Imetelstat Future Unclear in MDS

John Scarlett, MD

The future of imetelstat as a treatment for patients with myelodysplastic syndromes (MDS) is uncertain following an update on 2 clinical trials from Geron, which is codeveloping the telomerase inhibitor with Janssen.

The first study is the open-label phase II IMbark trial (NCT02426086), which is examining imetelstat in patients with relapsed/refractory intermediate-2 or high-risk myelofibrosis after the failure of a JAK inhibitor. Patients received imetelstat intravenously at either 4.7 mg/kg or 9.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

Spleen response rate and symptom response rate at 24 weeks are the comprimary endpoints of the study. Over 90 patients have been enrolled in the trial.

At a planned internal interim analysis, the researchers assessed results from 20 patients in each dosing group who have been enrolled in the trial for a minimum of 12 weeks.

“In the 4.7-mg/kg arm, there was clearly inadequate activity at 12 weeks, and the data suggested that additional time on drug [at that dose] would not result in an adequate response at 24 weeks. For that reason, this arm is being closed to further patient enrollment, effective today,” John A. Scarlett, MD, president and CEO of Geron, said on a conference call today.

Patients who received 4.7 mg/kg will now be allowed to increase their dose to 9.4 mg/kg pending investigator authorization.

The internal protocol criteria were also not met in the cohort of patients initially receiving 9.4 mg/kg of imetelstat; however, the researchers determined that a positive trend in the efficacy data justified further investigation of the telomerase inhibitor at the higher dose.

Patients enrolled in this cohort can continue treatment, but, “New enrollment in the 9.4-mg/kg arm will be suspended while the trial continues in order to obtain additional and more mature data that includes a longer follow-up of patients at 24 weeks, consistent with the comprimary efficacy endpoints,” said Scarlett.

Safety data for imetelstat at the internal review were consistent with previously reported adverse event (AE) data for the drug in hematologic myeloid malignancies.

Geron and Janssen hope to have the 24-week higher-dose data available by the second quarter of 2017, at which point the companies intend to restart enrollment in the 9.4-mg/kg cohort with or without amending the dose, add a new arm with a different dose, or close the trial.

The second study Geron provided an update on was the phase II/III IMerge trial (NCT02598661), which is examining imetelstat in transfusion dependent relapsed/refractory patients with low or intermediate-1 risk MDS after the failure of an erythropoiesis stimulating agent. The primary outcome measure of both parts of the trial is the percentage of patients able to go without a red blood cell transfusion for any consecutive 8-week period.

The open-label, single-arm phase II part of the study has enrolled approximately 30 patients. Following an internal review of data from a subset of patients, the researchers decided to continue the phase II part of the study. According to Scarlett, the efficacy and safety data that have emerged thus far are consistent with results from a pilot study of imetelstat in this setting.

“Further assessment of data from IMerge is expected to occur during the second quarter of 2017 [and will] include longer follow-up of all patients enrolled in [phase II]…A decision on whether to move forward to [phase III] of IMerge will be based on an assessment of the benefit/risk profile of imetelstat in these patients,” said Scarlett.

The double-blind phase III trial would launch around mid-2017 with a targeted enrollment of 170 patients who would be randomized to imetelstat or placebo. Full data from phase II of the trial will be presented at an upcoming medical meeting, said Scarlett.

Imetelstat was administered at a starting dose of 9.4 mg/kg once every 3 weeks (n = 19; group A) or weekly for 4 weeks followed by once every 3 weeks (n = 14; group B). Based on AEs, the dose could be reduced to 7.5 mg/kg or 6 mg/kg.

The objective response rate (ORR) with imetelstat was 21%. Of the 7 patients who responded, 4 had complete responses and 3 had partial responses. The median response duration for patients who experienced a complete response was 18 months. Those with a partial response had a median response duration of 10 months. Patients who experienced a complete response had documented reversal of bone marrow fibrosis and 3 experienced a molecular remission.

The ORR was 27% in 26 patients with a JAK2 mutation (n = 26) versus 0% in the 7 patients without this alteration (P = .3). In those without an ASXL1 mutation (n = 22) the ORR was 32% versus 0% in the 11 patients with this alteration (P = .07). The complete response rate was 38% among 8 patients with mutations in SF3B1 or U2AF1 versus 4% in the 25 patients without a mutation in these genes (P = .04).

Across both treatment doses, all-grade AEs were seen in 45% of patients treated with imetelstat. Grade 3 AEs were apparent in 27% of patients and grade 4 in 18%. Adverse events were found to be more severe in group A compared with group B (P = .48). Treatment-related AEs included grade 4 thrombocytopenia (18%), grade 4 neutropenia (12%), grade 3 anemia (30%), and grade 1 or 2 elevations AST (27%), ALP (21%), and bilirubin (12%).

On March 11, 2014, the FDA placed a full clinical hold on the development of imetelstat following concerns over consistent low-grade liver function test abnormalities. However, follow-up safety data showed a resolution of these symptoms for most patients resulting in the FDA lifting the hold on October 31, 2014.

Tefferi A, Lasho TL, Begna KH, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med. 2015; 373:908-919.

Results from a pilot study of imetelstat in myelofibrosis were published in The New England Journal of Medicine in September 2015. The study enrolled 33 patients with myelofibrosis, 52% with high-risk disease and 48% with intermediate-2 risk disease. Fifty-five percent of patients had primary myelofibrosis, 30% had post-polycythemia vera myelofibrosis, and 15% had post-essential thrombocythemia myelofibrosis. Seventy-nine percent of patients were pretreated, including 48% who received a JAK inhibitor.