Results posted in the online journal of Cancer of a Phase I-II study that evaluated the safety and efficacy of pixantrone (BBR 2778, Cell Therapeutics, Inc)when used in combination with fludarabine, dexamethasone and rituximab (“FPD-R”) replacing mitoxantrone in the standard FND-R regimen with FPD-R among 28 patients with relapsed or refractory indolent non-Hodgkin’s lymphoma (“INHL”)showed high rates of complete remissions.
Inhibiting Topo-isomerase II
Pixantrone is a novel, next generation antitumor aza-anthracenedione with a molecular structure similar to other topoisomerase II inhibitors, such as anthracyclines like doxorubicin. The investigational drug has distinct structural and physio-chemical properties that make its anti-tumor activity unique in this class of agents. However, being similar to anthracyclines, pixantrone inhibits Topo-isomerase II but unlike anthracyclines, pixantrone alkylates DNA rather than intercalation with DNA, forming stable DNA adducts with particular specificity for CpG-rich, hyper-methylated sites.
These structural differences resulted in significantly enhanced anti-lymphoma activity compared to doxorubicin in preclinical models. In addition, the structural motifs on anthracycline-like agents that are responsible for the generation of oxygen free radicals and the formation of toxic drug-metal complexes have also been modified in pixantrone in an effort to prevent the binding of iron and perpetuation of superoxide production – both of which are the putative mechanism for anthracycline induced acute cardiotoxicity. These novel pharmacologic differences may allow re-introduction of anthracycline-like potency in the treatment of relapsed/refractory diffuse large lymphoma without unacceptable rates of cardiotoxicity.
The Phase I-II study results showed that the FPD-R regimen was highly active in patients with relapsed or refractory INHL and produced complete responses (“CR”) in 63% of patients with an overall response rate (“ORR”) of 89%. Responses were long lasting for a median of 23 months with the longest responding patient in remission longer than 40 months, with an estimated 92% survival rate at three years. The primary side effects were hematologic with 89% of patients developing grade 3-4 neutropenia, which was managed with growth factor administration. No patient developed congestive heart failure with no grade 3-4 cardiac side effects observed. The authors concluded the FPD-R regimen was well-tolerated and highly active in patients with relapsed or refractory INHL.
“This study further adds to the evidence of substantial anti-tumor activity for pixantrone in late stage lymphoid malignancies,” said Jack W. Singer, M.D., Chief Medical Officer at CTI. “Of interest, of the 14 patients who were treated at M.D. Anderson Cancer Center, six who obtained a complete remission and did not have a stem-cell transplant remain in complete remission 55 to 83 months after completing therapy. Seven went on to receive a stem-cell transplant and six remain in remission. The high and durable complete response rate in this study indicates that additional clinical trials in relapsed or refractory INHL are warranted.”
For more information:
Srokowski TP,Liebmann JE,Modiano MR,Cohen GI, et al Pixantrone dimaleate in combination with fludarabine, dexamethasone, and rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma. A PhaseI Study With a Dose-Expansion Cohort. Article first published online: 16 JUN 2011. Cancer 2011 DOI: 10.1002/cncr.26121
Dose Ranging Trial for Pixantrone in the FND-R Variant Regimen in Indolent Non-Hodgkin’s Lymphoma (NCT00060684)