This open-label Phase I study aims at assessing primarily the safety of the NKR-2 treatment administered after a non-myeloablative preconditioning regimen in r/r AML/MDS patients. This Phase I study will contain two different sequential segments. The first segment will determine the recommended investigational treatment option (schedule of preconditioning and NKR-2 dose) and the second segment will expand to a larger number of r/r AML/MDS patients.
This open-label Phase I/II study aims at assessing primarily the safety and the clinical activity of the NKR-2 treatment administered after a non-myeloablative preconditioning regimen in r/r AML/MDS patients. The Phase I part of the study will contain two different sequential segments. The first segment (dose escalation segment) will determine the recommended investigational treatment option (schedule of preconditioning and NKR-2 dose) and the second segment (extension segment) will expand to a larger number of r/r AML/MDS patients. The Phase II part of the study will also contain two sequential segments, assessing the clinical activity of the NKR-2 treatment administrated as per the recommended investigational treatment option (schedule of preconditioning and NKR-2 dose). The Phase I dose escalation segment will evaluate the preconditioning regimen consisting in cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily (CYFLU) administrated 3 consecutive days at a specific interval prior to the NKR 2 administration. This segment is divided into four sequential cohorts to evaluate respectively: * Two different intervals between the preconditioning regimen and the NKR-2 administration i.e. NKR-2 administered 3 days (T3) or 7 days (T7) after the end of the preconditioning regimen, * Three different NKR-2 dose-levels i.e. dose-level 1 (1x108 NKR 2/injection), dose-level 2 (3x108 NKR-2/injection) and dose-level 3 (1x109 NKR-2/injection). The Phase I extension segment will enroll more r/r AML/MDS patients (to reach 9 evaluable patients in total) to further evaluate the recommended NKR-2 dose (1x108, 3x108 or 1x109 NKR-2/injection) administered at the recommended interval (T3 or T7) after the CYFLU preconditioning. The Phase II will enroll more r/r AML/MDS patients (13 patients in total in the segment 1 and 30 new patients in the segment 2) to further evaluate the recommended NKR-2 dose (1x108, 3x108 or 1x109 NKR-2/injection) administered at the recommended interval (T3 or T7) after the CYFLU preconditioning to assess the clinical activity. Each patient will receive a single administration of NKR-2 following the preconditioning regimen. Depending on the clinical response as evaluated at the first tumor assessment, scheduled three weeks after NKR-2 administration, three situations may arise: * If the patient is presenting a complete remission, partial remission, or stable disease, and meets all criteria for a consolidation cycle, then three new injections of NKR-2 at the recommended dose defined in the ongoing THINK study (THINK RecD), without prior preconditioning, will be administered with a two weeks interval, * If the patient is in PD, or does not meet all criteria for the consolidation cycle he/she will not receive any other NKR-2 injection but will follow other visits as scheduled. For each patient who received at least one NKR-2 administration, the overall study duration will be 15 years after first NKR-2 administration. The duration of the administration phase and treatment follow-up will be 24 months. Patients will be asked to complete a total of maximum 20 visits during the treatment administration phase, and maximum 6 visits during the treatment follow-up phase. During the long-term safety follow-up, yearly visits will be scheduled (up to Y15). Rationale for the study: NKR-2 has the potential to treat many distinct tumor-types because of a broad expression and important prevalence of the NKG2D ligands expression in various tumor types including in r/r AML/MDS. This Phase I study will explore the hypothesis that the administration of modified T-cells targeting NKG2D-ligands expressed by AML/MDS cells, after a prior nonmyeloablative preconditioning treatment, in patients refractory to and/or relapsing after prior therapies, is safe and, considering the poor outcomes and lack of therapeutic strategies for this patient population, may have a strategic advantage over current approaches and provide potential clinical benefit. Objectives of the study: Primary To document and characterize: * The safety of the NKR-2 treatment administration in r/r AML/MDS patients after a non-myeloablative preconditioning. (Phase I part) * The objective response rate (ORR) post the first NKR-2 administration. (Phase II part) Secondary To document and characterize: * The NKR-2 peripheral blood kinetics post-administration, * Indicators of clinical activity, * Additional indicators of safety.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
21
This Phase I study will explore the hypothesis that the administration of modified T-cells targeting NKG2D-ligands expressed by AML/MDS cells, after a prior nonmyeloablative preconditioning treatment, in patients refractory to and/or relapsing after prior therapies, is safe and, considering the poor outcomes and lack of therapeutic strategies for this patient population, may have a strategic advantage over current approaches and provide potential clinical benefit.
University of Colorado
Aurora, Colorado, United States
H. Lee Moffitt Cancer Center and Research Institute Hospital, Inc.,
Tampa, Florida, United States
Emory University
Atlanta, Georgia, United States
New York School of Medicine
New York, New York, United States
The occurrence of Dose-limiting toxicities (DLT) during the study treatment until 3 weeks after first NKR-2 study treatment administration.
Dose-limiting toxicity refers to a specific adverse event that is experienced during treatment and until 3 weeks after first NKR-2 dose administration, is new and at least possibly related to NKR-2 study treatment administered following a preconditioning regimen
Time frame: during the study treatment until 3 weeks after first NKR-2 study treatment administration.
The NKR-2 cell kinetics endpoint of this Phase I study is: The evaluation of the circulating NKR-2 peripheral blood kinetics post-administration.
NKR-2 detection in peripheral blood-isolated PBMC will be mandatory performed until the end of the administration phase. If positive at this visit, the evaluation will be performed during the follow-period visits and until 2 sequential tests are providing "undetectable" results, suggesting a lack of the NKR-2 persistence.
Time frame: From day 1 (visit 4) until the end of the administration phase (day 85 = week 12 = Visit 22).
Additional Safety Endpoint: the occurence of Adverse Events ans Serious Adverse Events and any toxicity linked to study participation until the end of the administration phase, and until the end of the treatment follow-up
The occurrence of AEs and SAEs and any toxicity linked to study participation until the end of the administration phase, and until the end of the treatment follow-up (at Month 24 - Visit 34).
Time frame: Until the end of the administration phase, and until the end of the treatment follow-up (at Month 24 - Visit 34).
Clinical activity secondary endpoints: The incidence of CR, CRMRD-, CRi, MLFS, PR, or SD for AML patients.
The incidence of CR, CRMRD-, CRi, MLFS, PR, or SD for AML patients at Week 5, Week 12, Week 19, Month 6, Month 9, Month 12, Month 18 and Month 24 post the first NKR-2 administration,
Time frame: From week 5 until Month 24.
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Universitair Ziekenhuis Antwerpen
Antwerp, Belgium
Institute Jules Bordet
Brussels, Belgium
UZ Gent
Ghent, Belgium
Clinical activity secondary endpoints: The incidence of CR, PR, marrow CR, cytogenic response, hematologic improvement or SD for MDS patients
The incidence of CR, PR, marrow CR, cytogenic response, hematologic improvement or SD for MDS patients at Week 5, Week 12, Week 19, Month 6, Month 9, Month 12, Month 18 and Month 24 post the first NKR-2 administration
Time frame: From week 5 until Month 24.
Clinical activity secondary endpoints: The objective clinical response rate (ORR) post the first NKR-2 administration
The objective clinical response rate (ORR) post the first NKR-2 administration
Time frame: From week 5 until Month 24.
Clinical activity secondary endpoints:The duration of response for patients with objective clinical response
The duration of response for patients with objective clinical response
Time frame: From week 5 until Month 24.
Clinical activity secondary endpoints: The ORR among subjects retreated with NKR-2.
The ORR and duration of second response among subjects retreated with NKR-2.
Time frame: From week 5 until Month 24.
Clinical activity secondary endpoints: The duration of second response among subjects retreated with NKR-2.
The ORR and duration of second response among subjects retreated with NKR-2.
Time frame: From week 5 until Month 24.
Clinical activity secondary endpoints: The overall survival (OS) from the study enrollment.
The overall survival (OS) from the study enrollment.
Time frame: From study enrollment until Month 24.
Clinical activity secondary endpoints: The relapse-free survival (RFS) from the study enrollment
The relapse-free survival (RFS) from the study enrollment
Time frame: From study enrollment until Month 24.
Clinical activity secondary endpoints: The event-free survival (EFS) from the study enrollment.
The event-free survival (EFS) from the study enrollment.
Time frame: From study enrollment until Month 24.
Clinical activity secondary endpoints: The cumulative incidence of relapse (CIR)
The cumulative incidence of relapse (CIR)
Time frame: From study enrollment until Month 24.
Clinical activity secondary endpoints: The cumulative incidence of death (CID)
The cumulative incidence of death (CID)
Time frame: From study enrollment until Month 24.
Clinical activity secondary endpoints: The non-relapse mortality (NMR) rate.
The non-relapse mortality (NMR) rate.
Time frame: From study enrollment until Month 24.
Mandatory correlative studies of this study are: The NKR-2 kinetics post-injection in the bone marrow.
The aim of this specific research is to identify the presence of NKR-2 within and its kinetics post-administration according to the dose and preconditioning chemotherapy regimen. Genomic DNA isolated from these samples will be evaluated by qPCR using a validated assay (VCN) that detects a DNA signature unique to the NKR-2 transgene.
Time frame: From week 5 until month 24
Mandatory correlative studies of this study are: Characterization of systemic cytokine level release post NKR-2 administration.
One of the key effector functions of NKR-2 is the release of soluble cytokines during antigen engagement. Consequently, a surrogate marker of NKR-2 in vivo activity is potentially raised levels of cytokines relevant to T cell activation within the peripheral circulation.
Time frame: From day 1 until day 134 (week 19)
Mandatory correlative studies of this study are: The evaluation of NKG2D ligand expression in patients' tumor cells prior to and after treatment.
The research will evaluate NKG2D ligand expression in patient tumor samples. The aim of this project is to establish whether a correlation can be drawn between with the level of NKG2D ligand tumoral expression and NKR-2 activity.
Time frame: From day 1 until day 134 (week 19)
Mandatory correlative studies of this study are: The evaluation of NKG2D ligand expression in patients' peripheral mononuclear cells prior to and after treatment.
The research will evaluate NKG2D ligand expression in patient normal cells pre/post preconditioning chemotherapy and NKR-2 administrations. The aim of this project is to establish whether chemotherapy induce expression of NKG2D ligand expression and the possible correlation to any potential toxicity of the NKR-2 treatment.
Time frame: From day 1 until day 134 (week 19)