Novel Agent Slows High-Risk Myelofibrosis in Initial Trial

A third of patients with previously treated, high- and intermediate-risk myelofibrosis had objective responses to the investigational Second mitochondria-derived activator of caspases mimetic LCL161.

Naveen Pemmaraju, MD

A third of patients with previously treated, high- and intermediate-risk myelofibrosis had objective responses to the investigational Second mitochondria-derived activator of caspases (SMAC) mimetic LCL161, results of a small phase II trial showed.

Seven of 21 evaluable patients had improvement in 1 or more clinical parameters during treatment with LCL161. The treatment was generally well tolerated with weekly oral dosing. Grade 3/4 toxicity consisted primarily of anemia and thrombocytopenia, as reported at the American Society of Hematology meeting in San Diego.

“LCL161 has a convenient dosing schedule, has a novel target for patients with myeloproliferative neoplasms, and is able to be administered to patients who have failed or demonstrated intolerance or are otherwise ineligible for JAK inhibitor therapy,” said Naveen Pemmaraju, MD, assistant professor of leukemia at the University of Texas MD Anderson Cancer Center in Houston. “Grade 2 fatigue was the most common toxicity observed, resulting in 6 out of 7 dose reductions during the study. This study has met criteria for preplanned analysis for safety, and therefore is now enrolling in stage II.”

No available standard therapy exists for intermediate-2 or high-risk myelofibrosis when patients have not responded or demonstrated intolerance to JAK inhibitors. SMAC mimetics, or apoptosis inhibitors, increase apoptotic cancer cell death, particularly in preclinical models of high TNF-alpha-expressing tumors.

In a phase I study of patients with advanced solid tumors, the SMAC mimetic LCL161 led to stable disease in 10 out of 53 patients.1 Correlative studies showed that LCL161 resulted in on-target degradation of cellular inhibitor of apoptosis protein-1 (cIAP1). The agent also was generally well tolerated. The only dose-limiting toxicity was cytokine release syndrome, which occurred in 3 patients.

The reported observation of increased levels of TNF-alpha in patients with myelofibrosis has emerged as a potential factor in the pathobiology of the disease.2 The observation also provided support for evaluation of LCL161 in patients with myelofibrosis.

Pemmaraju and colleagues conducted the first-ever clinical evaluation of LCL161 in myelofibrosis. The trial had a primary objective of efficacy, and secondary objectives included safety, durability of response, and change in symptom burden.

Investigators enrolled patients with intermediate-1/2 or high-risk myelofibrosis. Eligible patients were ineligible for, had demonstrated intolerance to, or had relapsed/refractory disease in response to treatment with JAC inhibitors. Patients received LCL161 once weekly at a dose of 1500 mg. Bone marrow examination and first assessment for objective response were performed after completion of the third 28-day cycle of treatment.

The study population comprised 25 patients who had a median age of 72. Review of treatment history showed that 18 patients had received 2 or more prior lines of therapy, and 16 of the patients had been treated with a JAK inhibitor. All but 7 patients had high-risk myelofibrosis by International Prognostic Scoring System (IPSS) criteria.

Grade 2 fatigue occurred in 11 patients, making it the most commonly reported adverse event in the study. Nine patients reported grade 1 nausea, and 9 reported dizziness/vertigo (grade 2 in two patients). Five patients developed grade 3 anemia, and 5 had grade 4 thrombocytopenia. Grade 3 syncope occurred in 2 patients, and 1 each developed grade 3 neutropenia and thrombocytopenia.

Five of the 7 patients with stable disease saw improvement in their symptoms, including 2 with accompanying improvement in splenomegaly, and 1 with improvement in hemoglobin. One patient had a cytogenetic response with improvement in hemoglobin, and 1 had improvement in hemoglobin alone. The time to improvement ranged from .9 to 8.1 months, and response duration ranged from 2.8 to 19.6 months.

The seven patients who required dose reductions included 1 with diarrhea and weakness, in addition to the 6 with grade 2 fatigue that led to dose reductions.

Median overall survival has yet to be reached, Pemmaraju and colleagues reported.

References

  1. Infante JR, Dees EC, Olszanski AJ, et al. Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2014;32(28):3103-3110. doi: 10.1200/JCO.2013.52.3993.
  2. Fleischman AG, Aichberger KJ, Luty SB, et al. TNFα facilitates cloncal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. Blood. 2011;118(24):6392-6398. doi: 10.1182/blood-2011-04-348144.
  3. Pemmaraju N, Carter BZ, Kantarjian H, et al. Results for phase II clinical trial of LCL161, a SMAC mimetic, in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocytosis myelofibrosis (post-ET MF). Paper presented at: 58th Annual ASH Meeting; December 3-6, 2016; San Diego, CA. Abstract 3105.