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

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ClinicalTrials.gov Identifier: NCT03117816
Recruitment Status : Recruiting
First Posted : April 18, 2017
Last Update Posted : May 21, 2019
Sponsor:
Collaborators:
Deutsche Krebshilfe e.V., Bonn (Germany)
AOP Orphan Pharmaceuticals AG
Information provided by (Responsible Party):
Kerstin Balthasar, Philipps University Marburg Medical Center

Tracking Information
First Submitted Date  ICMJE March 8, 2017
First Posted Date  ICMJE April 18, 2017
Last Update Posted Date May 21, 2019
Actual Study Start Date  ICMJE May 4, 2017
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 8, 2018)
RFS 7 [ Time Frame: 7 months after randomization ]
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
Original Primary Outcome Measures  ICMJE
 (submitted: April 12, 2017)
RFS 7 [ Time Frame: Month 7 ]
The primary efficacy endpoint is molecular relapse free survival, RFS, at month 7 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
Change History Complete list of historical versions of study NCT03117816 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 26, 2018)
  • RFS 13 [ Time Frame: 13 months after randomization ]
    The relapse free survival, RFS 13 months after randomization
  • RFS 25 [ Time Frame: 25 months after randomization ]
    The relapse free survival, RFS 25 months after randomization
  • 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) ]
    Adverse events, serious adverse events (AEs, SAEs)• Safety, tolerability and toxicity based on incidences of adverse events, serious adverse events
  • Quality of life measured by EORTC QLQ-C30 [ Time Frame: Day 0 - Month 25 ]
    The data will be compared between the treatment groups and to QoL of normal population.
  • Quality of life measured by EORTC-QLQ-CML24 [ Time Frame: Day 0 - Month 25 ]
    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
  • detection of blood parameter 95 CD86+pDC as RFS predictor [ Time Frame: Day 0 - Month 15 ]
    To validate the value of 95 CD86+pDC / 105 lymphocytes at baseline (before TKI stop) as a predictor of RFS
  • OS (overall survival) [ Time Frame: Day 0 - Month 25 (plus annual post study follow up Months 36,48,60) ]
    Overall survival (OS), defined as the time between the date of randomization and the date of death from any cause.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2017)
  • RFS 13 [ Time Frame: Month 13 ]
    The relapse free survival, RFS, at month 13 after randomization
  • RFS 25 [ Time Frame: Month 25 ]
    The relapse free survival, RFS, at month 25 after randomization
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [ Time Frame: Day 0 - Month 18 ]
    Adverse events, serious adverse events (AEs, SAEs)• Safety, tolerability and toxicity based on incidences of adverse events, serious adverse events, frequency of clinical laboratory tests by worst toxicity grade
  • Quality of life measured by EORTC QLQ-C30 [ Time Frame: Day 0 - Month 18 ]
    The data will be compared between the treatment groups and to QoL of normal population.
  • Quality of life measured by EORTC-QLQ-CML24 [ Time Frame: Day 0 - Month 18 ]
    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
  • detection of blood parameter 95 CD86+pDC as RFS predictor [ Time Frame: Day 0 - Month 25 ]
    To validate the value of 95 CD86+pDC / 105 lymphocytes at baseline (before TKI stop) as a predictor of RFS
  • OS (overall survival) [ Time Frame: Day 0 - Month 25 ]
    Overall survival (OS), defined as the time between the date of randomization and the date of death from any cause.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ENDURE - Efficacy and Safety of AOP2014 With CML Patients in Remission
Official Title  ICMJE 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
Brief Summary 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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description:
A randomized, open-label assessor blinded, multi-center, controlled phase II trial
Primary Purpose: Prevention
Condition  ICMJE Chronic Myeloid Leukemia in Remission
Intervention  ICMJE
  • Drug: AOP2014 / Pegylated-Proline-interferon alpha-2b
    AOP2014 as pre-filled auto-injection pen for subcutaneous injection, containing 250 µg AOP2014 / 0.5 ml. The solution also contains inactive ingredients (sodium chloride, polysorbate 80, benzyl alcohol, sodium acetate, and acetic acid). The solution is colorless to light yellow.
  • Other: Surveillance
    For patients randomized into this treatment arm stopp their standard treatment and will just be under observation.
Study Arms  ICMJE
  • Experimental: investigational arm A
    There 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.
    Intervention: Drug: AOP2014 / Pegylated-Proline-interferon alpha-2b
  • surveillance arm B
    This 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.
    Intervention: Other: Surveillance
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 12, 2017)
214
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2024
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Andreas Burchert, Prof. Dr. 0049 6421 586 ext 5611 burchert@staff.uni-marburg.de
Contact: Kerstin Balthasar 0049 6421 286 ext 6558 kerstin.balthasar@kks.uni-marburg.de
Listed Location Countries  ICMJE France,   Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03117816
Other Study ID Numbers  ICMJE KKS-227
2016-001030-94 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Kerstin Balthasar, Philipps University Marburg Medical Center
Study Sponsor  ICMJE Philipps University Marburg Medical Center
Collaborators  ICMJE
  • Deutsche Krebshilfe e.V., Bonn (Germany)
  • AOP Orphan Pharmaceuticals AG
Investigators  ICMJE
Study Director: Andreas Burchert, Prof. Dr. Philipps University Marburg Medical Center
Principal Investigator: Franck E Nicoloni, MD, PhD Centre Léon Bérard Lyon
PRS Account Philipps University Marburg Medical Center
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP