Results of a Phase I Study of GRN163L, a Direct Inhibitor of Telomerase, in Patients with Relapsed and Refractory Multiple Myeloma (MM)

• Published in: Blood Vol. 112; no. 11; p. 3688
• Main Authors: Chanan-Khan, Asher Alban, Munshi, Nikhil C., Hussein, Mohamad A., Elias, Laurence, Benedetti, Fabio, Smith, Jennifer, Khor, Soo-Peang, Huff, Carol A.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16-11-2008
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V112.11.3688.3688

Telomerase over-expression is the predominant mechanism by which cancer cells maintain adequate telomere length to achieve immortalization. Telomere length is often decreased and telomerase activity is often increased in MM. GRN163L is a 13-mer oligonucleotide that directly inhibits telomerase activity and has demonstrated anticancer effects in various preclinical models. We are conducting a phase I dose escalation study to define the maximum tolerated dose (MTD), safety, tolerability, efficacy as well as pharmacokinetics of GRN163L in patients with relapsed or refractory MM. Each treatment cycle consisted of 3 weekly 2 hr i.v. infusions of GRN163L. Dose escalation followed standard “3+3” dose finding rules.
To date, 12 patients, median age 61 years, have been treated in 3 dose cohorts (3.2, 4.8 and 7.2 mg/kg). Patients had received a median of 4.0 prior treatment regimens. All patients had normal baseline neutrophil and 10 had normal baseline platelet counts. Patients completed a median of 2 cycles of GRN163L treatment, with one receiving 4 and another 6 cycles. GRN163L has been generally well-tolerated to date. One patient had Gr 3 anorexia however all other related or possibly related non-hematologic AEs to date were Gr 1 or 2. Treatment related events included thrombocytopenia, neutropenia, aPTT prolongation, anemia, fatigue, nausea, anorexia, and dizziness. No dose limiting toxicity (DLT) occurred among patients in the first 2 cohorts. All patients exhibited transient dose-related aPTT prolongations, which resolved in parallel with decreasing GRN163L plasma levels. There were no bleeding episodes or clinical signs of complement activation. Two of the 5 patients in the 7.2 mg/kg cohort had transient prolongation of aPTT to > 3 fold of the upper limit of normal. One patient in the highest dose group had Gr 4 thrombocytopenia in Cycle 1, which constituted a DLT. Delayed (cycle 2 or later) Gr 3 or 4 neutropenia or thrombocytopenia was noted in 5 additional patients with no episodes of febrile neutropenia. Maximal post-infusion plasma concentrations (Cmax) of GRN163L have been linear with respect to dose. Mean (± SD) plasma concentration of GRN163L declined by 41.1 ±17.6 %, N=9, over the 2 hours following the first infusion, consistent with other previously reported studies. DLTs observed in this study were thrombocytopenia and aPTT prolongation.
The MTD for continuous weekly dosing of GRN163L in this heavily pretreated, relapsed and refractory MM population appears to be ≥ 4.8 and < 7.2 mg/kg. The most marked hematologic toxicity was observed in two patients with prior autologous stem cell transplantation. Exploration of intermediate dose levels in this range is continuing. Additional studies exploring alternative dosing schedules will be initiated.