Imetelstat Sodium in Treating Participants With Primary or Secondary Myelofibrosis

Phase 2CompletedNCT01731951

Geron Corporation80 enrolled

Overview

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.

PRIMARY OBJECTIVES: I. To evaluate overall response rate. SECONDARY OBJECTIVES: I. 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: I. 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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Primary Myelofibrosis Secondary Myelofibrosis Myeloid Malignancies

Interventions

ImetelstatDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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). * 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. Exclusion Criteria: * 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.

Locations (1)

Unnamed facility

Rochester, Minnesota, United States

Outcomes

Primary Outcomes

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.

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)

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.

Time frame: 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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

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

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.

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

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.

Time frame: 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.

Time frame: 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.

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 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.

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 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.

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

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.

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

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.

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

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.

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)

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.

Time frame: From Study Day 1 to the date of death from any cause (Up to approximately 5.7 years)