This phase III study seeks to understand what impact a targeted therapy (Imetelstat) will have on the overall survival of people with intermediate-2 or high-risk Myelofibrosis who are not responding to other forms of treatmentA Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat (GRN163L) Versus Best Available Therapy (BAT) in Patients With Intermediate-2 or High-risk Myelofibrosis (MF) Refractory to Janus Kinase (JAK)-Inhibitor

Inclusion

• Diagnosis of primary myelofibrosis according to the revised World Health Organization criteria or post-essential thrombocythemia-MF or post-polycythemia vera-MF according to the IWG-MRT criteria
• Dynamic International Prognostic Scoring System intermediate-2 or high-risk MF

• Relapsed/refractory to JAK-inhibitor treatment as defined in either inclusion (i), (ii) or (iii) and not eligible for allogeneic stem cell transplantation (ASCT) at screening:

  • (i) Treatment with JAK-inhibitor for >= 6 months duration, including at least 2 months at an optimal dose as assessed by the investigator for that participant and at least one of the following:

    1. no decrease in spleen volume (< 10% by MRI or CT) from the start of treatment with JAK-inhibitor
    2. no decrease in spleen size (< 30% by palpation or length by imaging) from the start of treatment with JAK-inhibitor
    3. no decrease in symptoms (< 20% by Myelofibrosis Symptom Assessment Form [MFSAF] or myeloproliferative neoplasm SAF) from the start of treatment with JAK-inhibitor
    4. a score of at least 15 on TSS assessed using the MFSAF v4.0 during screening.
  • (ii) Treatment with JAK-inhibitor treatment for>= 3 months duration with maximal doses (e.g., 20-25 mg twice daily ruxolitinib) for that participant and no decrease in spleen volume/size or symptoms as defined in inclusion criterion (i [a, b, or c]).

  • (iii) Following maximum tolerated doses of JAK inhibitor therapy for ≥3 months duration, having documented relapsed disease defined as either

    1. Increase in spleen volume from time of best response by 25% measured by MRI or CT, or

    2. Increase in spleen size by palpation, CT, or ultrasound

       • (b.i) For splenomegaly of 5-10 cm at the start of JAK inhibitor treatment, at least 100% increase in palpable spleen size from time of best response;
       • (b.ii) For splenomegaly of > 10 cm at the start of JAK inhibitor treatment, at least 50% increase in palpable spleen size from time of best response;

AND not a candidate for further JAK inhibitor at screening per investigator.

• Measurable splenomegaly demonstrated by a palpable spleen measuring >= 5 cm below the left costal margin or a spleen volume >= 450 cm^3 by MRI or CT
• Active symptoms of MF on the MFSAF v4.0 demonstrated by a symptom score of at least 5 points (on a 0 to 10 scale)
• Hematology laboratory test values within the protocol defined limits
• Biochemical laboratory test values must be within protocol defined limits
• Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2
• Participants should follow protocol defined contraceptives procedures
• A woman of childbearing potential must have a negative serum or urine pregnancy test at screening