Clinical Trial: NCT04347616 - My Cancer Genome

NCT04347616

Description:

This study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia exploiting administration of ex vivo-generated allogeneic natural killer (NK) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo IL-2 cytokine support.

Related Conditions:

Acute Myeloid Leukemia

Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

URL:

https://clinicaltrials.gov/show/NCT04347616

Trial Eligibility

Document

Title

Brief Title: Natural Killer-cell Therapy for Acute Myeloid Leukemia
Official Title: Infusion of ex Vivo-generated Allogeneic Natural Killer Cells in Combination With Subcutaneous IL-2 in Patients With Acute Myeloid Leukemia: a Phase I/IIa Study

Clinical Trial IDs

ORG STUDY ID: HEMAML42
SECONDARY ID: 2019-001929-27
NCT ID: NCT04347616

Conditions

Acute Myeloid Leukemia Refractory
Acute Myeloid Leukemia, Relapsed, Adult

Interventions

Drug	Synonyms	Arms
UCB-NK cells		NK cells with higher dose IL-2
IL-2	Aldesleukin	NK cells with higher dose IL-2

Purpose

Detailed Description

      This study investigates an innovative treatment for relapsed or refractory acute myeloid
      leukemia (AML) exploiting administration of ex vivo-generated allogeneic natural killer (NK)
      cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent
      in vivo IL-2 cytokine support.

      This is a prospective phase I/IIa study. The first phase is a IL-2 dose-escalating safety
      study in nine patients. The second phase of the study is designed as a Simon's optimal
      two-stage single-arm phase IIa study, comprising eighteen patients. Prior to NK cell
      infusion, all patients will receive cyclophosphamide and fludarabine (Cy/Flu) based
      lymphodepleting chemotherapy. On day 0, all patients will receive a fixed dose of 1.0-3.0 x
      10^9 allogeneic umbilical cord blood-derived NK cells (UCB-NK cells). These cells are
      generated ex vivo from CD34+ hematopoietic progenitor cells obtained from an allogeneic UCB
      unit.

      In phase I of the study patients will receive UCB-NK cells without subcutaneous (SC) IL-2,
      with lower dose SC IL-2 or with higher dose SC IL-2 (n=3 per treatment group). After
      establishing the safety of UCB-NK cells combined with SC IL-2, we will continue with phase
      IIa of the study, with eight patients in the first stage (including the three patients from
      phase I with comparable IL-2 dose) and if clinical efficacy is achieved an additional ten
      patients in the second stage.

Trial Arms

Name	Type	Description	Interventions
NK cells without IL-2	Experimental	On day 0, patients will receive a fixed dose of 1.0-3.0 x 10^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. NK cells administration will not be followed by sc IL-2. N=3.	UCB-NK cells
NK cells with low dose IL-2	Active Comparator	On day 0, patients will receive a fixed dose of 1.0-3.0 x 10^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. IL-2 will be administered in a fixed dose of 3.0 x 10^6 units starting 4 hours after NK cell infusion and given every other day for 6 doses in total. N=3	UCB-NK cells IL-2
NK cells with higher dose IL-2	Active Comparator	On day 0, patients will receive a fixed dose of 1.0-3.0 x 10^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. IL-2 will be administered in a fixed dose of 6.0 x 10^6 units starting 4 hours after NK cell infusion and given every other day for 6 doses in total.	UCB-NK cells IL-2

Eligibility Criteria

        Inclusion Criteria:

          -  AML patients (de novo and secondary) or patients with MDS excess blasts-2 according to
             WHO criteria 2016, who have stable disease or non-rapidly progressive disease with or
             without disease controlling medication who are (at time of inclusion) ineligible for
             allo-SCT.

          -  Patients may belong to any of the following categories:

               -  Relapsed/refractory disease after treatment with intensive chemotherapy,
                  hypomethylating agents, targeted agents, autologous or allo-SCT (at least 6
                  months ago) and DLI

               -  Newly diagnosed, untreated patients ineligible for allo-SCT

        Other inclusion criteria:

          -  Age ≥ 18 years

          -  WHO performance 0-2

          -  Life expectancy of > 4 months

          -  Written informed consent

          -  Hydrea is allowed as pre-treatment to control blast count until day -3

          -  Other disease controlling medication is allowed until day -7

        Exclusion Criteria:

          -  Progressive disease according to ELN criteria in case of previous therapy

          -  Patients on immunosuppressive drugs or active GvHD

          -  Patients with active infections (viral, bacterial or fungal); acute anti-infectious
             therapy must have been completed within 14 days prior to study treatment

          -  Severe cardiovascular disease (CTCAE III-IV)

          -  Severe pulmonary dysfunction (CTCAE III-IV)

          -  Severe renal dysfunction (CTCAE III-IV)

          -  Severe hepatic dysfunction (CTCAE III-IV)

          -  Severe neurological or psychiatric dysfunction (CTCAE III-IV)

          -  Presence of anti-HLA class I antibodies

          -  Patients on concurrent chemotherapy or interferon-alpha treatment

          -  Pregnancy or breastfeeding

Maximum Eligible Age:	N/A
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Phase I: Evaluate Safety and Toxicity using the CTCAE toxicity criteria
Time Frame:	28 days
Safety Issue:
Description:	Patients will be evaluated intensively using the CTCAE toxicity criteria and graft versus host disease (GvHD) classification criteria, defining dose limiting toxicities (DLTs): 1. Any treatment-emergent non-hematologic grade 3 toxicity lasting >72 hours, except for transient constitutional symptoms, diarrhea, fatigue or skin rash not requiring systemic steroid therapy. 2. Acute GvHD >grade 2 within 6 weeks of the first IL-2 dose. If in any of the three patients of each individual cohort of the phase I study a DLT occurs, the cohort will be extended to 6 patients. If 2 patients experience DLT within a cohort of 3 or 6 patients the study will be stopped in case the patients were only receiving NK cells or the study will be continued without IL-2 or the lower dose of IL-2 in case the patients were receiving NK cells in combination with IL-2. Serious, life threatening adverse events or grade 4 toxicity will be a reason to terminate the study or continue without IL-2 cytokine support.

Secondary Outcome Measures

Measure:	Evaluation of the in vivo lifespan and expansion potential of the NK cells following adoptive transfer and IL-2 administration.
Time Frame:	28 days
Safety Issue:
Description:	We will determine the percentage and absolute number of donor-derived NK cells in peripheral blood and bone marrow after infusion using flow cytometry and DNA chimerism analysis. A positive expansion rate of the infused NK cells requires an absolute number of ≥100 donor-derived NK cells per μl blood at day +7 and/or +14.

Measure:	Exploration of the functional activity of the donor NK cells in PB and BM, with or without SC IL-2 administration.
Time Frame:	28 days
Safety Issue:
Description:	NK cells from peripheral blood and bone marrow will be obtained. These cells will be stimulated in vitro for 4 hours and subsequently the degranulation marker CD107a and immunoregulatory marker IFNy will be measured by flow cytometry. These results can be compared between patients that did receive IL-2 or did not.

Measure:	Evaluation of plasma cytokine concentrations (IL-2, IL-15, IL-7, IFN-γ, TNFα, IL-6) pre- and post-infusion of IL-2.
Time Frame:	28 days
Safety Issue:
Description:	This will be correlated with absolute lymphocyte count and in vivo NK cell persistence and expansion.

Measure:	Number of patients eligible for allo-SCT based on hematologic response
Time Frame:	28 days
Safety Issue:
Description:	Only in Phase IIa.

Details

Phase:	Phase 1/Phase 2
Primary Purpose:	Interventional
Overall Status:	Recruiting
Lead Sponsor:	Radboud University

Trial Keywords

Natural Killer cells
Acute Myeloid Leukemia
Cellular Immunotherapy

Last Updated

December 30, 2020

Clinical Trials /

Natural Killer-cell Therapy for Acute Myeloid Leukemia