Discussion
nausea, T-cell ALL, tumor, cancers, fatigue, epithelial carcinomas, thrombocytopenia, thrombocyopenia, anemia, B-cell ALL, hepatocellular tumors, ALL, hepatocellular cancer, advanced/metastatic pancreatic cancer, cholangiocarcinoma
TUMOR, CANCERS, PANCREATIC TUMORS, DISEASE, THROMBOCYTOPENIA, B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA, ANEMIA, CHOLANGIOCARCINOMA
In this first-in-human, dose-escalation, Phase 1 study, OBI-3424, a small-molecule prodrug, was tolerated at doses of up to 14 mg/mThe most common TEAEs were anemia (64%), thrombocytopenia (49%), nausea (26%), and fatigue (21%). Three patients experienced serious TEAEs; all 3 experienced grade ≥3 anemia and 2 of the 3 also experienced grade ≥3 thrombocyopenia. The occurrence of transient thrombocytopenia is consistent with published data on AKR1C3 overexpression in normal bone marrow. In a recent study, 20 normal archival bone marrow samples from patients with B-cell acute lymphoblastic leukemia (ALL) and T-cell ALL were evaluated for AKR1C3 expression by IHC, protein Western blotting, and quantitative reverse-transcriptase PCR. An H-score was used to quantify the percentage of nuclear immunoreactivity for AKR1C3 with varying disease involvement. T-cell ALL samples had higher H-scores (172–190) than B-cell ALL samples (30–160). Follow-up IHC assessment of normal marrow specimens revealed that AKR1C3 is expressed in a subset of normal bone marrow cells that morphologically resemble erythroid lineage cells [OBI-3424 exhibited linear, dose-proportional pharmacokinetics at doses ranging from 1 mg/mThe best response to treatment with OBI-3424 was a partial response. One patient with cholangiocarcinoma had a partial response with 33% tumor reduction by local assessment while receiving OBI-3424 at a dose of 10 mg/mAKR1C3 is overexpressed in 90% of hepatocellular tumors and in 50% of pancreatic tumors, and there is a significant unmet need for better treatments in these cancers, especially for patients whose disease has progressed after surgery and/or systemic chemotherapy. Thus, a Phase 2 study of single-agent OBI-3424 is currently enrolling patients with locally advanced/metastatic pancreatic cancer, hepatocellular cancer, or other epithelial carcinomas with tumoral AKR1C3 overexpression.