Clinical trial NCT02921685: Study of a Humanized Antibody Initiated 2 Months After an HLA Matched Allogenic Stem Cell Transplantation
Official title: A Phase 1 Study of MONALIZUMAB (IPH2201), a Humanized Anti CD94/NKG2A Monoclonal Antibody (Mab) Initiated 2 Months After an HLA Matched Allogenic Stem Cell Transplantation (SCT) Prepared With a Reduced Intensity Conditioning
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Hematologic Malignancies
Lead sponsor: Institut Paoli-Calmettes
Sponsor class: OTHER
Collaborators: name: Innate Pharma
First posted: 2016-10-03
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will determine the Maximal Tolerated Dose if any and the recommended dose for phase 2 of monalizumab, a monoclonal antibody directed against the CD94/NKG2A receptor, after allogenic stem cell transplantation. All patients will receive one single intravenous administration of one of the four doses of monalizumab.

Detailed description: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative option for most of hematological malignancies, though the graft-versus-tumor (GVT) effect mediated by immune cells from the donor. However, the use of Allo-HSCT is limited by its toxicity, notably the graft-versus-host disease (GVHD) that is a major cause of non-relapse mortality (NRM). Conditioning regimens dramatically improved during the last fifteen years, with a decrease of both GVHD and NRM rates. Now, disease recurrence after Allo-HSCT is the first cause of treatment failure and remains a concern for approximately 30% of the patients.

Based on a safety immunologic platform (ATG based reduced toxicity conditioning regimens), it is needed to develop post Allo-HSCT strategies to decrease the incidence of relapse. In this context, the modulation of immune cell activity could play a role to prevent relapse. NK cells have a unique capacity to exert potent GVT effects without inducing GVHD. Moreover, NK cells recovery occurs early after Allo-HSCT and NK cells function are not severely impaired by the use of ciclosporin A, that is given for few months after Allo-HSCT as GVHD prophylaxis. Thus, NK cell modulation appears as a viable option for early immune intervention after Allo-HSCT.

Monalizumab (IPH2201), a monoclonal antibody has a non-depleting and purely blocking activity directed with high affinity and specificity against the CD94/NKG2A receptor expressed by subsets of NK cells, activated αβ CD8+ T cells, γδ-T cells and NK T cells. By suppressing the inhibitory signal transduced by NKG2A, IPH2201 enhances the anti-tumor functions, including cytolytic activity of these immune effector cells.The aim of the study is to determine the safety of IPH2201 after allogenic stem cell transplantation.

Eligibility criteria: Inclusion Criteria:

1. Patients presenting a hematological malignancy (acute myeloid leukemia, acute lymphoblastic leukemia, High risk R-IPSS myelodysplastic syndromes, multiple myeloma, chronic lymphoid leukemia, chronic myeloid leukemia, myeloproliferative neoplasm, Hodgkin lymphoma or Non-Hodgkin lymphoma) treated by allogeneic HSCT according to the following parameters :

   * Donor : HLA matched related or unrelated (10/10) donor
   * Graft : peripheral blood stem cells
   * Conditioning : All types of conditioning reduced toxicity conditioning regimens ATG as in-vivo T-cell depletion
   * GVHD prophylaxis by cyclosporine, still ongoing at full dose at the time of the inclusion
2. Patient being in one of the following post-graft situation at the time of inclusion:

   * Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) patients: in morphological complete remission (CR) with less than 5% bone marrow blast count.
   * High risk R-IPSS myelodysplastic syndromes patients: with at least marrow CR with less than 5% marrow blast count.
   * Multiple myeloma patients: in at least very good partial response.
   * Chronic Lymphoid Leukemia patients: in CR.
   * Chronic Myeloid Leukemia patients: in hematological CR.
   * Myeloproliferative neoplasm patients: no criteria for disease in acceleration phase.
   * Hodgkin lymphoma or Non-Hodgkin lymphoma patients: in CR.
3. Age ≥ 18 and ≤ 70 years
4. ECOG = 0-1 or Karnofsky index ≥ 70%
5. Clinical laboratory values at screening

   * Calculated creatinine clearance (according to MDRD) \> 50 ml/min/1.73 m2
   * Independence of red blood cell transfusion
   * Platelet count \> 75 x 109/l
   * ANC \> 1 x 109/l
   * Bilirubin \< 1.5 ULN
   * ALT and AST \< 3 ULN
6. Patients (male or female) who accept and are able to use contraceptive methods recognized as highly effective throughout the study and up to 5 months after the drug administration
7. Signed informed consent of the current clinical study, prior to any protocol-specific procedure
8. Patient affiliated to the national "Social Security" regimen or beneficiary of this regimen

Non inclusion Criteria:

1. Previous history of grade ≥ II acute GVHD (Glucksberg classification)
2. Current active disease or positive serology for HIV before grafting, and/or HCV with detectable viremia and/ or HBV with positive Hbs Antigen.
3. Abnormal cardiac status with any of the following :

   * Ejection fraction (measured by ultrasound or radionuclide imaging) \< 50%
   * Unstable angina
   * Myocardial infarction within the last 6 months
   * Presence or persistence of documented congestive heart failure (New York Heart Association functional classification III-IV)
   * Arrhythmia requiring treatment and which is not stabilized by the treatment.
   * QTc ≥ 450 ms (M) or 470 ms (F) (Bazett formula)
4. Previous other allogeneic hematopoietic transplantation or solid organ transplantation
5. Any other serious concurrent uncontrolled medical disorder within 4 weeks prior to IPH2201 administration
6. Use of systemic corticosteroids ongoing or within the last 1 week prior IPH2201 admin-istration
7. Use of any investigational agent within 3 months prior to first dosing (except procedure of conditioning regimen including registered drugs combinations, i.e. Busulfan and Fludarabine or Busulfan and Endoxan)
8. History of another malignancy (except, basal cell carcinoma of the skin, or in situ cervix carcinoma, or any other malignancy in complete remission for more than 3 years since the completion of the treatment). However in the case of leukemia or MDS a previous malignancy accountable for the present disease will not be an exclusion criteria if in complete remission for more than 2 years
9. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
10. Pregnant or lactating women

Primary outcomes:
measure: Occurence ratio of dose-limiting toxicity (DLT)
timeFrame: 4 weeks
Secondary outcomes:
measure: Incidence of acute GVHD of each grade or chronic GVHD of each degree of severity
timeFrame: from D0 to Week 26 after administration of IPH2201 and at 1 year after transplantation
measure: Probabilities of non-relapse mortality (NRM)
timeFrame: 1 year after the administration of IPH2201
measure: Cumulative incidence of relapse (CIR)
timeFrame: 1 year after administration of IPH2201.
measure: Probability of Disease Free Survival (DFS)
timeFrame: 1 year after the administration of IPH2201
measure: Probability of Overall survival (OS)
timeFrame: 1 year after the administration of IPH2201
Other outcomes:
Locations:
city: Marseille
country: France
facility: Institut Paoli Calmettes
state: Bouches Du Rhônes
Study officials:
affiliation: Institut Paoli-Calmettes
name: Didier BLAISE, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ruggeri L, Urbani E, Andre P, Mancusi A, Tosti A, Topini F, Blery M, Animobono L, Romagne F, Wagtmann N, Velardi A. Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells. Haematologica. 2016 May;101(5):626-33. doi: 10.3324/haematol.2015.135301. Epub 2015 Dec 31.
citation: Godal R, Bachanova V, Gleason M, McCullar V, Yun GH, Cooley S, Verneris MR, McGlave PB, Miller JS. Natural killer cell killing of acute myelogenous leukemia and acute lymphoblastic leukemia blasts by killer cell immunoglobulin-like receptor-negative natural killer cells after NKG2A and LIR-1 blockade. Biol Blood Marrow Transplant. 2010 May;16(5):612-21. doi: 10.1016/j.bbmt.2010.01.019. Epub 2010 Feb 6.
citation: Rathmann S, Glatzel S, Schonberg K, Uhrberg M, Follo M, Schulz-Huotari C, Kaymer M, Veelken H, Finke J, Fisch P. Expansion of NKG2A-LIR1- natural killer cells in HLA-matched, killer cell immunoglobulin-like receptors/HLA-ligand mismatched patients following hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2010 Apr;16(4):469-81. doi: 10.1016/j.bbmt.2009.12.008. Epub 2010 Jan 4.
citation: Pical-Izard C, Crocchiolo R, Granjeaud S, Kochbati E, Just-Landi S, Chabannon C, Frassati C, Picard C, Blaise D, Olive D, Fauriat C. Reconstitution of natural killer cells in HLA-matched HSCT after reduced-intensity conditioning: impact on clinical outcome. Biol Blood Marrow Transplant. 2015 Mar;21(3):429-39. doi: 10.1016/j.bbmt.2014.11.681. Epub 2015 Jan 9.