Clinical trial NCT01731951: Imetelstat Sodium in Treating Participants With Primary or Secondary Myelofibrosis
Official title: A Pilot Open-Label Study of the Efficacy and Safety of Imetelstat (GRN163L) in Myelofibrosis and Other Myeloid Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Myelofibrosis
Secondary Myelofibrosis
Myeloid Malignancies
Keywords: Myelofibrosis
Myelodysplastic Syndromes
Myeloproliferative Neoplasm
Imetelstat
GRN163L
Lead sponsor: Geron Corporation
Sponsor class: INDUSTRY
First posted: 2012-11-22
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
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
timeFrame: 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)
measure: Blastic MF/AML Participants: Percentage of Participants With Overall Response
timeFrame: Up to first 9 cycles of treatment (each cycle was of 28 days for Arm D)
measure: MDS Participants: Percentage of Participants With Overall Response (Hematologic Improvement [HI] or PR or CR) Per IWG Criteria
timeFrame: Up to first 9 cycles of treatment (each cycle was of 28 days for Arm G)
Secondary outcomes:
measure: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Grade >= 3 TEAEs and Treatment Related Adverse Events
timeFrame: 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)
measure: Number of Participants With Spleen Response Per IWG-MRT Criteria
timeFrame: Up to approximately 5.7 years
measure: MF and Blastic MF/AML Participants: Number of Participants With Transfusion Independence (CI by Anemia Response) Per IWG-MRT
timeFrame: Up to approximately 5.7 years
measure: MDS Participants: Number of Participants With Transfusion Independence (HI by Erythroid Response) Per IWG Criteria
timeFrame: Up to approximately 5.7 years
measure: MF Participants: Time to Response
timeFrame: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
measure: Blastic MF/AML Participants: Time to Response
timeFrame: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
measure: MDS Participants: Time to Response
timeFrame: From study Day 1 to the earliest date that a response was first documented (Up to approximately 5.7 years)
measure: MF Participants: Duration of Response (DOR) Per IWG-MRT Criteria
timeFrame: From time of initial response until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
measure: Blastic MF/AML Participants: Duration of Response
timeFrame: From time of initial response until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
measure: MDS Participants: Duration of Response Per IWG Criteria
timeFrame: From the time of initial response (CR/PR/HI) until documented disease progression or death whichever occurs first (Up to approximately 5.7 years)
measure: Overall Survival (OS)
timeFrame: From Study Day 1 to the date of death from any cause (Up to approximately 5.7 years)
Other outcomes:
Locations:
city: Rochester
country: United States
state: Minnesota
Study officials:
affiliation: Geron Corporation
name: Study Clinical Team
role: STUDY_DIRECTOR
References:
citation: 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.