A Phase I Study Using Single Agent Birinapant in Patients with Relapsed Myelodysplastic Syndrome and Acute Myelogenous Leukemia
Authors: Frey Noelle V. , Luger Selina , Mangan James , Zebrowski Alexis , Loren Alison W. , Minderman Hans , Baird John , Porter David L , Hexner Elizabeth O. , Kumar Anita J. , Luskin Marlise R. , Perl Alexander E , Carroll Martin 
Published: October 2019

Abstract
BACKGROUND: Effective and well tolerated treatment options for patients with relapsed acute myelogenous leukemia (AML) are limited. Birinapant is a small molecule, peptidomimetic of second mitochondrial-derived activator of caspases (SMAC) that selectively targets Inhibitor of Apotosis proteins (IAPs) resulting in tumor cell apoptosis and inactivation of NF-kB. SMAC mimetics represent a novel class of anti-tumor agents and birinapant has been explored as a single agent and in combination with chemotherapy in trials in solid tumors. Based on pre-clinical response observed in a mouse model with AML, we developed an investigator initiated Phase I clinical trial using single agent birinapant in pts with relapsed AML and high risk myelodysplastic syndrome (MDS).
METHODS: Eligible pts were >18 years old with non-M3 relapsed or refractory AML or high risk MDS refractory to a hypomethylating agent. A standard 3+3 dose escalation was planned using single agent birinapant at increasing dose levels and frequency. Subjects who did not complete at least one cycle of therapy (4 wks) or experience a dose limiting toxicity (DLT) were replaced. The primary endpoint was safety and determination a maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetic (PK) and pharmacodynamics (PD) analysis as well as disease response.
RESULTS: From 12/2011 to 05/2014, 20 subjects were enrolled at the Hospital of the University of Pennsylvania and received at least one dose of study drug, 1 had MDS, 19 had AML (9 with antecedent MDS). The median age was 75 (range 36 to 80). The median number of prior treatments was 2 (range 1 to 5) and 11 patients required hydroxyurea during study treatment. No other concurrent chemotherapy was permitted.
Several dose levels were tested varying the dose (17mg/m2, 22mg/m2 and 26mg/m2) and frequency (weekly, twice weekly (BIW) and 3 times weekly (TIW)) for 3 out of 4 wk cycles. Evaluable subjects have stayed on study drug for <1 wk to 45wks. Two dose levels tested resulted in a DLT. DLTs of grade 3 and grade 4 serum amylase and lipase abnormalities were observed in the 26mg/m2 weekly dose level. Pancreatic enzyme abnormalities were clinically silent and reversible with dose reduction or cessation. A DLT of Bell’s palsy was observed at 22mg/m2 BIW dosing level. No dose limiting toxicities were observed at 17mg/m2 weekly nor thus far at 17mg/m2 BIW. One subject only was treated at 17mg/m2 TIW dosing level who withdrew due to flare of underlying Behcets during week 1 of study treatment. Further exploration of TIW dosing was abandoned due to feasibility concerns. Enrollment continues at the final expanded cohort of 17mg/m2 BIW. The best disease response observed to date is stable disease at one month, 3 months and 6 months for some pts: one pt had a decline in their bone marrow blast count from 60% to 10% with single-agent birinapant.
PK and PD analysis were performed at specified time points. Feasibility of measuring cIAP1 and cIAP2 inhibition as well as NFkB activity as PD response parameters for birinapant was explored. cIAP1 and cIAP2 levels were evaluated via Western blot analysis of mononuclear cells from pts; NFkB activity was assessed by imaging flow cytometry prior to and during initiation of birinapant treatment. cIAP1/cIAP2 suppression as well as inhibition of NFkB were evident. PK levels in plasma and blasts were also assessed at the same specified time points. Based on analysis to date, birinapant has excellent drug exposure and target suppression of cIAP1/cIAP2 and inhibition of NF-kB activity during the BIW schedule of 17mg/m2 for 3 out of 4 wks.
CONCLUSIONS: This is the first study evaluating the safety and role of birinapant in pts with MDS and AML and first study in humans evaluating administration of this drug on a BIW dosing schedule. Observed adverse events related to study drug in this pt population include exacerbation of underlying autoimmune disease, Bell’s palsy and reversible and clinically silent elevation of amylase and lipase. Feasibility of measuring NFkB and cIAP1/2 expression as pharmacodynamics markers is established. Our study supports the safety and on tumor targeting of BIW dosing of birinapant which is currently under evaluation in combination with other agents in MDS.

Disclosures
Frey: Tetralogic Pharmaceuticals: Research Funding. Minderman:Tetralogic Pharmaceuticals: Research Funding. Porter:Novartis: managed according to U Penn Policy Patents & Royalties, Research Funding. Carroll:Tetralogic: Research Funding.