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

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).

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.