This open-label Phase I study aims to define the recommended dose for further clinical
development the NKR-2 treatment administered concurrently with AZA in treatment-naïve AML/MDS
patients not candidates for intensive chemotherapy or hematopoietic stem cell
transplantation.
This Phase I study is divided into three sequential cohorts evaluating three different
dose-levels of NKR-2 (1x108, 3x108 and 1x109 NKR-2 per injection) using a 3+3 design
evaluate. Further patients will be enrolled at the RecD to reach 9 evaluable patients in
total at the RecD.
The study consists of a screening phase, a treatment administration phase and a follow-up
phase divided into treatment follow-up (TFU) and long-term safety follow-up (LTSFU). For each
patient who received at least one NKR-2 administration, the overall study duration will be 15
years after first NKR-2 administration.
This open-label Phase I study aims to define the recommended dose for further clinical
development the NKR-2 treatment administered concurrently with AZA in treatment-naïve AML/MDS
patients not candidates for intensive induction chemotherapy. The treatment consists in six
consecutive cycles of AZA, administered at days
1. to 7 of a 28-day cycle. Patients will be treated with 8 injections of NKR-2 at day 9 and
23 of AZA cycles 2-3-4 and 5.
This Phase I study is divided into three sequential cohorts evaluating three different
dose-levels of NKR-2 (1x108, 3x108 and 1x109 NKR-2 per injection) using a 3+3 design.
Further patients will be enrolled at the RecD to reach 9 evaluable patients in total at
the RecD. The study consists of a screening phase, a treatment administration phase and
a follow-up phase divided into treatment follow-up (TFU) and long-term safety follow-up
(LTSFU). For each patient who received at least one NKR-
2. administration, the overall study duration will be 15 years after first NKR-
2 administration. Patients will be asked to complete a total of 54 visits during the
treatment administration phase, and 5 visits during the treatment follow-up phase. During the
LTSFU, yearly visits will be scheduled (up to Visit Y15).
1. The patient must have signed the written ICF and must accept that, beyond the
treatment period, and the treatment follow-up period, he/she will have to be monitored
for a Long-Term Safety Follow-Up (LTSFU) for up to 15 years after enrollment.
2. Both men and women of all races and ethnic groups are eligible.
3. The patient must be ≥ 18 years old at the time of signing the ICF.
4. The patient must be treatment-naïve with a confirmed diagnosis of either:
4.a. WHO-confirmed de novo or secondary acute myeloid leukemia (AML) with intermediate- or
adverse-risk cytogenetics. Note: Patient with AML M3 are excluded. or 4.b. WHO-confirmed
myelodysplastic syndrome (MDS) with Revised International Prognostic Scoring System
(R-IPSS) criteria [97] for Intermediate, High-risk or Very High-risk (High-grade) disease
or refractory anemia with excess blasts (RAEB-1 and RAEB-2).
5. The patient is not eligible for intensive induction chemotherapy. Note: The patient is
defined as not eligible for intensive induction chemotherapy on the basis of Investigator's
assessment of age, ECOG performance status, comorbidities, regional guidelines, or
institutional practice, or all these.
6. The white blood cell-count should be <15x109 cells/L prior to 1st infusion of NKR-2.
Note: Use of hydroxyurea (up to C1-D10) is permitted to achieve this concentration (see
Section 6.4).
7. The absolute bone marrow blast count should be > 5%. 8. The patient must have an Eastern
Cooperative Oncology Group (ECOG) performance status ≤ 2. Note: Patient with anemia
resulting in an ECOG performance status 3 is also eligible.
9. The patient must have adequate hepatic and renal functions described in Table 1, as
assessed by standard laboratory criteria (with LLN/ULN being the lower/upper limit of
normal, respectively): Serum creatinine ≤ 2.0 mg/dL Calculated creatinine clearance > 60
ml/min Total serum bilirubin ≤ 2.0 x ULN Or ≤ 3.0 x ULN with direct bilirubin within normal
range in patients with well documented Gilbert's Syndrome, hemolysis or transfusion
dependence ALT ≤ 3 x ULN AST ≤ 3 x ULN ALT: alanine aminotransferase; AST: aspartate
aminotransferase; ULN: upper limit of normal 10. The patient must have a left ventricular
ejection fraction (LVEF) of ≥ 40%, as determined by echocardiography or a multigated
acquisition (MUGA) scan.
11. The patient must have a good pulmonary function with a Forced Expiratory Volume in the
first second (FEV-1)/Forced Vital Capacity (FVC) ≥ 0.7 with FEV-1 ≥ 50% predicted as
determined by the spirometry performed at baseline (see Section 7.2.7), unless related to
the AML/MDS disease as judged by the Investigator.
12. Women of child-bearing potential and men must agree to use effective contraception
before, during and for at least 2 months after the last study treatment administration.
Notes: Adequate contraception is defined as methods of birth control that, alone or in
combination, result in a low failure rate (i.e., less than 1% per year) when used
consistently and correctly. These include established use of oral, injected or implanted
hormonal methods of contraception; placement of an intrauterine device or intrauterine
system; male sterilization, true abstinence (when this is in line with the preferred and
usual lifestyle of the patient).Women of non-childbearing potential may be enrolled in the
study. Non-childbearing potential is defined as the consequence of hysterectomy,
ovariectomy or post-menopause.
13. The patient must, in the opinion of the Investigator, be able to adhere with the study
visit schedule and all study procedures described in this protocol.
Exclusion criteria
The patients may not be included in the study if one or more of the following criteria is
met:
1. Patients with confirmed or history of tumor involvement in the central nervous system
(CNS).
2. Patients who have received any prior AML/MDS therapy (investigational agent or not).
Note: Patients are authorized to receive hydroxyurea according to specific conditions
as detailed in Section 6.4.
3. Patients who are planned to receive, concurrently receiving or have received any
investigational agent within 3 weeks before the planned day for the first NKR-2
administration.
4. Patients who are under systemic immunosuppressive drugs, unless specific cases
authorized per protocol (see Section 6.4).
5. Presence of any indwelling catheter or drain (e.g., percutaneous nephrostomy tube,
indwelling foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter)
may be permissible unless they have a catheter-associated infection that cannot be
cleared with antibiotics. Ommaya reservoirs and dedicated central venous access
catheters such as a Port-a-Cath, peripherally inserted central catheter, or Hickman
catheter are permitted.
6. Patients who underwent major surgery within 4 weeks before the planned day for the
first NKR-2 administration. Note: Placement of vascular access device is authorized
until 10 days before the planned day for the first NKR-2 administration.
7. Patients who have received a live vaccine ≤ 6 weeks prior to each NKR-2
administration.
8. Patients with uncontrolled intercurrent illness or serious uncontrolled medical
disorder including, but not limited to evidence of active pneumonitis on screening
chest imaging, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia history (or evidenced after the electrocardiogram planned at screening)
and/or pronounced disturbances of the electrical conduction system of the heart, or
significant thromboembolic events.
9. Patients with significant disorder of coagulation or receiving treatment with warfarin
derivatives or heparin.
Note: Patients receiving systemic individual doses of low molecular weight heparin
outside 24 hours prior to each NKR-2 administration are eligible.
10. Patients who have active infections including, but not limited to viral, bacterial or
fungal infections necessitating use of antibiotics/antivirals/antifungal treatment
(prophylaxis is acceptable).
11. Patients who are known to be positive or screened positive for hepatitis B (HBsAg
positive) or C (anti-HCV positive).
12. Patients who are known to be positive or screened positive for the human
immunodeficiency virus (HIV).
13. Patients with a family history of congenital or hereditary immunodeficiency.
14. Patients with a history of allergic reactions or hypersensitivity attributed to Human
serum albumin, Plasma-lyte A.
15. Patients with a history of idiopathic pulmonary fibrosis, organizing pneumonia,
drug-induced pneumonitis, idiopathic pneumonitis and/or active or acute exacerbation
of chronic obstructive pulmonary disease (COPD).
16. Patients on supplemental home oxygen.
17. Patients with a history of any autoimmune disease including, but not limited to
inflammatory bowel disease (including ulcerative colitis and Crohn's Disease),
systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune
vasculitis (e.g.,Wegener's granulomatosis), CNS or motor neuropathy considered of
autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple
sclerosis). Patients with Graves disease and vitiligo will be allowed.
18. Patients with a history of a malignancy other than the one evaluated in this study,
with exception of the following circumstances:
- Patients with a history of malignancy who have been adequately treated and have
been disease-free for at least 1 year, and
- Patients with adequately treated active non-invasive cancers (such as
non-melanomatous skin cancer or in-situ bladder, cervical and breast cancers).
19. Patients with psychiatric/social situations or addictive disorders that may compromise
the ability of the patients to give informed consent or to comply with the study
procedures.