In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 25, No. 18_suppl ( 2007-06-20), p. 2517-2517
Abstract:
2517 Background: PM00104 (Zalypsis [Z]) is a novel synthetic alkaloid related to the marine compounds Jorumycin and the family of Renieramycins. Preliminary analyses of its mechanisms of action suggest effects on the cell cycle, DNA binding properties, as well as transcriptional inhibition. Z has shown antitumor activity in vitro (IC 50 =10 -8 M) and in xenografts models, and an acceptable toxicology profile. Methods: Patients (pts) with advanced cancers or lymphoma were enrolled to determine the safety, tolerability, maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK) and antitumor activity of Z administered as a 1- hour IV infusion every 3 weeks. Sequential cohorts of 3–6 pts received the following doses: 0.225, 0.45, 0.9, 1.8, 3.0 and 3.6 mg/m 2 . Results: 27 pts were treated (19 M; median age: 58, range: 39–79; ECOG PS =2). 2 of 6 pts at 3.6 mg/m 2 experienced dose-limiting toxicities (DLT), defining the MTD; 1 pt with colorectal cancer with extensive liver metastases developed grade 4 thrombocytopenia and neutropenia, grade 3 transaminase elevation, and grade 4 troponin I rise without cardiac symptoms or electrocardiogram alterations. These toxicities all resolved. Another pt with adrenal carcinoma developed grade 3 nausea, vomiting and asthenia despite anti-emetics, which resolved with dexamethasone 2 days after infusion. Other toxicities were =grade 2 and included: nausea, vomiting, transient transaminase elevation and asthenia at doses =0.225 mg/m 2 and myelosuppression (neutropenia and leukopenia) at doses =3.0 mg/m 2 . No DLTs were seen in 6 pts at a dose of 3.0 mg/m 2 , establishing this dose as the RD. 3 more pts were added to complete the expanded cohort at this RD. To date, 2 pts have SD lasting 〉 3 months. PK data indicate that drug AUC and C max increase proportionally across the dose range until doses =3.0 mg/m 2 , when a disproportionate increase in AUC and C max was seen. Z has a long half-life (=50 hours) and wide volume of distribution (Vss ∼500 l/m 2 ). Conclusions: Z has a favorable safety profile. The MTD on this schedule has been established at 3.6 mg/m 2 . Alternative schedules are being evaluated to try and increase dose intensity. No significant financial relationships to disclose.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2007.25.18_suppl.2517
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2007
detail.hit.zdb_id:
2005181-5
