Phase-1 study of isophosphoramide mustard (IPM)-lysine in advanced cancers

• Published in: Journal of clinical oncology Vol. 24; no. 18_suppl; p. 9524
• Main Authors: Gale, R., Van Vugt, A., Rosen, L., Chang, L., Lorusso, P., Valdivieso, M., Malburg, L., Struck, R., Morgan, L.
• Format: Journal Article
• Language: English
• Published: 20.06.2006
• DOI: 10.1200/jco.2006.24.18_suppl.9524
• ISSN: 0732-183X

Abstract only 9524 Background: IPM is a bi-functional alkylator which cross-links DNA through G:C base-pairs resulting in irreparable 7-atom inter-strand cross-links. IPM is the active moiety of ifosfamide (IFOS), a pro-drug of IPM. IPM is active in diverse cancer models but is unstable. We stabilized IPM with lysine (IPM-lysine; ZIO-201). ZIO-201 was active in pre-clinical models including human cancer cell lines, human-mouse xenografts and cancers resistant to cyclophosphamide (CPA) and IFOS. Because ZIO-201 is not metabolized to acrolein or chloroacetaldehyde, bladder and CNS toxicities are unlikely. Methods: Phase-1 trial in subjects with advanced cancers. ZIO-201 was given daily for 3 consecutive d at a starting dose of 30 mg/me 2 /d every 3 w. Neither mesna nor IV hydration were given. 11 dose levels were studied in 18 subjects up to 795 mg/me 2 /d; dose-escalation continues. Data on the 1st 15 subjects are available for analysis. Results: Median age was 59 y (range, 18–70 y); 10 subjects were male. Diagnoses included colorectal cancer (N=5), sarcoma (N=3) and 1 subject each with gastric, lung, bladder, prostate, ovary and thyroid cancers and mesothelioma. 7 had extensive and 8, limited disease. All subjects received extensive prior therapy. Median N cycles was 2 (range, 1–13). Toxicities ≥ grade-2 occurring in > 20% of subjects included anemia (N subjects=4) and diverse GI complaints (N=4). 4 of 8 subjects receiving doses > 445 mg/me2/d had transient proximal renal tubular acidosis. There was no hemorrhagic cystitis or CNS toxicity. 1 subject with mesothelioma had stable disease > 13 mo. Pharmacokinetic studies at 595 mg/me 2 /d showed a t max = 13 min (SD ± 9 min), C max = 44.7 μg/mL (SD ± 34.1 μg/mL), t 1/2 = 35 min (SD ± 7 min) and AUC 0-∞ = 1.68 mg·min/ml (SD ± 1.26 mg·min/ml). Conclusions: These data suggest a possible role for ZIO-201 in IFOS-sensitive cancers (especially sarcoma and lymphoma). ZIO-201 may also be active in CPA and IFOS-resistant cancers. Comparable or greater efficacy with less toxicity is expected. [Table: see text]