A phase I trial of imetelstat in children with refractory or recurrent solid tumors: a Children's Oncology Group Phase I Consortium Study (ADVL1112)

Abstract

Purpose: Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase II dose of imetelstat in children with recurrent or refractory solid tumors.

Experimental design: Imetelstat was administered intravenously more than two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m(2) were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle.

Results: Twenty subjects were enrolled (median age, 14 years; range, 3-21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in 2 of 6 patients at 360 mg/m(2). Pharmacokinetics is dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m(2). Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed.

Conclusions: The recommended phase II dose of imetelstat given on days 1 and 8 of a 21-day cycle is 285 mg/m(2).

Figure 1

PBMC telomerase activity in a representative patient as assessed by the telomeric repeat amplification protocol. Lane 1 shows presence of telomerase activity pre-dose characterized by 6-bp telomeric repeat ladder TRAP products, but no activity at Day #2 or Day #8 of Cycle #1, lanes 3–4. Lane 2 represents telomerase activity 6–8 hrs after the first dose. Telomerase activity is again observed on the pre-dose sample for Cycle #2; lane 5–6, indicating that telomerase inhibition is sustained through Day #8. A and B in lanes 5–6 indicate blood samples from two different vials drawn at the same time point. This patient with paraspinal Ewing sarcoma had a partial response to therapy before having progressive disease after Cycle #8 of therapy. Lane 7, represents telomerase activity pre-dose at day 1 of cycle 3. IC is the PCR internal control; lane 8, Taq polymerase negative control; lane 9, telomerase activity negative control (lysis buffer only, CHAPS); lane 10, telomerase activity positive control (from 1000 HeLa cells).