 mg; no PSA declines 50% were observed at the interim analysis and recruitment was stopped. A total of 33 patients were then treated at 1,050 mg, and no PSA declines 50% were observed at the interim analysis. Pertuzumab was well tolerated. CONCLUSION: Pertuzumab has no clinically significant single-agent activity in castrate patients with HRPC at either of the tested dose levels. This may reflect the continued presence of significant levels of intraprostatic androgen driving androgen receptor signaling.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Prostate-Specific Antigen/blood , Prostatic Neoplasms/drug therapy , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized , Antineoplastic Agents, Hormonal/pharmacology , Drug Resistance, Neoplasm , Humans , Male , Middle Aged , Prostatic Neoplasms/blood , Prostatic Neoplasms/pathology , Treatment Outcome
4.
N Engl J Med ; 352(26): 2705-13, 2005 Jun 30.
Article in English | MEDLINE | ID: mdl-15987919

ABSTRACT

BACKGROUND: Daclizumab, a humanized monoclonal antibody against the interleukin-2 receptor, reduced the risk of rejection without increasing the risk of infection among renal-transplant recipients and, in a single-center trial, among cardiac-transplant recipients. We conducted a multicenter, placebo-controlled, double-blind study to confirm these results in cardiac-transplant patients. METHODS: We randomly assigned 434 recipients of a first cardiac transplant treated with standard immunosuppression (cyclosporine, mycophenolate mofetil, and corticosteroids) to receive five doses of daclizumab or placebo. The primary end point was a composite of moderate or severe cellular rejection, hemodynamically significant graft dysfunction, a second transplantation, or death or loss to follow-up within six months. RESULTS: By six months, 104 of 218 patients in the placebo group had reached the primary end point, as compared with 77 of the 216 patients in the daclizumab group (47.7 percent vs. 35.6 percent, P=0.007), a 12.1 percent absolute risk reduction and a 25 percent relative reduction. The rate of rejection was lower in the daclizumab group than in the placebo group (41.3 percent vs. 25.5 percent). Among patients reaching the primary end point, the median time to the end point was almost three times as long in the daclizumab group as in the placebo group during the first 6 months (61 vs. 21 days) and at 1 year (96 vs. 26 days). More patients in the daclizumab group than in the placebo group died of infection (6 vs. 0) when they received concomitant cytolytic therapy. CONCLUSIONS: Daclizumab was efficacious as prophylaxis against acute cellular rejection after cardiac transplantation. Because of the excess risk of death, concurrent or anticipated use of cytolytic therapy with daclizumab should be avoided.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Graft Rejection/prevention & control , Heart Transplantation , Immunoglobulin G/therapeutic use , Immunosuppressive Agents/therapeutic use , Mycophenolic Acid/analogs & derivatives , Adolescent , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Cyclosporine/therapeutic use , Daclizumab , Double-Blind Method , Drug Therapy, Combination , Female , Graft Rejection/epidemiology , Heart Transplantation/mortality , Humans , Immunoglobulin G/adverse effects , Immunosuppressive Agents/adverse effects , Logistic Models , Male , Middle Aged , Mycophenolic Acid/therapeutic use , Opportunistic Infections/epidemiology , Opportunistic Infections/microbiology , Opportunistic Infections/mortality , Survival Analysis
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