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

Chronic Myeloid Leukemia in Remission Clinical Trial

— ENDURE-CML-IX  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03117816
• Other study ID #: KKS-227
• Secondary ID: 2016-001030-94
• Status: Completed
• Phase: Phase 3
• Start date: May 4, 2017
• Est. completion date: December 12, 2022

Study information

• Verified date: March 2023
• Source: Philipps University Marburg Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 214
• Est. completion date: December 12, 2022
• Est. primary completion date: January 26, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia in Remission
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

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.

Locations

Country	Name	City	State
France	Institut Bergonié	Bordeaux
France	Centre Léon Bérard	Lyon
France	CHRU de Nancy - Hôpitaux de Brabois	Vandœuvre-lès-Nancy
Germany	03 Universitätsklinikum Aachen, Hämatologie/Onkologie	Aachen
Germany	18 Studienzentrum Aschaffenburg	Aschaffenburg
Germany	06 Universitätsmedizin Berlin Charite- Campus Virchow Klinikum, Klinik für Hämatologie und Onkologie	Berlin
Germany	19 Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik III	Bonn
Germany	16 Klinikum Bremen Mitte, Medizinische Klinik I	Bremen
Germany	22 BAG / Onkologische Gemeinschaftspraxis	Dresden
Germany	05 Universitätsklinikum Düsseldorf, Klinik für Hämatologie, Onkologie und Klinische Immunologie	Dusseldorf
Germany	07 Universitätsklinikum Erlangen, Medizinische Klinik 5	Erlangen
Germany	20 Universitätsklinikum Essen, Klinik für Hämatologie	Essen
Germany	17 Klinikum der Goethe Universität, Medizinische Klinik II	Frankfurt a. Main
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	24 Institut für Versorgungsforschung in der Onkologie GbR	Koblenz
Germany	13 Universitätsklinikum Leipzig, Abteilung für Hämatologie u. Internistische Onkologie	Leipzig
Germany	14 Johannes-Gutenberg-Universität III. Medizinische Klinik	Mainz
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	08 Universitätsklinikum Münster, Medizinische Klinik, Innere Medizin A	Muenster
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

Sponsors (3)

Lead Sponsor	Collaborator
Philipps University Marburg Medical Center	AOP Orphan Pharmaceuticals AG, Deutsche Krebshilfe e.V., Bonn (Germany)

Countries where clinical trial is conducted

France,  Germany, 

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* Note: There are 61 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	mRFS	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.	Randomization until time of relapse
Secondary	mRFS 7	The primary efficacy endpoint is molecular relapse free survival, RFS 7 months after	7 months after randomization
Secondary	mRFS 13	The relapse free survival, RFS 13 months after randomization	13 months after randomization
Secondary	mRFS 25	The relapse free survival, RFS 25 months after randomization	25 months after randomization
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.03	Adverse events, serious adverse events (AEs, SAEs)• Safety, tolerability and toxicity based on incidences of adverse events, serious adverse events	Day 0 - Month 15 (Arm B) or Month 16 (additional safety visit one month after last application for Arm A)
Secondary	Quality of life measured by EORTC QLQ-C30	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.	Day 0 - Month 25
Secondary	Quality of life measured by EORTC-QLQ-CML24	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	Day 0 - Month 25
Secondary	OS (overall survival)	Overall survival (OS), defined as the time between the date of randomization and the date of death from any cause.	Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)
Secondary	Kinetics of BCR-ABL transcript level over time after TKI stop	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)
Secondary	For Germany: Detection of blood parameters 95 CD86+pDC as mRFS predictor	For Germany: To explore the value of 95 CD86+pDC / 105 lymphocytes at baseline in predicting risk of molecular relapse (loss of MMR)	Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)
Secondary	For Germany: Explore immunological and genetic biomarkers and identify predictors	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-a, IL 10, and others).	Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)
Secondary	For Germany: Evaluation of cytokines/chemokines	For Germany: Evaluation of cytokines/chemokines (i.e., IL-6, IFN-a, IL 10, and others)	Day 0 - Month 25 (plus annual post study follow up Months 36,48,60)