A population PK model was developed for pertuzumab, the first monoclonal IgG1 antibody in a new class of agents known as HER dimerization inhibitors. In addition, our analyses demonstrate the feasibility of administering pertuzumab using a fixed dose in women with ovarian and breast cancers.

Summary:develop invasive fungal infections. [1][2][3][4] The diagnosis of fungal infections is particularly difficult in immunocompromised patients, and most patients are treated presumptively. Sixty-four adult patients (median age 43) with hematologic malignancies who were immunocompromised after Early institution of anti-fungal therapy is associated with better outcome, and withholding therapy until a definitive allogeneic (n = 23) or autologous (n = 9) blood/marrow transplantation, or chemotherapy (n = 32) received 68 diagnosis is made results in dissemination of the infection with a high mortality. 4 courses of amphotericin B lipid complex (ABLC, Abelcet) at the daily dose of 5 mg/kg for presumed Amphotericin B is the primary treatment for systemic fungal infections in immunocompromised patients because (n = 52) or proven (n = 16) fungal infection. The major indications for ABLC were failure of previous antifunof its broad spectrum of activity. 5,6 However, its use is limited by a variety of adverse effects including severe gal therapy and/or renal dysfunction. Fifty-three treatment courses in 49 patients comprising 4-58 doses systemic reactions such as fever, rigors, phlebitis and bronchospasm. 6 The major problem with amphotericin is (median 10) were considered evaluable. Fourteen courses administered for confirmed infections resulted its dose-related nephrotoxicity which compromises its efficacy in treating systemic fungal infections and restricts its in nine complete and one partial responses, and four failures (71% response). Thirty-nine empiric courses prophylactic use. 7 Drug-induced renal dysfunction is a major concern after blood or marrow transplantation resulted in 18 complete and six partial responses, and 14 failures (64% response). The overall response rate (BMT), 8,9 where the use of a less nephrotoxic formulation of amphotericin would be particularly attractive. 10 was 66%. Five of seven evaluable patients with aspergillus pneumonia responded. Response rates were compa-A number of lipid-based formulations of amphotericin have been developed to improve the tissue distribution of rable for chemotherapy, autograft and allograft recipients. The change in serum creatinine from the beginning amphotericin and to reduce the toxicity associated with conventional amphotericin. 10 Amphotericin B lipid comto the end of therapy was −284 to +277 mol/l (median +24). The creatinine doubled during seven evaluable plex (ABLC) is derived from a liposomal formulation of amphotericin B consisting of dimyristoyl-phosphatidylcourses of therapy, five of which were associated with concomitant nephrotoxic therapy. Nephrotoxicity was choline and dimyristoyl-phosphatidylglycerol in a 7:3 molar ratio. Unlike the original liposomal formulation, comparable for transplant and chemotherapy patients. Renal dysfunction necessitated discontinuation of ABLC has a ribbon-like appearance. 10 Here, we report our experience with the use of ABLC ABLC in only four patients. These data suggest that ABLC is effective in presumed or co...

Summary:The clinical features of chronic graft-versus-host disease (cGVHD) following a non-myeloablative peripheral blood stem cell (PBSC) transplant may differ from those that occur after a conventional allograft. We describe a man with Hodgkin's disease refractory to chemotherapy and radiotherapy who was transplanted from an HLAidentical brother, who developed cGVHD characterised, in particular, by polymyositis, polyserositis with a large pericardial effusion and constrictive pericarditis, 1 month after donor lymphocyte infusion for relapsed disease. Constrictive pericarditis has not been previously reported after a conventional allograft, and none of these features have been reported after a non-myeloablative transplant. The course of cGVHD necessitated potent immunosuppression leading to the presumed loss of graft-versus-lymphoma (GVL) effect. Bone Marrow Transplantation (2001) 27, 231-233. Keywords: polyserositis; pericardial effusion; constrictive pericarditis; myositis; graft-versus-host diseaseThe current approach to the diagnosis and management of chronic graft-versus-host disease (cGVHD) is based on extensive experience of conventional allografting. It is unknown whether clinical manifestations and response to treatment may be different, if cGVDH occurs in the setting of a non-myeloablative transplant. We describe a patient who developed myositis, polyserositis with a large pericardial effusion and constrictive pericarditis following a nonmyeloablative stem cell transplant and subsequent donor lymphocyte infusion. cGVHD progressed despite treatment with steroids and cyclosporin A. Case reportA 36-year-old man with Hodgkin's disease (nodular sclerosis) who was in second complete remission after BEAM chemotherapy and autologous stem cell rescue presented with back pain. Computed tomography (CT) demonstrated retroperitoneal relapse. Physical examination and routine pre-transplant investigations (blood count, biochemistry studies, echocardiogram) were normal, apart from lung function tests which showed slightly reduced transfer factor (67% predicted). HIV, HbsAg tests and viral serology (hepatitis C, VZV, CMV) were negative in both the patient and the donor.He underwent a non-myeloablative PBSC transplant from his HLA-identical brother. Conditioning included fludarabine 25 mg/m 2 (day −6 to day −2) and cyclophosphamide 1 g/m 2 (day −3 and −2 ). GVHD prophylaxis consisted of methotrexate 10 mg/m 2 (days +1, +3, +6 and +11) and cyclosporin A 5 mg/kg from day −1, reduced to 3 mg/kg from day +4 and adjusted to maintain the level between 150 and 300 g/l. The dose of nucleated cells infused on day 0 was 6.44 × 10 8 /kg and CD34 + cells 4.86 × 10 6 /kg. Chimerism was evaluated by analysis of minisatellite variable number of tandem repeats on whole blood. The patient had 63% donor-derived cells on day 16 and converted to full donor chimaerism by week 12. The dose of cyclosporin A was reduced from week 13.Six months after the transplant he reported recurrence of the back pain. CT and positron emission tomography (...

Both the development of factor VIII inhibitors and infection by hepatitis C virus are serious complications of haemophilia A. We describe the first reported case of the subsequent development of a factor VIII inhibitor in a patient with haemophilia A after treatment with interferon-alpha for chronic active hepatitis C.

RAS proteins are small GTPases that drive cell proliferation and survival when bound to GTP. Mutant RAS proteins are found in approximately one-third of human cancers, and exist predominantly in the GTP-bound state, leading to excessive downstream signaling via interaction with effectors such as RAF. A KRAS mutation in which glycine-12 is mutated to cysteine (KRASG12C) is found in 11-12% of non-small cell lung cancers. Recently, multiple potent, covalent inhibitors of KRASG12C have been reported that target the inactive, GDP-bound form of KRASG12C, and thus rely on the residual intrinsic hydrolysis of GTP to cycle KRASG12C proteins through the inactive, GDP-bound state. This mechanism is vulnerable to adaptive responses in cancer cells that can activate RAS by increasing upstream signaling and further increase the relative abundance of KRASG12C(GTP) over KRASG12C(GDP). An inhibitor that directly targets the active, GTP-bound form of KRASG12C would overcome this limitation. Drawing inspiration from natural products like cyclosporine and rapamycin, we have developed tri-complex inhibitors of KRASG12C(GTP) that promote a ternary complex between KRASG12C and the abundant immunophilin cyclophilin A (CypA). These sanglifehrin-inspired inhibitors exploit significant non-covalent interactions in the SWI/SWII region of KRAS combined with an electrophilic cysteine-targeted warhead to potently and irreversibly inhibit KRASG12C(GTP). The inhibitors selectively drive formation of KRASG12C-inhibitor-CypA ternary complexes that are sterically prevented from interacting with the RAS Binding Domain (RBD) of BRAF in biochemical studies. In cellular models, KRASG12C(GTP) inhibitors attenuate both RAS-MAPK signaling and cell viability in cancer cell lines bearing KRASG12C mutations, but not other mutations in RAS or other pathway oncoproteins. In vivo administration of a KRASG12C(GTP) inhibitor drives dose-dependent tumor regressions in the NCI-H358 KRASG12C NSCLC xenograft mouse model and is well-tolerated. Consistent with targeting the KRAS(GTP) state, inhibitory activity in vitro is unaffected by RTK activation, whereas the activity of first generation KRASG12C(GDP) inhibitors is significantly attenuated. In addition, proliferation of NCI-H358 and MIA PaCa-2 cells in vitro is suppressed for a significantly longer duration with KRASG12C(GTP) inhibitor treatment compared to KRASG12C(GDP) inhibitors. The combination of sub-maximal concentrations of a MEK inhibitor and a KRASG12C(GTP) inhibitor drove pronounced cell death. In contrast, the MEK and KRASG12C(GDP) inhibitor combination evoked a modest enhancement of the antiproliferative effects and does not cause cell death. Tri-complex inhibitors that target the active, GTP-bound form of KRAS thus represent a second generation of KRASG12C inhibitor. Chemical modulation of the non-covalent and covalent interactions of our tri-complex inhibitors provides an exciting opportunity to step beyond KRASG12C to target the GTP-bound state of additional RAS variants, and we demonstrate in vitro covalent inhibition of KRASG13C. By directly targeting active RAS-GTP, tri-complex inhibitors have the potential to overcome adaptive resistance mechanisms that emerge following inhibition of aberrant RAS-MAPK pathway activation. Citation Format: Christopher J Schulze, Alun Bermingham, Tiffany J Choy, James J Cregg, Gert Kiss, Abby Marquez, Denise Reyes, Mae Saldajeno-Concar, Caroline E Weller, Daniel M Whalen, Yu C Yang, Elena S Koltun, Robert J Nichols, Mallika Singh, David Wildes, Adrian L Gill, Richard L Hansen, Steve Kelsey, Mark A Goldsmith, Jacqueline A.M. Smith. Tri-complex inhibitors of the oncogenic, GTP-bound form of KRASG12C overcome RTK-mediated escape mechanisms and drive tumor regressions in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR10. doi:10.1158/1535-7163.TARG-19-PR10