Dr. Lindsay Wilde, an oncologist at the Hematologic Malignancies Division of Jefferson University, recently contributed to an article in the Oncology Times outlining her research team’s new study and its ambitious goals.
Dr. Wilde and the researchers are interested in OPB-111077 (OBP). OBP is a low-molecular-weight compound that exhibited the ability to inhibit the growth of AML (acute myeloid leukemia) cells when combined with decitabine.
The combination of decitabine and venetoclax was FDA approved in the latter part of 2018. Venetoclax has become the new standard of care for AML when combined with hypomethylating agents.
About the Initial Study
The initial study examined the oral compound OBP and decitabine. OBP was of interest due to its inhibition of mitochondrial electron transport (ETC). The ETC transfers electrons from electron donors to acceptors by way of redox reactions (simultaneous oxidation and occurrence.)
Dr. Wilde described the team’s observation when using metabolomics, which is the study of small molecules. She said that the team observed changes in patients’ “metabolomic signatures” that gave rise to the theory that the usual resistance seen in their venetoclax patients had been met and conquered.
The expansion in analytical chemistry is responsible for the emergence of metabolomics. Metabolomics facilitates hundreds to thousands of metabolites, the end product of metabolism, to track changes in metabolic networks and pathways.
The study grew out of results from clinical research data that implied that targeting OXPHOS (mitochondrial oxidative phosphorylation) is a possible strategy in targeting leukemic stem cells when addressing relapse.
Dr. Wilde expressed hope that by adding OPB to the drugs, patients who had been in remission will again respond.
About the Trial
Patients were eligible to participate if they had non-PL AML that had relapsed or was resistant to any type of intensive therapy. Patients would also be considered for the trial if they had not been willing to take part in other procedures due to their intensity.
OPB-111077 was administered on the first day of the initial cycle. Decitabine was given at 20 mg/m2 for five days beginning on the fourth day of the first cycle.
Dosing adjustments were made for patients who received a prophylaxis to prevent adverse advents resulting from dying tumor cells releasing their contents into the blood.
The study dictated that if a response is seen in the first two cycles, patients may continue therapy until they experience disease progression, toxicity, or another therapy is made available.
For this study, the primary endpoint was dose-limiting toxicity. A total of nine patients received dosing of OPB-111077 at 150mg combined with decitabine followed by venetoclax. The researchers did not uncover any toxicities that required a dose reduction.
Dr. Wilde reported that the team had initially been working with OPB and decitabine. At the same time, they were receiving data about venetoclax, which had become the standard of care. It was this introduction to venetoclax that convinced them to combine the three drugs in pre-clinical work and eventually move to a clinical trial.
The team found that the triplet produced greater efficacy than that of a single agent. Specifically, the researchers discovered that combining OPB-111077 with venetoclax against the AML cells that had been genetically engineered, brought about cell death or prevented tumor expansion to a greater extent.
About Adverse Events
Dr. Wilde commented that although no grade three or four toxicities were evident, nausea at the grade 2 level did appear quite often. The staff was able to overcome that problem with antiemetics.
And Now the Clinical Trial
At this point, the trial has just three participants. Dr. Wilde said that the team is interested in observing their biochemical fingerprint (metabolomic signatures). The recommended dose for phase II has not yet been determined, but the team is very enthused about the triplet’s potential.
