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

Phase 3

Completed

• Conditions: Chronic Myeloid Leukemia in Remission
• Interventions: Drug: AOP2014 / Pegylated-Proline-interferon alpha-2b; Other: Surveillance

• Registration Number: NCT03117816
• Lead Sponsor: Philipps University Marburg Medical Center

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.

Study Timeline

• Study First Submitted: 2017-03-08
• Study First Submitted QC: 2017-04-12
• Study First Posted: 2017-04-18
• Study Start: 2017-05-04
• Primary Completion: 2022-01-26
• Study Completion: 2022-12-12
• Status Verified: 2023-03
• Last Update Submitted: 2023-03-30
• Last Update Posted: 2023-03-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 214

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
investigational arm A	AOP2014 / Pegylated-Proline-interferon alpha-2b	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.
surveillance arm B	Surveillance	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.

Primary Outcome Measures

Name	Time	Method
mRFS	Randomization until time of relapse	The primary efficacy endpoint is molecular relapse free survival (mRFS). 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 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

Name	Time	Method
Quality of life measured by EORTC-QLQ-CML24	Day 0 - Month 25	The QoL assessment in this study is planned to gain information on the QoL of CML patients under stopping conditions. 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
For Germany: Explore immunological and genetic biomarkers and identify predictors	Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)	For Germany: Explore immunological and genetic biomarkers to study biology of TFR, and identify predictors IFN response (e.g. mRNA sequencing of whole blood or leukocyte subpopulations, PD-L1-, PD1-, CD62L- measurements by FACS on peripheral blood subsets, T-cell activation and exhaustion marker measurements, PR1-CTL assessment and cytokines). Evaluation of cytokines/chemokines (i.e., IL-6, IFN-α, IL 10, and others).
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03	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
Kinetics of BCR-ABL transcript level over time after TKI stop	Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)	Kinetics of BCR-ABL transcript level over time after TKI stop
mRFS 7	7 months after randomization	The primary efficacy endpoint is molecular relapse free survival, RFS 7 months after
mRFS 13	13 months after randomization	The relapse free survival, RFS 13 months after randomization
For Germany: Detection of blood parameters 95 CD86+pDC as mRFS predictor	Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)	For Germany: To explore the value of 95 CD86+pDC / 105 lymphocytes at baseline in predicting risk of molecular relapse (loss of MMR)
mRFS 25	25 months after randomization	The relapse free survival, RFS 25 months after randomization
Quality of life measured by EORTC QLQ-C30	Day 0 - Month 25	The QoL assessment in this study is planned to gain information on the QoL of CML patients under stopping conditions. The data will be compared between the treatment groups and to QoL of normal population.
OS (overall survival)	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.
For Germany: Evaluation of cytokines/chemokines	Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)	For Germany: Evaluation of cytokines/chemokines (i.e., IL-6, IFN-α, IL 10, and others)

Trial Locations

Locations (26)

Centre Léon Bérard; 🇫🇷 Lyon, France

Institut Bergonié; 🇫🇷 Bordeaux, France

CHRU de Nancy - Hôpitaux de Brabois; 🇫🇷 Vandœuvre-lès-Nancy, France

03 Universitätsklinikum Aachen, Hämatologie/Onkologie; 🇩🇪 Aachen, Germany

06 Universitätsmedizin Berlin Charite- Campus Virchow Klinikum, Klinik für Hämatologie und Onkologie; 🇩🇪 Berlin, Germany

18 Studienzentrum Aschaffenburg; 🇩🇪 Aschaffenburg, Germany

19 Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik III; 🇩🇪 Bonn, Germany

07 Universitätsklinikum Erlangen, Medizinische Klinik 5; 🇩🇪 Erlangen, Germany

16 Klinikum Bremen Mitte, Medizinische Klinik I; 🇩🇪 Bremen, Germany

05 Universitätsklinikum Düsseldorf, Klinik für Hämatologie, Onkologie und Klinische Immunologie; 🇩🇪 Dusseldorf, Germany

22 BAG / Onkologische Gemeinschaftspraxis; 🇩🇪 Dresden, Germany

17 Klinikum der Goethe Universität, Medizinische Klinik II; 🇩🇪 Frankfurt a. Main, Germany

20 Universitätsklinikum Essen, Klinik für Hämatologie; 🇩🇪 Essen, Germany

24 Institut für Versorgungsforschung in der Onkologie GbR; 🇩🇪 Koblenz, Germany

21 Universitätsklinikum Hamburg Eppendorf, Klinik für Onkologie, Hämatologie und KMT; 🇩🇪 Hamburg, Germany

23 Evangelische Krankenhaus Hamm gGmbH, Klinik für Hämatologie, Onkologie und Palliativmedizin; 🇩🇪 Hamm, Germany

02 Universitätsklinikum Jena, linik für Innere Medizin II Abt. für Hämatologie und Internistische Onkologie; 🇩🇪 Jena, Germany

13 Universitätsklinikum Leipzig, Abteilung für Hämatologie u. Internistische Onkologie; 🇩🇪 Leipzig, Germany

14 Johannes-Gutenberg-Universität III. Medizinische Klinik; 🇩🇪 Mainz, Germany

08 Universitätsklinikum Münster, Medizinische Klinik, Innere Medizin A; 🇩🇪 Muenster, Germany

04 Universitätsmedizin Mannheim, III. Medizinische Klinik; 🇩🇪 Mannheim, Germany

01 Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg, Klinik für Hämatologie, Onkologie und Immunologie; 🇩🇪 Marburg, Germany

10 Technische Universität München (TUM) Klinikum rechts der Isar, III. Medizinische Klinik und Poliklinik; 🇩🇪 Munich, Germany

09 Universitätsklinikum Tübingen, Medizinische Klinik; 🇩🇪 Tübingen, Germany

12 Universitätsklinikum Ulm, Klinik für Innere Medizin III; 🇩🇪 Ulm, Germany

15 Universitätsklinikum Würzburg, Zentrum für Innere Medizin; 🇩🇪 Würzburg, Germany