Subject(s)
Adenine , Benzamides , Piperidines , Pyrazines , Pyrazoles , Pyrimidines , Humans , Piperidines/therapeutic use , Adenine/analogs & derivatives , Benzamides/therapeutic use , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Pyrimidines/administration & dosage , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Pyrazoles/administration & dosage , Pyrazines/therapeutic use , Pyrazines/adverse effects , Pyrazines/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Aminobutyrates/therapeutic use , Aminobutyrates/adverse effects , Male , Female , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Aged , Thiazoles/therapeutic use , Thiazoles/adverse effects , Thiazoles/administration & dosage , Genomics/methods , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Middle Aged , MutationABSTRACT
PURPOSE: To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone. PATIENTS AND METHODS: In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences. RESULTS: Overall, 13 and 129 patients were enrolled in phase Ib and II, respectively. Dose-limiting toxicity was not reported in patients during phase Ib and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase II, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide versus placebo/enzalutamide arm (3.8 vs. 2.8 months; P = 0.003 and 10.2 vs. 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide versus placebo/enzalutamide arm (13.2 months vs. 5.3 months; P = 0.03). CONCLUSIONS: Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone, and this may be enriched in patients with PTEN intact and no androgen receptor splice variant 7.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Benzamides , Humans , Male , Nitriles/therapeutic use , Phenylthiohydantoin/adverse effects , Prostatic Neoplasms, Castration-Resistant/pathology , Protein Kinase Inhibitors/therapeutic use , Pyridines , Quinolones , Receptors, Androgen , Treatment OutcomeABSTRACT
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common histology of non-Hodgkin lymphoma, representing 25% to 35% of new cases annually. The incidence of DLBCL has doubled in the past decades, highlighting the need for more effective treatment regimens. METHODS: This article reviews the current protocols applicable to this aggressive lymphoma and discusses ongoing research that is focusing on molecular diagnostics, prognostic factors have also been defined for DLBCL. RESULTS: Patients with DLBCL vary in clinical presentation, prognosis, and response to current therapies. While current therapy in the rituximab era has led to improved outcomes with reduced toxicity, novel treatment approaches for localized, advanced, and relapsed/refractory DLBCL are being pursued in clinical trials. Several studies have shown promise, such as trials involving proteasome inhibitors, lenalidomide, and antibody drug conjugates. CONCLUSIONS: Recent discoveries in the spectrum of care for patients with DLBCL have prompted a renaissance for personalized cancer medicine and molecularly targeted therapy. Potential targets and novel drug combinations are undergoing continued study in the hope of achieving successful and personalized care of this disease.
Subject(s)
Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/therapy , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Agents/therapeutic use , Forecasting , Humans , Lymphoma, Large B-Cell, Diffuse/pathology , RituximabABSTRACT
Plasmablastic lymphoma (PBL) is a rare aggressive B-cell lymphoproliferative disorder. HIV-negative PBL has not been extensively reported. Nine HIV-negative PBL patients evaluated at Moffitt Cancer Center were studied. Eight patients had extranodal diseases. All patients were treated with CHOP or hyper-CVAD. Responses were observed in 8 cases (7 complete, 1 partial responses). Four patients underwent consolidation with autologous hematopoietic stem cell transplant (HSCT) in first complete remission (CR1). At median follow-up of 23.9 months, 7 patients were alive and 5 were disease-free. Aggressive induction chemotherapy and consolidation with autologous HSCT in CR1 might be considered for patients with HIV-negative PBL.
