Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis.
Naveen PemmarajuBing Z CarterPrithviraj BoseNitin JainTapan M KadiaGuillermo Garcia-ManeroCarlos E Bueso-RamosCourtney D D DiNardoSharon BledsoeNaval G DaverUday R PopatMarina Y KonoplevaLingsha ZhouSherry PierceZeev E EstrovGautam M BorthakurMaro OhanianWei QiaoLucia MasarovaXuemei WangPo Yee MakJorge CortesElias JabbourSrdan VerstovsekPublished in: Blood advances (2021)
Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/μL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.
Keyphrases
- clinical trial
- oxidative stress
- chronic kidney disease
- end stage renal disease
- study protocol
- phase ii
- physical activity
- healthcare
- endoplasmic reticulum stress
- phase iii
- cell death
- ejection fraction
- stem cells
- newly diagnosed
- open label
- rheumatoid arthritis
- middle aged
- emergency department
- cell cycle arrest
- bone marrow
- community dwelling
- prognostic factors
- mesenchymal stem cells
- chemotherapy induced
- drug induced
- signaling pathway
- adverse drug
- glycemic control
- wound healing