Primary MyelofibrosisPhase 2NCT01731951
Imetelstat Sodium in Treating Participants With Primary or Secondary Myelofibrosis
A Phase 2 study testing Imetelstat in people with Primary Myelofibrosis and Secondary Myelofibrosis, run by Geron Corporation at 1 site in United States.
Trial summary
This pilot clinical trial studies how well imetelstat sodium works in treating participants with primary or secondary myelofibrosis and other myeloid malignancies. Imetelstat sodium may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Primary Myelofibrosis, Secondary Myelofibrosis, Myeloid Malignancies
- What is being tested?
- Imetelstat
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- 1 siteUnited States
- Study dates
- 29 Oct 2012to 24 May 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of one of the following:
- Primary myelofibrosis (PMF) per the revised World Health Organization (WHO) criteria.
- Post-polycythemia vera/essential thrombocythemia myelofibrosis (Post-ET/PV MF) per the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria.
- High-risk or Intermediate-2 risk MF (as defined by the Dynamic International Prognostic Scoring System [DIPSS-plus]).
- Life expectancy of greater than or equal to (>=) 12 weeks.
- Able to provide informed consent and be willing to sign an informed consent form.
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- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<2.5 x upper limit of normal (ULN) (or =<5 x ULN if in the investigator's opinion the elevation is due to extramedullary hematopoiesis).
- Serum glutamic pyruvate transaminase (SGPT) alanine aminotransferase (ALT) =<2.5 x ULN (or =<5 x ULN if in the investigator's opinion the elevation is due to extramedullary hematopoiesis).
- Total bilirubin =<3.0 mg/dL (or direct bilirubin < 1 mg/dL).
- Creatinine =<3.0 mg/dL.
- Absolute neutrophil count >=1000/microliter (mcL).
- Platelet count >=50,000/mcL.
- Absence of active treatment with systemic anticoagulation and a baseline prothrombin time (PT) and activated partial thromboplastin time (aPTT) that does not exceed 1.5 x ULN.
- Females of childbearing potential must have a negative pregnancy test =<7 days prior to registration, unless they are surgically sterile for at least 3 months (i.e., hysterectomy), OR postmenopausal for at least 12 months (follicle-stimulating hormone [FSH] >30 U/mL).
- Females of childbearing potential must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through end of study; permitted methods for preventing pregnancy must be communicated to study participants and their understanding confirmed.
- Males must agree to take appropriate precautions to avoid fathering a child (with at least 99% certainty) from screening through follow-up; permitted methods for preventing pregnancy should be communicated to the participants and their understanding confirmed.
Who cannot join
- Females who are pregnant or are currently breastfeeding.
- Any chemotherapy (e.g., hydroxyurea), immunomodulatory drug therapy (e.g., thalidomide), immunosuppressive therapy, corticosteroids > 10 mg/day prednisone or equivalent, growth factor treatment (e.g., erythropoietin) or Janus kinase (JAK) inhibitor therapy =<14 days prior to registration.
- Participants with another active malignancy.
- Note: participants with early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin or cervical intraepithelial neoplasia are eligible for enrollment.
- Known positive status for human immunodeficiency virus (HIV).
- Any unresolved toxicity greater or equal to grade 2 from previous anticancer therapy, except for stable chronic toxicities not expected to resolve.
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- Incomplete recovery from any prior surgical procedures or had surgery =<4 weeks prior to registration, excluding the placement of vascular access.
- Presence of acute active infection requiring antibiotics.
- Uncontrolled intercurrent illness or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the participant or compliance with the protocol.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Pilot Open-Label Study of the Efficacy and Safety of Imetelstat (GRN163L) in Myelofibrosis and Other Myeloid Malignancies
This pilot clinical trial studies how well imetelstat sodium works in treating participants with primary or secondary myelofibrosis and other myeloid malignancies. Imetelstat sodium may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Read the detailed description
PRIMARY OBJECTIVES:
- To evaluate overall response rate.
SECONDARY OBJECTIVES:
- To evaluate the safety and tolerability of imetelstat (imetelstat sodium) in myelofibrosis (MF).
II. To evaluate the efficacy of imetelstat in the reduction of spleen size, as measured by physical examination (palpable distance from the left costal margin).
III. To evaluate the efficacy of imetelstat in improving anemia or inducing red blood cell transfusion-independence in previously transfusion-dependent participants (per International Working Group for Myelofibrosis Research and Treatment [IWG-MRT] criteria).
IV. To evaluate onset and durability of response as defined in primary and secondary endpoints
EXPLORATORY OBJECTIVES:
- To evaluate the effect of imetelstat on bone marrow histology, karyotype and JAK2V617F allele burden II. To evaluate the effect of imetelstat on leukocytosis, circulating blast count, circulating immature myeloid cell count and thrombocytosis.
OUTLINE: Participants receive imetelstat sodium intravenously (IV) over 2 hours on day 1. Participants may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study end. The study end when all participants discontinued study drug, the last participant enrolled has been treated for approximately 5.7 years, or imetelstat is commercially available in the United States, whichever occurs first.
Maximum duration of study was approximately 5.7 years. Arm C was never initiated, and participants allocated to Arm C (Imetelstat 9.4 mg/kg [with MF]) were reassigned to Arms A and B.
- Being tested
- Imetelstat
- Keywords
- Myelofibrosis, Myelodysplastic Syndromes, Myeloproliferative Neoplasm, Imetelstat, GRN163L
- Medical subject headings
- Primary Myelofibrosis, Myelodysplastic Syndromes, Myeloproliferative Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ImetelstatDrug
Also called GRN163L
Imetelstat sodium administered as IV over 2 hours with treatment as long as participants derive clinical benefit or until end of study.
| Study group | Role | What they receive |
|---|---|---|
| Arm A: Imetelstat 9.4 mg/kg (Myelofibrosis [MF]) | Experimental | Participants with MF regardless of spliceosome mutation status or presence of ring sideroblasts received imetelstat 9.4 milligram per kilogram (mg/kg), intravenously (IV) as 2-hour infusion on Day 1 of each 21-day cycle in Core Phase up to 9 cycles. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). Receives: Drug: Imetelstat |
| Arm B: Imetelstat 9.4 mg/kg as Induction + Maintenance (MF) | Experimental | Participants with MF regardless of spliceosome mutation status or presence of ring sideroblasts received imetelstat 9.4 mg/kg, IV as 2-hour infusion on Days 1, 8, and 15 of 21-day cycle in Cycle 1 followed by 9.4 mg/kg on Day 1 of each 21-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). Receives: Drug: Imetelstat |
| Arm D: Imetelstat 9.4 mg/kg (Blast-phase MF/Acute Myeloid Leukemia) | Experimental | Participants with blast-phase myelofibrosis/acute myeloid leukemia (MF/AML) received imetelstat 9.4 mg/kg, IV as 2-hour infusion weekly on Days 1, 8, 15, 22 of a 28-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). Receives: Drug: Imetelstat |
| Arm E: Imetelstat 7.5 - 9.4 mg/kg (MF [with Spliceosome Mutation or Ring Sideroblasts]) | Experimental | Participants with MF and spliceosome mutations or ring sideroblasts present received 2 cycles (Cycles 1-2) of imetelstat 7.5 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or the possibility of dose escalation to imetelstat 9.4 mg/kg weekly if response to the initial dose was insufficient up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). Receives: Drug: Imetelstat |
| Arm F: Imetelstat 7.5 - 9.4 mg/kg (MF [without spliceosome mutation and ring sideroblasts]) | Experimental | Participants with MF without spliceosome mutations or ring sideroblasts present received 2 cycles (Cycles 1-2) of imetelstat 9.4 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or imetelstat 7.5 mg/kg twice weekly on Days 1, 3 for 2 cycles of 28-day cycle (Cycles 3-4) followed by imetelstat 7.5 mg/kg 3-times-weekly on Days 1, 3, 5 of Cycles 5 and beyond of 28-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). Receives: Drug: Imetelstat |
| Arm G: Imetelstat 7.5 - 9.4 mg/kg (MDS/MPN or MDS with Spliceosome Mutations or Ring Sideroblasts) | Experimental | Participants with either myelodysplastic syndromes/ myeloproliferative neoplasm (MDS/MPN) or MDS and spliceosome mutations or ring sideroblasts present received 2 cycles of 28-day cycle (Cycles 1-2) of imetelstat 7.5 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or the possibility of dose escalation to imetelstat 9.4 mg/kg weekly if response to the initial dose was insufficient up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). Receives: Drug: Imetelstat |
What is being measured
The primary outcome is the main question the study is designed to answer.
MF Participants: Percentage of Participants With Overall Response (OR) - (Clinical Improvement[CI] or Partial Remission[PR] or Complete Remission[CR]) Per International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria
OR:CI/PR/CR per IWG-MRT. CR:Bone marrow (BM):<5% blasts;≤Grade 1 MF, AND Peripheral blood:Hemoglobin (Hb) ≥100 g/liter (g/L) and <upper normal limit (UNL);Neutrophil count(NC) ≥1x10^9/L and <UNL; Platelet(PLT) count ≥100x10^9/L and <UNL;<2% immature myeloid cells(IMCs), AND Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence of extramedullary hematopoeisis(EMH). PR:All CR criteria plus peripheral blood: Hb≥85 but <100g/L and <UNL; NC ≥1x10^9/L and <UNL; PLT count ≥50 but <100x10^9/L and <UNL;<2%IMCs. CI:achievement of anemia (≥20 g/L increase in Hb level), spleen(baseline splenomegaly palpable at 5-10 cm, below left costal margin(LCM), becomes not palpable), symptoms response (50% reduction in total symptom score) without progressive disease (PD) (appearance of new splenomegaly- palpable at least [≥]5 cm below LCM)/increase in severity of anemia, thrombocytopenia/neutropenia. Data is reported separately for arms whose response was assessed per IWG-MRT.
Measured: Up to first 9 cycles of treatment (each cycle was of 21 days for Arms A and B and 28 days for Arms E and F)
Blastic MF/AML Participants: Percentage of Participants With Overall Response
For this pilot study, overall response was defined as achievement of a leukemic response (i.e. a clinically meaningful reduction in Blast cells). This was quantified as <5% peripheral blood and bone marrow blasts % that lasts for at least two months. Data is reported separately for this arm where response was assessed by this specific criterion.
Measured: Up to first 9 cycles of treatment (each cycle was of 28 days for Arm D)
MDS Participants: Percentage of Participants With Overall Response (Hematologic Improvement [HI] or PR or CR) Per IWG Criteria
OR: HI/PR/CR per IWG. CR: BM:≤5% myeloblasts (all cell lines normal maturation), Peripheral blood:Hgb ≥11g/dL, PLTs ≥100x10^9/L, Neutrophils ≥1.0x10^9/L, Blasts 0%. PR: All CR criteria if abnormal before treatment except- BM blasts decreased ≥50% over pretreatment but still >5%, Cellularity, morphology not relevant. HI responses:1) Erythroid: Hgb increase ≥1.5 g/dL, Relevant reduction of red blood cell(RBC) units transfusions by absolute ≥4 RBC transfusions/8 week (wk) compared with pretreatment transfusion number in previous 8 wk. Only RBC transfusions given for Hgb of ≤9.0 g/dL.2)PLTs:Absolute increase ≥30x10^9/L starting >20x10^9/L PLTs; Increase from <20x10^9/L to >20x10^9/L and by ≥100%; 3)Neutrophil: ≥100% increase, absolute increase >0.5x10^9/L; 4)Progression/relapse after HI:≥1 of following:≥50% decrement from maximum response levels in granulocytes/PLTs, Reduction in Hgb ≥1.5 g/dL,Transfusion dependence. Data is reported separately for arm whose response was assessed per IWG.
Measured: Up to first 9 cycles of treatment (each cycle was of 28 days for Arm G)
Secondary outcomes (11)
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Grade >= 3 TEAEs and Treatment Related Adverse Events
TEAEs defined as those events that 1) occur on or after the first dose of study drug, through the treatment phase, and for 30 days following the last dose of study drug or until subsequent anti-cancer therapy if earlier; 2) any event that is considered study drug-related regardless of the start date of the event; or 3) any event that is present at baseline but worsens in severity or is subsequently considered drug-related by the investigator. Grade >=3 TEAE defined as events that are severe, life-threatening or disabling, or fatal and considered related to imetelstat as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. An AE was considered related to the study drug if the event was assessed by the investigator as probably or possibly related.
Measured: From first dose of study drug up to 30 days from the last dose of study drug or until subsequent anti-cancer therapy if earlier (Up to approximately 5.7 years)
Number of Participants With Spleen Response Per IWG-MRT Criteria
Spleen response per IWG-MRT criteria defined as baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable, OR A baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by ≥50%. Baseline splenomegaly that is palpable at <5 cm, below the LCM, is not eligible for spleen response. Confirmation by Magnetic resonance imaging (MRI) or computerized tomography (CT) showing ≥35% spleen volume reduction is recommended (but not required). Spleen response was assessed only in participants with MF.
Measured: Up to approximately 5.7 years
MF and Blastic MF/AML Participants: Number of Participants With Transfusion Independence (CI by Anemia Response) Per IWG-MRT
Transfusion dependency was defined by a history of at least 2 units of red blood cell transfusions in the last month for a hemoglobin level of less than 85 g/L that was not associated with clinically overt bleeding. A participant who was transfusion dependent at baseline was considered transfusion independent if the participant met either of the following conditions: Received no more than 1 unit of red blood cell transfusions in a rolling time interval of 30 days or more, and had a hemoglobin level increase over baseline more than 2 g/dL if participant baseline hemoglobin level was less than 85 g/L and received no transfusion. Anemia response per IWG-MRT Criteria- Transfusion-independent participants: a ≥20 g/L increase in hemoglobin level. Transfusion-dependent participants: becoming transfusion-independent. Data is reported separately for arms assessed as per the IWG-MRT criteria.
Measured: Up to approximately 5.7 years
MDS Participants: Number of Participants With Transfusion Independence (HI by Erythroid Response) Per IWG Criteria
Transfusion dependency was defined by a history of at least 2 units of red blood cell transfusions in the last month for a hemoglobin level of less than 85 g/L that was not associated with clinically overt bleeding. A participant who was transfusion dependent at baseline was considered transfusion independent if the participant met either of the following conditions: Received no more than 1 unit of red blood cell transfusions in a rolling time interval of 30 days or more, and had a hemoglobin level increase over baseline more than 2 g/dL if participant baseline hemoglobin level was less than 85 g/L and received no transfusion. HI responses included: 1) Erythroid: Hgb increase ≥1.5 g/dL, Relevant reduction of RBC units transfusions by absolute number of >=4 RBC transfusions/8 week compared with pretreatment transfusion number in previous 8 week. Only RBC transfusions given for Hgb of ≤9.0 g/dL. Data is reported separately for arm assessed as per IWG criteria.
Measured: Up to approximately 5.7 years
MF Participants: Time to Response
Time to response was defined as the duration from study Day 1 to the earliest date that a response is first documented. The response CI/CR/PR was assessed by IWG-MRT criteria.
Measured: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
Blastic MF/AML Participants: Time to Response
Time to response was defined as the duration from study Day 1 to the earliest date that a response is first documented. Response was defined as achievement of a leukemic response (i.e. a clinically meaningful reduction in Blast cells). This was quantified as <5% peripheral blood and bone marrow blasts % that lasts for at least two months. Data for time to response is reported as per criteria of response assessment.
Measured: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
MDS Participants: Time to Response
Time to response was defined as the duration from study Day 1 to the earliest date that a response is first documented. Response was defined as HI, PR or CR per IWG criteria. Data for time to response is reported as per criteria of response assessment.
Measured: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
MF Participants: Duration of Response (DOR) Per IWG-MRT Criteria
DOR measured from time of initial response (CR/PR/CI) until documented PD or death whichever occurs first. If no PD/death occurs DOR is censored at last disease evaluation date for responders. CR:BM: <5%blasts; ≤Grade 1 MF, AND Peripheral blood:Hb≥100 g/L and <UNL;Neutrophil count≥1x10^9/L and <UNL;PLT count≥100x10^9/L and <UNL;<2% IMCs, AND Clinical:Resolution of disease symptoms;Spleen and liver not palpable;No evidence of EMH.PR:All CR criteria plus peripheral blood:Hb≥85 but <100g/L and <UNL;NC≥1x10^9/L and <UNL;PLTcount ≥50 but<100x10^9/L and<UNL;<2%IMCs. CI:achievement of anemia(≥20 g/L increase Hb level),spleen(baseline splenomegaly-palpable at 5-10cm,below LCM,becomes not palpable) or symptoms response(50% reduction in total symptom score) without PD(appearance of new splenomegaly- palpable[>= 5 cm below LCM) or increase in severity of anemia, thrombocytopenia or neutropenia. Data is reported separately for arms whose DOR was assessed per IWG-MRT. Kaplan-Meier method was used.
Measured: From time of initial response until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
Blastic MF/AML Participants: Duration of Response
DOR was measured from the time of initial response until documented disease progression or death whichever occurs first. If no PD/death occurs the DOR is censored at last disease evaluation date for responders. Response is defined as achievement of <5% peripheral blood and bone marrow blast % that lasts for at least two months. PD is the appearance of new splenomegaly that is palpable at least 5 cm below the LCM. Data is reported separately for arm whose DOR was assessed by a specific criterion. Kaplan-Meier method was used.
Measured: From time of initial response until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
MDS Participants: Duration of Response Per IWG Criteria
DOR: time of initial response (CR/PR/HI) until documented PD/death whichever occurs first. If no PD/death occurs DOR is censored at last disease evaluation date for responders. Data reported separately for arm assessed per IWG. Kaplan-Meier method was used.
Measured: From the time of initial response (CR/PR/HI) until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
Overall Survival (OS)
OS was defined as the as the interval from Study Day 1 to the date of death from any cause. Survival time of living participants was censored on the last date a participant is known to be alive or lost to follow-up. Overall Survival was estimated by Kaplan-Meier method.
Measured: From Study Day 1 to the date of death from any cause (Up to approximately 5.7 years)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Nov 2012 (estimated)
- Study start29 Oct 2012
- Primary completion24 May 2018
- Study completion24 May 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Primary MyelofibrosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 80 participants (actual)
Sponsor and investigators
- Lead sponsor
- Geron Corporation
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Study Clinical Team, Study director, Geron Corporation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01731951
- Sponsor's protocol ID
- CR107110
- Other IDs
- CP14B019
- Status last verified
- Aug 2021
- First submitted
- 18 Nov 2012
- Last updated
- 21 Sep 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, Laborde RR, Wassie E, Schimek L, Hanson CA, Gangat N, Wang X, Pardanani A. A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. N Engl J Med. 2015 Sep 3;373(10):908-19. doi: 10.1056/NEJMoa1310523.
PubMed 26332545
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Open-Label Study of the Efficacy and Safety of Imetelstat (GRN163L) in Myelofibrosis and Other Myeloid Malignancies
- ClinicalTrials.gov ID
- NCT01731951
- Acronym / sponsor ID
- CR107110
- Keywords
- Myelofibrosis, Myelodysplastic Syndromes, Myeloproliferative Neoplasm, Imetelstat, GRN163L
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 80 participants (actual)
- Lead sponsor
- Geron CorporationIndustry (pharma, biotech, devices)
- Study start
- 29 Oct 2012 (actual)
- Primary completion
- 24 May 2018 (actual)
- Study completion
- 24 May 2018 (actual)
- First posted
- 22 Nov 2012 (estimated)
- Results
- Posted 21 Sep 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This pilot clinical trial studies how well imetelstat sodium works in treating participants with primary or secondary myelofibrosis and other myeloid malignancies. Imetelstat sodium may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES:
- To evaluate overall response rate.
SECONDARY OBJECTIVES:
- To evaluate the safety and tolerability of imetelstat (imetelstat sodium) in myelofibrosis (MF).
II. To evaluate the efficacy of imetelstat in the reduction of spleen size, as measured by physical examination (palpable distance from the left costal margin).
III. To evaluate the efficacy of imetelstat in improving anemia or inducing red blood cell transfusion-independence in previously transfusion-dependent participants (per International Working Group for Myelofibrosis Research and Treatment [IWG-MRT] criteria).
IV. To evaluate onset and durability of response as defined in primary and secondary endpoints
EXPLORATORY OBJECTIVES:
- To evaluate the effect of imetelstat on bone marrow histology, karyotype and JAK2V617F allele burden II. To evaluate the effect of imetelstat on leukocytosis, circulating blast count, circulating immature myeloid cell count and thrombocytosis.
OUTLINE: Participants receive imetelstat sodium intravenously (IV) over 2 hours on day 1. Participants may continue to receive imetelstat study treatment for as long as they derive clinical benefit or until study end. The study end when all participants discontinued study drug, the last participant enrolled has been treated for approximately 5.7 years, or imetelstat is commercially available in the United States, whichever occurs first.
Maximum duration of study was approximately 5.7 years. Arm C was never initiated, and participants allocated to Arm C (Imetelstat 9.4 mg/kg [with MF]) were reassigned to Arms A and B.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Arm A: Imetelstat 9.4 mg/kg (Myelofibrosis [MF]) | Experimental | Drug: ImetelstatParticipants with MF regardless of spliceosome mutation status or presence of ring sideroblasts received imetelstat 9.4 milligram per kilogram (mg/kg), intravenously (IV) as 2-hour infusion on Day 1 of each 21-day cycle in Core Phase up to 9 cycles. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Arm B: Imetelstat 9.4 mg/kg as Induction + Maintenance (MF) | Experimental | Drug: ImetelstatParticipants with MF regardless of spliceosome mutation status or presence of ring sideroblasts received imetelstat 9.4 mg/kg, IV as 2-hour infusion on Days 1, 8, and 15 of 21-day cycle in Cycle 1 followed by 9.4 mg/kg on Day 1 of each 21-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Arm D: Imetelstat 9.4 mg/kg (Blast-phase MF/Acute Myeloid Leukemia) | Experimental | Drug: ImetelstatParticipants with blast-phase myelofibrosis/acute myeloid leukemia (MF/AML) received imetelstat 9.4 mg/kg, IV as 2-hour infusion weekly on Days 1, 8, 15, 22 of a 28-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Arm E: Imetelstat 7.5 - 9.4 mg/kg (MF [with Spliceosome Mutation or Ring Sideroblasts]) | Experimental | Drug: ImetelstatParticipants with MF and spliceosome mutations or ring sideroblasts present received 2 cycles (Cycles 1-2) of imetelstat 7.5 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or the possibility of dose escalation to imetelstat 9.4 mg/kg weekly if response to the initial dose was insufficient up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Arm F: Imetelstat 7.5 - 9.4 mg/kg (MF [without spliceosome mutation and ring sideroblasts]) | Experimental | Drug: ImetelstatParticipants with MF without spliceosome mutations or ring sideroblasts present received 2 cycles (Cycles 1-2) of imetelstat 9.4 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or imetelstat 7.5 mg/kg twice weekly on Days 1, 3 for 2 cycles of 28-day cycle (Cycles 3-4) followed by imetelstat 7.5 mg/kg 3-times-weekly on Days 1, 3, 5 of Cycles 5 and beyond of 28-day cycle up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
| Arm G: Imetelstat 7.5 - 9.4 mg/kg (MDS/MPN or MDS with Spliceosome Mutations or Ring Sideroblasts) | Experimental | Drug: ImetelstatParticipants with either myelodysplastic syndromes/ myeloproliferative neoplasm (MDS/MPN) or MDS and spliceosome mutations or ring sideroblasts present received 2 cycles of 28-day cycle (Cycles 1-2) of imetelstat 7.5 mg/kg, IV as 2-hour infusion on Day 1 of a 28-day cycle followed by maintenance therapy with the same regimen or the possibility of dose escalation to imetelstat 9.4 mg/kg weekly if response to the initial dose was insufficient up to 9 cycles in the Core Phase. Participants could receive imetelstat beyond Cycle 9 in the Extension Phase if they did not meet any of the withdrawal criteria, did not have disease progression and were receiving clinical benefit from treatment as determined by the investigator. Following treatment discontinuation, participants entered the Event Monitoring Phase for collection of survival status, disease status, and subsequent treatment information (Up to approximately 5.7 years). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Diagnosis of one of the following:
- Primary myelofibrosis (PMF) per the revised World Health Organization (WHO) criteria.
- Post-polycythemia vera/essential thrombocythemia myelofibrosis (Post-ET/PV MF) per the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria.
- High-risk or Intermediate-2 risk MF (as defined by the Dynamic International Prognostic Scoring System [DIPSS-plus]).
- Life expectancy of greater than or equal to (>=) 12 weeks.
Key exclusion criteria (9 listed)
- Females who are pregnant or are currently breastfeeding.
- Any chemotherapy (e.g., hydroxyurea), immunomodulatory drug therapy (e.g., thalidomide), immunosuppressive therapy, corticosteroids > 10 mg/day prednisone or equivalent, growth factor treatment (e.g., erythropoietin) or Janus kinase (JAK) inhibitor therapy =<14 days prior to registration.
- Participants with another active malignancy.
- Note: participants with early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin or cervical intraepithelial neoplasia are eligible for enrollment.
- Known positive status for human immunodeficiency virus (HIV).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ImetelstatAlso: GRN163LImetelstat sodium administered as IV over 2 hours with treatment as long as participants derive clinical benefit or until end of study. | Drug | Arm A: Imetelstat 9.4 mg/kg (Myelofibrosis [MF]), Arm B: Imetelstat 9.4 mg/kg as Induction + Maintenance (MF), Arm D: Imetelstat 9.4 mg/kg (Blast-phase MF/Acute Myeloid Leukemia), Arm E: Imetelstat 7.5 - 9.4 mg/kg (MF [with Spliceosome Mutation or Ring Sideroblasts]), Arm F: Imetelstat 7.5 - 9.4 mg/kg (MF [without spliceosome mutation and ring sideroblasts]), Arm G: Imetelstat 7.5 - 9.4 mg/kg (MDS/MPN or MDS with Spliceosome Mutations or Ring Sideroblasts) |
Primary outcome
MF Participants: Percentage of Participants With Overall Response (OR) - (Clinical Improvement[CI] or Partial Remission[PR] or Complete Remission[CR]) Per International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria
Time frame: Up to first 9 cycles of treatment (each cycle was of 21 days for Arms A and B and 28 days for Arms E and F)
OR:CI/PR/CR per IWG-MRT. CR:Bone marrow (BM):<5% blasts;≤Grade 1 MF, AND Peripheral blood:Hemoglobin (Hb) ≥100 g/liter (g/L) and <upper normal limit (UNL);Neutrophil count(NC) ≥1x10^9/L and <UNL; Platelet(PLT) count ≥100x10^9/L and <UNL;<2% immature myeloid cells(IMCs), AND Clinical: Resolution of disease symptoms; Spleen and liver not palpable; No evidence of extramedullary hematopoeisis(EMH). PR:All CR criteria plus peripheral blood: Hb≥85 but <100g/L and <UNL; NC ≥1x10^9/L and <UNL; PLT count ≥50 but <100x10^9/L and <UNL;<2%IMCs. CI:achievement of anemia (≥20 g/L increase in Hb level), spleen(baseline splenomegaly palpable at 5-10 cm, below left costal margin(LCM), becomes not palpable), symptoms response (50% reduction in total symptom score) without progressive disease (PD) (appearance of new splenomegaly- palpable at least [≥]5 cm below LCM)/increase in severity of anemia, thrombocytopenia/neutropenia. Data is reported separately for arms whose response was assessed per IWG-MRT.
Blastic MF/AML Participants: Percentage of Participants With Overall Response
Time frame: Up to first 9 cycles of treatment (each cycle was of 28 days for Arm D)
For this pilot study, overall response was defined as achievement of a leukemic response (i.e. a clinically meaningful reduction in Blast cells). This was quantified as <5% peripheral blood and bone marrow blasts % that lasts for at least two months. Data is reported separately for this arm where response was assessed by this specific criterion.
MDS Participants: Percentage of Participants With Overall Response (Hematologic Improvement [HI] or PR or CR) Per IWG Criteria
Time frame: Up to first 9 cycles of treatment (each cycle was of 28 days for Arm G)
OR: HI/PR/CR per IWG. CR: BM:≤5% myeloblasts (all cell lines normal maturation), Peripheral blood:Hgb ≥11g/dL, PLTs ≥100x10^9/L, Neutrophils ≥1.0x10^9/L, Blasts 0%. PR: All CR criteria if abnormal before treatment except- BM blasts decreased ≥50% over pretreatment but still >5%, Cellularity, morphology not relevant. HI responses:1) Erythroid: Hgb increase ≥1.5 g/dL, Relevant reduction of red blood cell(RBC) units transfusions by absolute ≥4 RBC transfusions/8 week (wk) compared with pretreatment transfusion number in previous 8 wk. Only RBC transfusions given for Hgb of ≤9.0 g/dL.2)PLTs:Absolute increase ≥30x10^9/L starting >20x10^9/L PLTs; Increase from <20x10^9/L to >20x10^9/L and by ≥100%; 3)Neutrophil: ≥100% increase, absolute increase >0.5x10^9/L; 4)Progression/relapse after HI:≥1 of following:≥50% decrement from maximum response levels in granulocytes/PLTs, Reduction in Hgb ≥1.5 g/dL,Transfusion dependence. Data is reported separately for arm whose response was assessed per IWG.
11 secondary outcomes
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Grade >= 3 TEAEs and Treatment Related Adverse Events
Time frame: From first dose of study drug up to 30 days from the last dose of study drug or until subsequent anti-cancer therapy if earlier (Up to approximately 5.7 years)
Number of Participants With Spleen Response Per IWG-MRT Criteria
Time frame: Up to approximately 5.7 years
MF and Blastic MF/AML Participants: Number of Participants With Transfusion Independence (CI by Anemia Response) Per IWG-MRT
Time frame: Up to approximately 5.7 years
MDS Participants: Number of Participants With Transfusion Independence (HI by Erythroid Response) Per IWG Criteria
Time frame: Up to approximately 5.7 years
MF Participants: Time to Response
Time frame: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
Blastic MF/AML Participants: Time to Response
Time frame: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
MDS Participants: Time to Response
Time frame: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
MF Participants: Duration of Response (DOR) Per IWG-MRT Criteria
Time frame: From time of initial response until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
Blastic MF/AML Participants: Duration of Response
Time frame: From time of initial response until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
MDS Participants: Duration of Response Per IWG Criteria
Time frame: From the time of initial response (CR/PR/HI) until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
Overall Survival (OS)
Time frame: From Study Day 1 to the date of death from any cause (Up to approximately 5.7 years)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 26332545Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, Laborde RR, Wassie E, Schimek L, Hanson CA, Gangat N, Wang X, Pardanani A. A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. N Engl J Med. 2015 Sep 3;373(10):908-19. doi: 10.1056/NEJMoa1310523.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Study Clinical Team study director
Geron Corporation
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Imetelstat in people with Primary Myelofibrosis and Secondary Myelofibrosis, run by Geron Corporation at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 21 Sep 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
MF Participants: Percentage of Participants With Overall Response (OR) - (Clinical Improvement[CI] or Partial Remission[PR] or Complete Remission[CR]) Per International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria (time frame: Up to first 9 cycles of treatment (each cycle was of 21 days for Arms A and B and 28 days for Arms E and F)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01731951, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2021.