Exportin 1 (XPO1/CRM1) is overexpressed in MM and was identified as an essential protein for MM cell growth. The majority of Tumor Suppressor Proteins (TSP) are transported out of the nucleus ...exclusively by XPO1, leading to their inactivation. Selinexor (KPT-330) is a potent, selective oral inhibitor of XPO1 and shows potent anti myeloma activity in preclinical models.
Patients (pts) with advanced, relapsed/refractory MM or WM were dosed with oral Selinexor (8-10 doses / 4-week cycle) as part of a broad Phase 1 program (NCT 01607892) in advanced hematological malignancies. Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and tumor biopsies on selected patients were performed. Response evaluation was performed every cycle. All pts in this study had documented progressive disease on study entry and were relapsed/refractory to at least one proteasome inhibitor and one immunomodulating agent.
17 MM and 2 WM pts with median age 67yrs (range 50-75); ECOG PS 0/1: 6/13; median number of prior regimens: 5 range 1-13, received Selinexor across 6 dose levels (3 to 30 mg/m2). Five patients experienced drug-related grade 3/4 Adverse Events (AEs), including thrombocytopenia without bleeding (n=4), neutropenia (n=4), impaired renal function (n=1), decreased WBC (n=1) and febrile neutropenia (n=1). The most common grade 1/2 toxicities are gastrointestinal (GI) including nausea (16/19; 84%), anorexia (11/19pts; 58%), vomiting (8/19; 42%), diarrhea (7/19pts; 37%), weight loss (4/19; 21%) and dysgeusia (4/19; 21%). Grade 1/2 study drug related fatigue was also observed in 10/19 or 53% of the patients. No grade ≥3 GI related AEs were observed. These side effects were well managed with supportive care. No clinically significant cumulative drug toxicities have been noted and patients have remained on therapy for >8 months (median duration on therapy 50 days, range 8-274 days). Two pts died during the study, one due to E.coli sepsis and the other due to renal dysfunction, both events deemed by treating investigators to be unrelated to study drug. PK analysis demonstrated total exposure increased with increasing dose, with no accumulation and without affecting half-life (5-7 hrs) or clearance of KPT-330. At 23 mg/m2, exposure (Cmax 289 ng/mL and AUC0-inf 2219 ng*h/mL) was comparable to anti tumor exposure observed in mice and dogs. Significant increases (2-20x) in leukocyte XPO1 mRNA levels (PDn marker) were observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA. Response was evaluable in 15 MM pts: Partial response (PR) in 1 pt (6.7%) at 35mg/m2, Minimal Response (MR) in 6 pts (40%) at doses of 16.8 to 30mg/m2, Stable Disease (SD) in 5 pts (33%) and Progressive Disease (PD) in 3 pts (20%). One MR and 1 SD were observed in the 2 WM pts. Evaluation of serial bone marrow samples from one patient confirms Selinexor-induced nuclear localization of multiple TSPs as well as reduction in CD138+ MM cells. Dose escalation is ongoing at 35 mg/m2 twice weekly.
Oral Selinexor treatment is generally well tolerated, with favorable PK and PDn properties. Prolonged disease control and responses are observed in heavily pretreated patients with progressive MM whose disease is relapsed or refractory to available agents.
Chen:Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Experimental use of Selinexor, a drug not yet approved. Baz:Celgene, Millennium, BMS, Novartis, Karyopharm, Sanofi: Research Funding. Reece:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium Pharmaceuticals: Research Funding; Novartis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; BMS: Research Funding; Otsuka: Honoraria, Research Funding; Onyx: Consultancy. Siegel:Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau. Kuruvilla:Seattle Genetics : Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Karyopharm: Research Funding. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Rashal:Karyopharm Therapeutics Inc.: Employment, Equity Ownership. McCauley:Karyopharm Therapeutics: Employment, Equity Ownership. Saint-Martin:Karyopharm Therapeutics Inc.: Employment, Equity Ownership. McCartney:Karyopharm Therapeutics Inc.: Employment, Equity Ownership. Landesman:Karyopharm Therapeutics: Employment, Equity Ownership, Patents & Royalties. Klebanov:Karyopharm Therapeutics: Employment, Equity Ownership. Pond:Osmozis : Consultancy. Kauffman:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Mirza:Karyopharm Therapeutics Inc.: Consultancy, Equity Ownership.
Discusses the methodology and progress of the Phytophthora ramorum eradication programme. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal ...Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Two new diterpenoids from Teucrium fruticans Savona, Giuseppe; Passannanti, Salvatore; Paternostro, M. Pia ...
Journal of the Chemical Society, Perkin Transactions 1,
1978
4
Journal Article
PDF
