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A Study Comparing Imetelstat Versus Best Available Therapy for the Treatment of Intermediate-2 or High-risk Myelofibrosis (MF) Who Have Not Responded to Janus Kinase (JAK)-Inhibitor Treatment

PHASE3RECRUITING

The purpose of the study is to evaluate the overall survival of participants treated with imetelstat compared to best available therapy with intermediate-2 or high-risk Myelofibrosis (MF) who are relapsed/refractory (R/R) to Janus Kinase (JAK)-Inhibitor treatment.

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Study details:

This is a multicenter study with 2 arms, and will include 3 phases: a) screening phase of up to 28 days before randomization during which participants will complete a 14-day washout period from all prior therapies including JAK-inhibitor treatment, and the participant's eligibility will be reviewed; b) treatment phase, from randomization until study treatment (imetelstat or BAT) discontinuation; and c) post treatment follow-up phase, that begins when the participant discontinues treatment, and will continue until death, lost to follow-up, withdrawal of consent, or study end, whichever occurs first. Participants will be randomized (2:1) into 2 Arms (Arm A will receive imetelstat and Arm B will receive BAT). Participants who meet progressive disease criteria and discontinue BAT, may crossover to receive imetelstat treatment after sponsor's approval.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

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:

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: no decrease in spleen volume (< 10% by MRI or CT) from the start of treatment with JAK-inhibitor; no decrease in spleen size (< 30% by palpation or length by imaging) from the start of treatment with JAK-inhibitor; no decrease in symptoms (< 20% by Myelofibrosis Symptom Assessment Form [MFSAF] or myeloproliferative neoplasm SAF) from the start of treatment with JAK-inhibitor; a score of at least 15 on TSS assessed using the MFSAF v4.0 during screening.

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]).

Following maximum tolerated doses of JAK inhibitor therapy for ≥3 months duration, having documented relapsed disease defined as either Increase in spleen volume from time of best response by 25% measured by MRI or CT, or Increase in spleen size by palpation, CT, or ultrasound.

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

Exclusion criteria

Peripheral blood blast count of >= 10% or bone marrow blast count of >=10%

Known allergies, hypersensitivity, or intolerance to imetelstat or its excipients

Prior treatment with imetelstat

Any chemotherapy or MF directed therapy, including investigational drug regardless of class or mechanism of action, immunomodulatory or immunosuppressive therapy, corticosteroids greater than 30 mg/day prednisone or equivalent, and JAK-inhibitor treatment less than equal to 14 days prior to randomization

Diagnosis or treatment for malignancy other than MF except: Malignancy treated with curative intent and with no known active disease present for >= 3 years before randomization; Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; Adequately treated cervical carcinoma in situ without evidence of disease

Known history of human immunodeficiency virus or any uncontrolled active systemic infection requiring IV antibiotics

Active systemic hepatitis infection requiring treatment (carriers of hepatitis virus are permitted to enter the study), or any known acute or chronic liver disease requiring treatment unless related to underlying hepatosplenomegaly due to MF

Major surgery within 28 days prior to randomization

Any life-threatening illness (e.g., coronavirus disease-2019), medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the participant's safety, interfere with the imetelstat metabolism, or put the study outcomes at undue risk

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2021-04-12

Primary completion: 2026-11-25

Study completion finish: 2026-11-25

Study type

TREATMENT

Phase

PHASE3

Trial ID

NCT04576156

Intervention or treatment

DRUG: Imetelstat

DRUG: Best Available Therapy (BAT)

Conditions

• Myelofibrosis

Condition: Myelofibrosis
DRUG: Imetelstat and other drugs
St Leonards, New South Wales, Australia and more
Sponsor: Geron Corporation

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Find a site

Closest Location:

Royal North Shore Hospital

Research sites nearby

Select from list below to view details:

Royal North Shore Hospital
St Leonards, New South Wales, Australia
Royal Hobart Hospital
Hobart, Tasmania, Australia
Epworth Healthcare
Richmond, Victoria, Australia
Royal Brisbane and Women's Hospital
Herston, Queensland, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Imetelstat Participants will receive imetelstat sodium at 9.4 mg/kg intravenous (IV) every 21 days (±3 days), until disease progression or unacceptable toxicity, treatment discontinuation or study end.	DRUG: Imetelstat Imetelstat sodium will be given intravenously at 9.4 mg/kg every 21 days, until disease progression or unacceptable toxicity, treatment discontinuation or study end.
ACTIVE_COMPARATOR: Best Available Therapy (BAT) Participants will receive BAT (investigator-selected non-JAK-inhibitor treatment), until disease progression or unacceptable toxicity, treatment discontinuation or study end. Participants on BAT who meet protocol-defined criteria for progressive disease may crossover to receive imetelstat treatment after sponsor's approval.	DRUG: Best Available Therapy (BAT) Non-JAK-inhibitor treatment will be given, which may include but is not limited to hydroxyurea, thalidomide or an analog of thalidomide, interferon, danazol, hypomethylating agents, chemotherapy or radiotherapy.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Overall survival (OS)	Overall survival is defined as the time interval from randomization date to date of death from any cause.	Baseline (Day 1) until End of Study (EOS) (approximately 3 years )]

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Symptom response rate	The proportion of participants achieving a ≥50% reduction in Total Symptom Score (TSS) measured at Week 24 compared to baseline	Baseline (Day 1), and at Week 24
Progression-free survival	Progression-free survival is defined as the time interval from randomization date to the first date of disease progression (worsening splenomegaly or leukemic transformation per 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria) or death from any cause, whichever occurs first.	Baseline (Day 1) until End of Study (EOS) (approximately 3 years)
Spleen response rate	The proportion of participants who achieve a reduction in spleen volume of ≥ 35% from baseline at Week 24.	Baseline (Day 1), and at Week 24
Complete remission (CR), partial remission (PR), clinical improvement (CI), spleen response, symptoms response, and anemia response per modified 2013 IWG-MRT criteria	The proportion of participants achieving CR or PR, CI, spleen response, symptom response, and anemia response per modified 2013 IWG-MRT criteria.	Baseline (Day 1) until End of Treatment (approximately 3 years)
Reduction in the degree of bone marrow fibrosis	Reduction in the degree of bone marrow fibrosis will be assessed.	Baseline (Day 1) until End of Treatment (approximately 3 years)
Number of Participants with Adverse Events	Safety will be assessed based on the incidence and severity (according to the Common Terminology Criteria for Adverse Events) of treatment emergent adverse events from the time of randomization until 30 days after completion of treatment	Screening (Day -28 to -1) until End of Study (approximately 3 years)
Assessment of Cmax	Maximum Observed Plasma Concentration (Cmax).	Day 1 of all cycles (each cycle is 21 days)
Assessment of Tmax	Time to reach the maximum observed plasma concentration	Day 1 of all cycles (each cycle is 21 days)
Assessment of t1/2	Elimination half-life.	Day 1 of all cycles (each cycle is 21 days)
Assessment of AUC	Area under the drug concentration-plasma time curve (AUC) from time zero to last measurable concentration	Day 1 of all cycles (each cycle is 21 days)
European Organization for Research and Treatment of Cancer Quality-of-Life-Questionnaire-Core-30 (EORTC QLQ-C30) scores	Patient-reported outcomes including health-related quality of life, pain, and overall change in participant's health will be assessed using the EORTC QLQ-C30. The EORTC QLQ-C30 includes 30 items resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Scores are transformed to a 0 to 100 scale. Higher scores indicated worse outcome.	Baseline to End of Study (approximately 3 years)
EuroQol-EQ-5D (EQ-5D-5L) questionnaire scores	EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).	Baseline to End of Study (approximately 3 years)

Frequently Asked Questions

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References

Clinical Trials Gov: A Study Comparing Imetelstat Versus Best Available Therapy for the Treatment of Intermediate-2 or High-risk Myelofibrosis (MF) Who Have Not Responded to Janus Kinase (JAK)-Inhibitor Treatment