A Phase I Clinical Trial of Darinaparsin in Patients with Refractory Solid Tumors

Abstract

Purpose: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer. (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for z4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer. Conclusions: The recommended dose for phase II trials is 300 mg/m 2 i.v. given daily for 5 days every 4 weeks.Arsenic has been used medicinally for >2,400 years (1).Arsenic trioxide (ATO), an inorganic arsenic compound, is approved for the treatment of relapsed acute promyelocytic leukemia. However, the use of ATO is limited by its narrow range of activity and systemic toxicity, most notably cardiotoxicity and neurotoxicity (2 -4). S-dimethylarsino-glutathione (ZIO-101; darinaparsin), a small-molecule organic arsenic compound, was synthesized by conjugating dimethylarsenic acid to glutathione. Darinaparsin was selected for development by The University of Texas M. D. Anderson Cancer Center and Texas A&M University from a number of organic arsenic derivatives because of its in vitro and in vivo antitumor activity (5, 6).Darinaparsin and ATO inhibit the growth of malignant cells in vitro by inducing cell cycle arrest and apoptosis. The mechanism of action of darinaparsin involves induction of mitochondrial damage, which, in turn, results in ATP depletion and apoptosis. 5 In vitro data showed that, in contrast to ATO, darinaparsin does not modulate bcl-2 and its mechanism of apoptosis induction is independent from promyelocytic leukemia/retinoic acid receptor a and/or promyelocytic leukemia proteins. In addition, the cytotoxicity of darinaparsin, unlike that of ATO, is unaffected by modulation of glutathione levels. Further, darinaparsin induces higher reactive oxygen species levels than those induced by ATO. Both darinaparsin and ATO-induced cytotoxicity are c-Jun-NH 2 -kinase dependent, but only ATO-induced cytotoxicity is dependent on apoptosis signal-regulating kinase 1 (7). In addition, darinaparsin exerts antitumor activity against ATO-resistant cell lines overexpressing multidrug resistance protein 1/ATP-binding cassette, subfamily C, member 1 (MRP1/ABCC1). Unlike ATO, darinaparsin does not seem to be the substrate of the MRP1/ABCC1 efflux pump because MRP1/ABCC1 inhibition has no effect on 5 A. Heyfets, E. Flescher. A new organic arsenic derivate, darinaparsin, acts directly on isolated human cancer cell mitochondria, submitted manuscript.

Darinaparsin Inhibits Prostate Tumor–Initiating Cells and Du145 Xenografts and Is an Inhibitor of Hedgehog Signaling

“…The development of an oral form of darinaparsin and evidence of antitumor activity in phase I and II trials (6,18), together with the results of this study, provide a rationale for evaluating darinaparsin in patients with castrate-resistant prostate cancer. Xenograft studies with darinaparsin.…”

“…Phase I studies with darinaparsin in patients with advanced refractory solid tumors showed that 300 mg/m 2 i.v. for 5 consecutive days every 4 weeks was well tolerated (6). Phase II studies in both hematologic malignancies and solid cancers are currently under way (7,8).…”

Outcomes of Patients with Advanced Non-Small Cell Lung Cancer Treated in a Phase I Clinic

“…Of 85 patients treated, 50 (59%) received single-agent targeted phase I therapy [15][16][17][18][19][20][21][22][23], 14 (16%) received a combination of targeted agents, 13 (15%) received chemotherapy combined with targeted agents [24,25], and eight (10%) received chemotherapy alone (Table 2) [26]. None of the patients was treated in a genotype-specific trial such as with anti-epidermal growth factor receptor (EGFR) therapy in patients with tumors harboring EGFR mutations or antianaplastic lymphoma kinase (ALK) therapy in tumors with EML4 -ALK fusion.…”

Speciation, Metabolism, Toxicity, and Protein-binding of Different Arsenic Species in Human Cells

“…4,5,79,80 Compared to IV ATO therapy, oral ATO has slower absorption resulting in reduced peak arsenic plasma concentration, which was found to be associated with lower levels of cardiotoxicity. 76,81 ATO induces apoptosis (cell death) and cell differentiation, inhibits proliferation and angiogenesis.…”

“…91 Arsenic trioxide and Darinaparsin are uptaken by different transport mechanisms, illicit somewhat differing protective responses, and they are metabolized by cells differently. 79,91,92 Darinaparsin was initially administered in IV (intravenous) form (no first-pass metabolism), but it is currently being evaluated as an orally administered medication. Current results show activity but as with all orally taken medications, first-pass metabolism could potentially limit its bioavailability.…”