Clinical Trials /

ENDURE - Efficacy and Safety of AOP2014 With CML Patients in Remission

NCT03117816

Description:

A randomized, open-label assessor blinded, multi-center, controlled phase II Trial to evaluate the efficacy of AOP2014 administered bi-weekly subcutaneously (s.c.) in preventing molecular relapse (loss of MMR) in CML patients, who discontinue ABL tyrosine kinase inhibitor therapy (TKI) in deep molecular remission of MR4 or better (MR4.5, or MR5).

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ENDURE - Efficacy and Safety of AOP2014 With CML Patients in Remission
  • Official Title: Efficacy and Safety of Pegylated Proline Interferon Alpha 2b (AOP2014) in Maintaining Deep Molecular Remissions in Patients With Chronic Myeloid Leukemia (CML) Who Discontinue ABL-Kinase Inhibitor Therapy - a Randomized Phase II, Multicenter Trial With Post-study Follow-up

Clinical Trial IDs

  • ORG STUDY ID: KKS-227
  • SECONDARY ID: 2016-001030-94
  • NCT ID: NCT03117816

Conditions

  • Chronic Myeloid Leukemia in Remission

Interventions

DrugSynonymsArms
AOP2014 / Pegylated-Proline-interferon alpha-2binvestigational arm A

Purpose

A randomized, open-label assessor blinded, multi-center, controlled phase II Trial to evaluate the efficacy of AOP2014 administered bi-weekly subcutaneously (s.c.) in preventing molecular relapse (loss of MMR) in CML patients, who discontinue ABL tyrosine kinase inhibitor therapy (TKI) in deep molecular remission of MR4 or better (MR4.5, or MR5).

Detailed Description

      Four hypotheses are tested in hierarchical order. To avoid inflation of type 1 error (false
      rejection of a null hypothesis), further confirmatory testing has to be stopped as soon as a
      null hypothesis could not be rejected.

      All four hypotheses are tested at significance level 0.05. Null hypotheses 1, 2, and 4 deal
      with probabilities of molecular relapse-free survival 7, 13, and 25 months after
      randomisation, respectively; arms A and B are compared with the uncorrected chi-square test.
      Null hypothesis 3 investigates molecular relapse-free survival as a time-to-event variable;
      the two arms are compared with the log-rank test
    

Trial Arms

NameTypeDescriptionInterventions
investigational arm AExperimentalThere will be an overlapping treatment with AOP2014 and TKI for one month. After one month, the TKI therapy will be stopped and patient will receive only AOP2014 treatment for the next 14 months.
  • AOP2014 / Pegylated-Proline-interferon alpha-2b
surveillance arm BOtherThis is an open-label study with a "surveillance" group as comparator arm. Similar as in the arm A, patient will discontinue TKI therapy one month after randomization. From then on patient will receive no further CML treatment.

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Signed written informed consent form.
    
              2. Capability and willingness to comply with study procedures and ability to
                 self-administration of the study drug.
    
              3. Male or female aged ≥ 18 years.
    
              4. At least three years of TKI therapy.
    
              5. BCR-ABL-positive, chronic phase CML patients with a transcript level according to the
                 international scale (IS) of at least MR4, or better (MR4.5, MR5). MR4 is defined as
                 (i) detectable disease ≤0.01% BCR-ABL IS or (ii) undetectable disease in cDNA with
                 ≥10,000 ABL or ≥24,000 GUS transcripts for at least one year. There have to be at
                 least three consecutive PCR-results with MR4 or better within the last year (+ months)
                 before study entry. The latest of these PCRs must be a confirmatory MR4 measurement
                 prior to randomization by the EUTOS-certified Study Reference Laboratories for PCR
                 (BCR-ABL mRNA). No PCR-results in the last year before randomisation can be worse than
                 MR4. If the last PCR was not done within two months from baseline (day 0) in an
                 EUTOS-certified study Reference Laboratory; the PCR sample must be sent to an
                 EUTOS-certified study Reference Laboratory at screening.
    
              6. Patients who had failed to discontinue TKI in a prior discontinuation attempt are
                 eligible for this protocol, if they fulfil criterion 5 after retreatment with TKI. A
                 prior TKI discontinuation failure must be specifically indicated at inclusion and
                 documented.
    
              7. Adequate organ function:
    
                 especially total bilirubin, lactate dehydrogenase [LDH], aspartate aminotransferase
                 [AST], alanine aminotransferase [ALT] and coagulation parameters ≤ 2 × upper limit of
                 normal (ULN)
    
              8. Adequate hematological parameters:
    
                 platelet count ≥ 100 × 1000000000/L; white blood cell count ≥ 2.5 × 1000000000/L;
                 lymphocytes ≥ 1.0 × 1000000000/L; hemoglobin ≥ 9.0 g/dL or 5.59 mmol/L.
    
              9. Female patients with reproductive potential must agree to maintain highly effective
                 methods of contraception by practicing abstinence or by using at least two methods of
                 birth control from the date of consent through the end of the study. If abstinence
                 could not be practiced, a combination of hormonal contraceptive (oral, injectable, or
                 implants) and a barrier method (condom, diaphragm with a vaginal spermicidal agent)
                 has to be used. Male patients must agree to use condoms during study participation.
    
             10. Negative serum pregnancy test in women of childbearing potential.
    
             11. Date of diagnosis of CML confirmed by laboratory PCR must be known.
    
            Exclusion Criteria:
    
              1. Rare variants of BCR-ABL not quantifiable by RT-PCR according to the international
                 scale (IS).
    
              2. Current or previous autoimmune diseases requiring treatment.
    
              3. Immunosuppressive treatment of any kind; transplant recipients
    
              4. Prior allogeneic stem cell transplantation.
    
              5. Prior pegylated IFN therapy. Prior low dose conventional IFN treatment with ≤ 3 x 3
                 Mio I.E. / week for less than 1 year is acceptable.
    
              6. History of TKI resistance within the last 4 years of TKI therapy.
    
              7. History of accelerated phase or blast crisis.
    
              8. Hypersensitivity/allergy to the active substance or excipients of the formulation.
    
              9. Severe hepatic dysfunction or decompensated cirrhosis.
    
             10. End stage renal disease (GFR <15 ml/min)
    
             11. Thyroid disease that cannot be controlled by conventional therapy.
    
             12. Uncontrolled diabetes mellitus
    
             13. Epilepsy or other disorders of the central nervous system.
    
             14. Severe cardiac disease history including unstable or uncontrolled cardiac disease in
                 the previous 6 months.
    
             15. Uncontrolled hypertension
    
             16. Any history of retinopathy e.g. retinal detachment, degeneration or thromboembolic
                 events.
    
             17. Clinically significant concomitant diseases or conditions, which, in the opinion of
                 the investigator, would lead to an unacceptable risk for the patient to participate in
                 the study (please refer also to the actual Investigator Brochure).
    
             18. Other malignancy, except adequately treated superficial bladder cancer, basal or
                 squamous cell carcinoma of the skin, or other cancer(s) for which the patient has been
                 disease free for more than 3 years.
    
             19. Active or uncontrolled infections at the time of randomization.
    
             20. Pregnant and/or nursing women.
    
             21. Use of antibiotic therapy within the last 2 weeks prior to randomization
    
             22. Concurrent use of molecular targeted therapy.
    
             23. Tested HIV sero-positivity or tested active hepatitis B or C infection.
    
             24. Participation in another clinical study with other investigational drugs within 14
                 days prior to randomization.
    
             25. Vaccination within 1 month prior to randomization.
    
             26. Any medical, mental, psychological or psychiatric condition (particularly severe
                 depression, suicidal ideation or suicide attempt) that in the opinion of the
                 investigator would not permit the patient to complete the study or comply to study
                 procedures.
    
             27. Drug and/or alcohol abuse.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:RFS 7
    Time Frame:7 months after randomization
    Safety Issue:
    Description:The primary efficacy endpoint is molecular relapse free survival, RFS 7 months after randomization. Relapse is defined as loss of major molecular remission, MMR, which is any increase of the BCR-ABL ratio to > 0.1% according to the international scale (IS). Time to relapse is defined as the time from randomization to relapse

    Secondary Outcome Measures

    Measure:RFS 13
    Time Frame:13 months after randomization
    Safety Issue:
    Description:The relapse free survival, RFS 13 months after randomization
    Measure:RFS 25
    Time Frame:25 months after randomization
    Safety Issue:
    Description:The relapse free survival, RFS 25 months after randomization
    Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
    Time Frame:Day 0 - Month 15 (Arm B) or Month 16 (additional safety visit one month after last application for Arm A)
    Safety Issue:
    Description:Adverse events, serious adverse events (AEs, SAEs)• Safety, tolerability and toxicity based on incidences of adverse events, serious adverse events
    Measure:Quality of life measured by EORTC QLQ-C30
    Time Frame:Day 0 - Month 25
    Safety Issue:
    Description:The data will be compared between the treatment groups and to QoL of normal population.
    Measure:Quality of life measured by EORTC-QLQ-CML24
    Time Frame:Day 0 - Month 25
    Safety Issue:
    Description:The data will be compared between the treatment groups and to QoL of normal population. Furthermore, results of the CML24 module should be shared with the EORTC group to complete the validation of this questionnaire
    Measure:detection of blood parameter 95 CD86+pDC as RFS predictor
    Time Frame:Day 0 - Month 15
    Safety Issue:
    Description:To validate the value of 95 CD86+pDC / 105 lymphocytes at baseline (before TKI stop) as a predictor of RFS
    Measure:OS (overall survival)
    Time Frame:Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)
    Safety Issue:
    Description:Overall survival (OS), defined as the time between the date of randomization and the date of death from any cause.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Philipps University Marburg Medical Center

    Trial Keywords

    • deep molecular remission of MR4 or better

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