A Phase 1 Study of Imetelstat, a Telomerase Inhibitor, in Children With Refractory or Recurrent Solid Tumors and Lymphomas
- Telomerase is an enzyme that plays a critical role in maintaining telomeres, the
specialized structures at the end of chromosomes involved in the replication and
stability of the chromosome. Inhibition of telomeres causes the length of the telomere
to shorten, and the cell becomes either senescent or undergoes apoptosis.
- In vitro and in vivo studies have demonstrated that imetelstat, a telomerase inhibitor,
inhibits primary tumor growth and prevents metastases; while six Phase 1 studies in
adults have demonstrated reasonable toxicity profiles with hematologic toxicity the
primary cause of dose limiting toxicity.
- Objective responses have been observed with repeated dosing when imetelstat was
administered in combination with bortezomib to patients with multiple myeloma, with
paclitaxel and bevacizumab to patients with advanced breast cancer, and with paclitaxel
plus carboplatin in patients with advanced NSCLC.
- To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose of
imetelstat administered as a 2-hour intravenous infusion, weekly X 2, every 21 days, to
children with refractory or recurrent solid tumors.
- To define and describe the toxicities of imetelstat administered on this schedule.
- To characterize the pharmacokinetics of imetelstat in children with recurrent or
refractory solid tumors.
- To preliminarily define antitumor effects of imetelstat and to assess the biological
activity by assessing telomerase activity, telomere length, hTERT protein, hTERT mRNA and
hTR levels in patient PBMNC samples pretreatment and while on treatment, and assess
telomerase activity, hTERT expression and hTERT protein, telomere length, hTERT mRNA and hTR
levels in patient's pretreatment tumor samples.
- Patients > 12 months and less than or equal to 21 years of age with recurrent or
refractory solid tumors, including lymphomas, without CNS tumors or known CNS metastases,
and with adequate hematologic, hepatic, renal and cardiac status. Must meet safety
laboratory testing levels.
- In this phase I study, the maximum tolerated dose of imetelstat will be determined
using a rolling 6 design where a minimum of 2 evaluable patients will be entered at
each of 4 dose levels, where imetelstat is administered intravenously over two hours on
Day 1 and 8 of a 21-day cycle in children with recurrent or refractory solid tumors,
for up to 17 cycles, up to a total duration of therapy of 18 cycles (approximately 12
- Premedication with acetaminophen and diphenhydramine will be administered prior to each
dose; anaphylactic precautions should be adhered to, and steroids may be used for
symptom control or as premedication after the first dose. Doses subsequent to the first
dose may be delayed or withheld for toxicity.
This study will include a required pharmacokinetic component, and one optional PK draw at 48
hours after the first dose (Day 1, Cycle 1). Patients will be asked to participate in
optional blood and tissue correlative biology studies. Radiology studies will undergo
central radiology review.
- Once MTD has been defined, up to 12 additional patients with relapsed/refractory solid
CNS tumors and lymphomas, may be enrolled to acquire additional PK data at the recommended
phase 2 dose, attempting to enroll at least 6 patients < 12 years of age. With a maximum
number of patients of
45, this study is anticipated to be completed within 22 to 25 months. Up to 5 patients will
be enrolled at NCI.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Estimate the maximum tolerated dose (MTD) of imetelstat given as a 2-hour IV infusion on D1 and D8 every 21 days.
William L Dahut, M.D.
National Cancer Institute (NCI)
United States: Federal Government