Clinical trial NCT03117816: 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 III, Multicenter Trial With Post-study Follow-up
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Myeloid Leukemia in Remission
Keywords: deep molecular remission of MR4 or better
Lead sponsor: Philipps University Marburg
Sponsor class: OTHER
Collaborators: name: Deutsche Krebshilfe e.V., Bonn (Germany)
name: AOP Orphan Pharmaceuticals AG
First posted: 2017-04-18
Enrollment: 214
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: A randomized, open-label assessor blinded, multi-center, controlled phase III 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 hypothesis 1 is the primary endpoint and investigates molecular relapse-free survival as a time-to-event variable; the two arms are compared with the log-rank test. Null hypotheses 2, 3, and 4 deal with probabilities of molecular relapse-free survival 7, 13, and 25 months after randomization, respectively; arms A and B are compared with the uncorrected chi-square test.

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.

Primary outcomes:
measure: mRFS
timeFrame: Randomization until time of relapse
Secondary outcomes:
measure: mRFS 7
timeFrame: 7 months after randomization
measure: mRFS 13
timeFrame: 13 months after randomization
measure: mRFS 25
timeFrame: 25 months after randomization
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
timeFrame: Day 0 - Month 15 (Arm B) or Month 16 (additional safety visit one month after last application for Arm A)
measure: Quality of life measured by EORTC QLQ-C30
timeFrame: Day 0 - Month 25
measure: Quality of life measured by EORTC-QLQ-CML24
timeFrame: Day 0 - Month 25
measure: OS (overall survival)
timeFrame: Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)
measure: Kinetics of BCR-ABL transcript level over time after TKI stop
timeFrame: Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)
measure: For Germany: Detection of blood parameters 95 CD86+pDC as mRFS predictor
timeFrame: Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)
measure: For Germany: Explore immunological and genetic biomarkers and identify predictors
timeFrame: Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)
measure: For Germany: Evaluation of cytokines/chemokines
timeFrame: Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Institut Bergonié
city: Lyon
country: France
facility: Centre Léon Bérard
city: Vandœuvre-lès-Nancy
country: France
facility: CHRU de Nancy - Hôpitaux de Brabois
city: Aachen
country: Germany
facility: 03 Universitätsklinikum Aachen, Hämatologie/Onkologie
city: Aschaffenburg
country: Germany
facility: 18 Studienzentrum Aschaffenburg
city: Berlin
country: Germany
facility: 06 Universitätsmedizin Berlin Charite- Campus Virchow Klinikum, Klinik für Hämatologie und Onkologie
city: Bonn
country: Germany
facility: 19 Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik III
city: Bremen
country: Germany
facility: 16 Klinikum Bremen Mitte, Medizinische Klinik I
city: Dresden
country: Germany
facility: 22 BAG / Onkologische Gemeinschaftspraxis
city: Dusseldorf
country: Germany
facility: 05 Universitätsklinikum Düsseldorf, Klinik für Hämatologie, Onkologie und Klinische Immunologie
city: Erlangen
country: Germany
facility: 07 Universitätsklinikum Erlangen, Medizinische Klinik 5
city: Essen
country: Germany
facility: 20 Universitätsklinikum Essen, Klinik für Hämatologie
city: Frankfurt a. Main
country: Germany
facility: 17 Klinikum der Goethe Universität, Medizinische Klinik II
city: Hamburg
country: Germany
facility: 21 Universitätsklinikum Hamburg Eppendorf, Klinik für Onkologie, Hämatologie und KMT
city: Hamm
country: Germany
facility: 23 Evangelische Krankenhaus Hamm gGmbH, Klinik für Hämatologie, Onkologie und Palliativmedizin
city: Jena
country: Germany
facility: 02 Universitätsklinikum Jena, linik für Innere Medizin II Abt. für Hämatologie und Internistische Onkologie
city: Koblenz
country: Germany
facility: 24 Institut für Versorgungsforschung in der Onkologie GbR
city: Leipzig
country: Germany
facility: 13 Universitätsklinikum Leipzig, Abteilung für Hämatologie u. Internistische Onkologie
city: Mainz
country: Germany
facility: 14 Johannes-Gutenberg-Universität III. Medizinische Klinik
city: Mannheim
country: Germany
facility: 04 Universitätsmedizin Mannheim, III. Medizinische Klinik
city: Marburg
country: Germany
facility: 01 Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg, Klinik für Hämatologie, Onkologie und Immunologie
city: Muenster
country: Germany
facility: 08 Universitätsklinikum Münster, Medizinische Klinik, Innere Medizin A
city: Munich
country: Germany
facility: 10 Technische Universität München (TUM) Klinikum rechts der Isar, III. Medizinische Klinik und Poliklinik
city: Tübingen
country: Germany
facility: 09 Universitätsklinikum Tübingen, Medizinische Klinik
city: Ulm
country: Germany
facility: 12 Universitätsklinikum Ulm, Klinik für Innere Medizin III
city: Würzburg
country: Germany
facility: 15 Universitätsklinikum Würzburg, Zentrum für Innere Medizin
Study officials:
affiliation: Philipps University Marburg
name: Andreas Burchert, Prof. Dr.
role: STUDY_DIRECTOR
affiliation: Centre Léon Bérard Lyon
name: Franck E Nicoloni, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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