Abstract
The analog, rebeccamycin tartrate salt (NSC 655649, Cancer Therapy Evaluation Program, National Cancer Institute) has broad preclinical anti-neoplastic activity. Preliminary data from phase I study demonstrated anti-tumor activity in colorectal carcinoma. This phase II trial evaluates its efficacy in patients with minimally treated metastatic colorectal cancer. Eligibility included Karnofsky performance status ≥70%, age ≥18 years and bidimensionally measurable disease. Thirteen patients were treated with NSC 655649 at 500 mg/m2 by central venous catheter once every 3 weeks by bolus injection. Thirty-four cycles (median [range] 2 [1–6]) of therapy were administered. Twelve patients are eligible for response assessment. No major objective responses were seen using the RECIST criteria; however stable disease was observed in three patients with mean duration of 15 weeks. The median time to progression was 8 weeks. There was no toxic death. Four patients received only one cycle of treatment, and three had disease progression. Toxicities were tolerable and hematologic toxicity was the most common. The median (range) granulocyte and platelet nadir counts were 2043/μl (116–16,374/μl) and 276×103/μl (5–769), respectively. Non-hematologic toxicities were moderate, including generalized weakness/fatigue, nausea/vomiting, diarrhea and anorexia. One patient required dose reduction; three patients required dose delays. NSC 655649 at this dose and schedule is inactive against advanced previously minimally treated metastatic colorectal cancer and further study of this drug as a single agent in this disease using an every three-week schedule is not warranted.
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Lam KS, Schroeder DR, Veitch JM, Colson KL, Matson JA, Rose WC, Doyle TW, Forenza S: Production, isolation and structure determination of novel fluoroindolocarbazoles from Saccharothrix aerocolonigenes ATCC 39243. J Antibiot Tokyo 54: 1–9, 2001
Kaneko T, Wong H, Utzig J, Schurig J, Doyle T: Water soluble derivatives of rebeccamycin. J Antibiot Tokyo 43: 125–127, 1990
Pearce CJ, Doyle TW, Forenza S, Lam KS, Schroeder DR: The biosynthetic origins of rebeccamycin. J Nat Prod 51: 937–940, 1988
Bush JA, Long BH, Catino JJ, Bradner WT, Tomita K: Production and biological activity of rebeccamycin, a novel antitumor agent. J Antibiot Tokyo 40: 668–678, 1987
Gilbert EJ, Chisholm JD, Van Vranken DL: Conformational Control in the Rebeccamycin Class of Indolocarbazole Glycosides. J Org Chem 64: 5670–5676, 1999
Prudhomme M: Recent developments of rebeccamycin analogues as topoisomerase I inhibitors and antitumor agents. Curr Med Chem Rev 7: 1189–1212, 2002
Arimondo PB, Bailly C, Boutorine A, Sun JS, Garestier T, Helene C: Targeting topoisomerase I cleavage to specific sequences of DNA by triple helix-forming oligonucleotide conjugates. A comparison between a rebeccamycin derivative and camptothecin. CR Acad Sci III 322: 785–790, 1999
Tolcher AW, Eckhardt SG, Kuhn J, Hammond L, Weiss G, Rizzo J, Aylesworth C, Hidalgo M, Patnaik A, Schwartz G, Felton S, Campbell E, Rowinsky EK: Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties. J Clin Oncol 19: 2937–2947, 2001
Dowlati A, Hoppel CL, Ingalls ST, Majka S, Li X, Sedransk N, Spiro T, Gerson SL, Ivy P, Remick SC: Phase I clinical and pharmacokinetic study of rebeccamycin analog NSC 655649 given daily for five consecutive days. J Clin Oncol 19: 2309–2318, 2001
Weitman S, Moore R, Barrera H, Cheung NK, Izbicka E, Von Hoff DD: In vitro antitumor activity of rebeccamycin analog (NSC# 655649) against pediatric solid tumors. Pediatr Hematol Oncol 20: 136–139, 1998
Ibrahim D, Hussain M, LoRusso P, Flaherty L: Rebeccamycin analog (BMY-27557–14) in renal cell cancer (RCC): Preliminary results of a phase II trial. Abstract # 2373. Proceedings of the 37th Annual Meeting of the American Society of Clinical Oncology, 2001
Bailly C, Colson P, Houssier C, Rodrigues-Pereira E, Prudhomme M, Waring MJ: Recognition of specific sequences in DNA by a topoisomerase I inhibitor derived from the antitumor drug rebeccamycin. Mol Pharmacol 53: 77–87, 1998
Bailly C, Riou JF, Colson P, Houssier C, Rodrigues-Pereira E, Prudhomme M: DNA cleavage by topoisomerase I in the presence of indolocarbazole derivatives of rebeccamycin. Biochemistry 36: 3917–3929, 1997
Investigator's Brochure: Rebeccamycin Analog NSC 655649
Miller AB, Hoodgstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47: 207–214, 1981
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205–216, 2000
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Goel, S., Wadler, S., Hoffman, A. et al. A Phase II Study of Rebeccamycin Analog NSC 655649 in Patients with Metastatic Colorectal Cancer. Invest New Drugs 21, 103–107 (2003). https://doi.org/10.1023/A:1022980613420
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DOI: https://doi.org/10.1023/A:1022980613420