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ABSTRACT
Final results of phase I and pharmacokinetic trial of SJG-136 administered on a daily x 3 schedule.

Sub-category:
Phase I Studies http://www.abstract.asco.org/CatAbstView_55_86_AA.html

Category:
Developmental Therapeutics: Cytotoxic Chemotherapy

Meeting:
2008 ASCO Annual Meeting http://www.abstract.asco.org/ConfCatView_55.html

Abstract No:
2504

Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 2504)

Author(s):
I. Puzanov, W. Lee, J. D. Berlin, M. W. Calcutt, D. L. Hachey, W. L. Vermeulen, V. J. Spanswick, J. A. Hartley, A. P. Chen, M. L. Rothenberg

Abstract:

Background: SJG-136 is a pyrrolobenzodiazepine dimer that forms DNA crosslinks and has demonstrated a broad antitumor activity. Daily x 5 schedule led to edema and delayed liver toxicity (AACR/EORTC/NCI 2006). We report results of a daily x 3 schedule with dexamethasone premedication (dex) and diuretic support.

Methods: Pts with refractory solid tumors received SJG-136 IV daily x 3, every 21 days, starting dose 20ug/m2/day and 3+3 design with fixed-dose increments. Pts received dex on D -1 to 3 of each cycle and followed a diuresis protocol with spironolactone (S). Pharmacokinetics was assessed on Days 1 and 3 of Cycle 1 and 2 using a sensitive HPLC/MS/MS assay. Single cell gel electrophoresis (comet) was used to detect DNA crosslinks in PBMCs.

Results: 14 pts (8M, 6F) were enrolled. Median age: 55 (range: 41-81), median PS: 1 (0-1), median # of prior regimens: 3 (1-5). Dose levels tested (ug/m2/day): 20 (3 pt), 25 (3 pt), 30 (6 pts), 35 (2 pts).

DLT/Toxicity: DLT was Gr 3 soft tissue edema, dyspnea, fatigue in one and Gr 3 transaminitis in the second pt at the 35ug/m2/day. Gr 1 edema occurred during Cycles 2-4 in 4 additional pts treated at the 30ug/m2/day dose level. This was manageable with diuretics without need for dose interruption.

Other toxicities: hypophosphatemia, hypoalbuminemia, myalgias. No significant myelosuppression was observed. MTD/RPTD: 30ug/m2/day daily x 3 q 21 days.

Pharmacokinetics: The PK analysis revealed dose-dependent increases in AUC and Cmax on Day 1 of Cycle 1. In some patients, repeated SJG-136 dosing appeared to induce substantial changes in the PK parameters of SJG-136, in particular, volume of distribution (Vss). Pharmacodynamics: DNA crosslinks were detectable in PBMCs on D3.

Responses: 2 PR (ovarian CA, poorly dif. CA) by RECIST. 1 pt with SD for 4.5 months (leiomyosarcoma), 2 pts with SD (SCLC, bladder) > 3 months. Conclusions: The RPTD of SJG-136 administered on a daily x 3 basis is 30ug/m2/day. At this dose 2 out of 6 pts achieved PR. The premedication with dex and S diuresis can successfully manage the delayed hepatotoxicity and soft tissue edema. Day 3 increase in Vss may correlate with subsequent development of significant soft tissue edema. DNA crosslinks were detectable in PBMCs on Day 3. Supported by NIH U01 CA099177, M01 RR00095 and CRUK C2259/A3083.