Phase I, open label, single arm, non-randomized, multicenter, prospective dose escalation study in subjects with acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT).

The aim of the study is to determine a recommended dose for F16IL2 in combination with BI 836858 in AML relapse after alloHSCT and investigating safety and tolerability of the combination regimen.

Dose escalation will be guided by a Bayesian logistic regression model (BLRM) with overdose control that will be fitted to binary toxicity outcomes. The estimate of parameters will be updated as data are accumulated using the BLRM. At the end of the dose escalation phase, the probability of toxicity at each dose combination level will be calculated to determine an estimate of the MTD. Once the MTD or a biological active dose has been defined, additional patients (up to 10) will be treated with F16IL2 and BI 836858 dosed at this dose combination in order to confirm the safety profile of the combination.

Inclusion Criteria:

1. Patients with de novo or secondary AML according to the WHO/FAB classification relapsing after alloHSCT, and fulfilling at least one of the following:

   1. bone marrow blasts ≥ 5% of all nucleated cells
   2. appearance of blasts in the peripheral blood
   3. extramedullary AML relapse

2. Age 18 - 75 years.

3. ECOG ≤ 2.

4. Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of HBsAg, anti-HBsAg-Ab and anti-HBCAg-Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV-DNA is required.

5. Negative serum pregnancy test for females of childbearing potential* within 14 days of starting treatment.

6. Informed consent personally signed and dated to participate in the study.

7. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

   • Women of childbearing potential (WOCBP) must be using, from the screening to six months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesteron-only or combined (estrogen- and progesteron-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the end of treatment visit.

Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy)

Exclusion Criteria:

1. Known central nervous system manifestation of AML.
2. Previous treatment (e.g., stem cell transplantation, chemotherapy, radiotherapy, investigational drugs) within 4 weeks or a minimum of 5 half-lifes of the treatment, whatever is shorter, of the first study drug intake for this current AML relapse after alloHSCT, except hydroxyurea to control peripheral cell counts up to one day before study medication.
3. Active GvHD requiring systemic immunosuppression, unless controlled with low dose steroids equivalent to a maximum of 10 mg methylprednisolone per day.
4. Chronically impaired renal function (estimated creatinine clearance < 30 ml/min).
5. Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 3.0 x ULN), if not caused by leukemic infiltration.
6. Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.
7. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
8. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
9. Irreversible cardiac arrhythmias requiring permanent medication.
10. Uncontrolled hypertension.
11. Ischemic peripheral vascular disease (Grade IIb-IV).
12. Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative retinopathy.
13. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 4 weeks of administration of study treatment.
14. Pregnancy or breast-feeding.
15. Requirement of chronic administration of corticosteroids. However, low dose corticosteroids (maximum 10 mg methylprednisolone or equivalent per day when administered for GVHD) are allowed.
16. Presence of active and uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
17. Known active or latent tuberculosis (TB).
18. Known hereditary fructose intolerance.
19. Concurrent malignancies other than AML (except basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the patient has been disease-free for at least 2 years.
20. Concomitant treatment with angiogenesis inhibitors or other drugs with proven anti-leukemic activity.
21. Prior treatment with CD33 antibody.
22. Serious, non-healing wound, ulcer or bone fracture.
23. Allergy to study medication or excipients in study medication.
24. Concurrent use of other anti-cancer treatments or agents.
25. Failure to fulfil inclusion criteria.