Imetelstat Sodium in Treating Participants With Primary or Secondary Myelofibrosis

NCT01731951 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: CR107110CP14B019
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Primary Myelofibrosis; Secondary Myelofibrosis; Myeloid Malignancies

Keywords

Myelofibrosis; Myelodysplastic Syndromes; Myeloproliferative Neoplasm; Imetelstat; GRN163L

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  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

  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

  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

  Up to approximately 5.7 years

• MDS Participants: Number of Participants With Transfusion Independence (HI by Erythroid Response) Per IWG Criteria

  Up to approximately 5.7 years

• MF Participants: Time to Response

  From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)

Study Arms (6)

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).

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).

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).

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).

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).

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).

Drug: Imetelstat

Interventions

Imetelstat DRUG

Imetelstat sodium administered as IV over 2 hours with treatment as long as participants derive clinical benefit or until end of study.

Also known as: GRN163L

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)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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).

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Geron Corporation: lead

Study Sites (1)

Unknown Facility

Rochester, Minnesota, United States

Location

Related Publications (1)

• 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.

  PMID: 26332545 DERIVED

MeSH Terms

Conditions

Primary Myelofibrosis; Myelodysplastic Syndromes; Myeloproliferative Disorders

Interventions

imetelstat; GRN163L peptide

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Study Director
• Organization: Geron Corp.

myf2001-info@geron.com

650-473-7700

Study Officials

• Study Clinical Team

  Geron Corporation

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2012
• First Posted: November 22, 2012
• Study Start: October 29, 2012
• Primary Completion: May 24, 2018
• Study Completion: May 24, 2018
• Last Updated: September 21, 2021
• Results First Posted: September 21, 2021

Record last verified: 2021-08

Locations

US (1)