A Study to Evaluate Imetelstat (JNJ-63935937) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS) that is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

IImetelstat (GRN163L) is a covalently-lipidated 13-mer thiophosphoramidate
oligonucleotide that acts as a potent specific inhibitor of telomerase.
Telomerase inhibition leads to loss of a cancer cell*s ability to maintain
telomere length (TL), resulting in cell-cycle arrest, apoptosis, or senescence.
Imetelstat binds with high affinity to the template region of the ribonucleic
acid (RNA) component of human telomerase reverse transcriptase (hTERT) and is a
competitive inhibitor of telomerase enzymatic activity.2,24 Treatment of
various cancer cells with imetelstat in vitro increases their sensitivity to
radiation, decreases their clonogenic potential, and results in altered
expression of stem-cell related genes. Clinical data in a small number of MDS
subjects further indicate that treatment with imetelstat resulted in
transfusion independence and other measures of hematologic improvement.

This study has been transitioned to CTIS with ID 2024-511348-25-00 check the CTIS register for the current data.

Part 1: To evaluate the efficacy and safety of imetelstat in transfusion
dependent subjects with low or intermediate-1 risk MDS that is
relapsed/refractory to ESA treatment.
Part 2: To compare the efficacy, in terms of red blood cell (RBC) transfusion
independence (TI), of imetelstat to placebo in transfusion dependent subjects
with low or intermediate-1 risk MDS that is relapsed/refractory to ESA
treatment.
Extension Phase: To evaluate the long-term safety, overall survival (OS), and
disease progression, including progression to acute myeloid leukemia (AML) in
transfusion dependent subjects with low or immediate-1 risk to MDS that is
relapsed/refractory to ESA treatment receiving imetelstat.

This is a multicenter study of imetelstat in transfusion-dependent subjects
with low or intermediate-1 risk MDS that is relapsed/refractory to ESA
treatment (as per inclusion criteria). The study will consist of 2 parts, and
approximately 270 subjects will be enrolled. Part 1 was an open-label,
single-arm design to assess the efficacy and safety of imetelstat, which
enrolled 57 subjects. Part 2 is a double-blind, randomized, placebo-controlled
design to compare the efficacy of imetelstat with placebo. In addition to the
approximately 170 subjects to be enrolled in the main study in Part 2,
approximately 45 subjects will be enrolled in a separate Ventricular
Repolarization substudy. Subjects should be enrolled in the main study of Part
2 until enrollment is complete unless a subject is known to meet criteria that
would make the subject ineligible for the main study (eg, del 5 q, prior HMA
therapy). The sponsor has reviewed and assessed all available data in Part 1,
including blood counts, transfusion requirement, tolerability, pharmacokinetic,
and pharmacodynamic biomarker data.

Intravenous administration of imetelstat or placebo.

Possible Adverse Events include cytopenias (particularly thrombocytopenia and
neutropenia), liver function test (LFT) abnormalities (or clinical hepatic
adverse events), fatigue, nausea, aPTT prolongation, constipation, cough,
anemia, anorexia, dyspnea, diarrhea, dizziness, vomiting and decreased appetite.
Refer to the patient information sheet for a complete overview of
risks/benefits for participating patients.