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SNCTP000003955 | EUCTR2019-003686-17 | BASEC2020-00698

Eine prospektive Phase I-IIa, offene Multizenterstudie zur Prüfung der Sicherheit und Wirksamkeit von oNKord®, eines standardisierten, ex vivo-kultivierten allogenen natürlicher Killerzellen (NK)-Zellpräparats, bei Personen mit akuter myeloischer Leukämie, die sich in vollständiger morphologischer Remission mit messbarer Resterkrankung befinden und bei denen keine deutliche Indikation für eine Stammzelltransplantation vorliegt.

Data source: BASEC (Imported from 20.10.2020), WHO (Imported from 18.10.2020)
Changed: 18.10.2020
Disease category: Leukemia

Brief description of trial (Data source: BASEC)

Die Studie untersucht oNKord®, eine neue Therapieform für Personen mit akuter myeloischer Leukämie (AML), die bereits gegen AML behandelt wurden, aber nach wie vor Krebszellen aufweisen und bei denen eine Blutstammzelltransplantation nicht möglich oder nicht angeraten ist. oNKord® stellt allenfalls eine wirksame Möglichkeit dar, die verbleibenden Krebszellen bei Personen mit AML zu beseitigen, die keine Blutstammzelltransplantation erhalten Diese Studie soll die Sicherheit von oNKord® prüfen, wenn das Medikament in 1, 2 oder 3 Dosen verabreicht wird.

Health conditions investigated (Data source: BASEC)

Das Zielkollektiv besteht aus akuter myeloischer Leukämie (AML)-Patienten in vollständiger morphologischer Remission mit messbare Resterkrankung , bei denen eine Blutstammzelltransplantation keine geeignete oder keine bevorzugte Option ist.

Health conditions (Data source: WHO)

acute myeloid leukaemia
MedDRA version: 21.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000004864;Therapeutic area: Diseases [C] - Cancer [C04]

Rare disease (Data source: BASEC)

Yes

Intervention investigated (e.g. drug, therapy or campaign) (Data source: BASEC)

Diese Studie der Phase I-IIa ist dafür ausgelegt, die Sicherheit, Verträglichkeit und Wirksamkeit der mehrmaligen Anwendung von oNKord® nach nicht-myeloablativer Cy/Flu-Konditionierung bei erwachsenen AML-Patienten (≥ 18 Jahre alt) in CMR mit MRD und ohne starke Indikation für eine allogene HSCT zu bewerten.
oNKord® stellt den Wirkstoff und das Prüfpräparat (IMP) dar.
oNKord® ist ein seriell hergestelltes kryokonserviertes Präparat aus ex vivo kultivierten allogenen NK-Zellen für die adoptive Immuntherapie, die kein Matching der humanen Leukozytenantigene (Human Leukocyte Antigens, HLA) erfordert.
Insgesamt umfasst die Prüfbehandlung eine nicht-myeloablative Konditionierung bestehend aus Cyclophosphamid (Cy) und Fludarabin (Flu) vor der Infusion von oNKord® in Kombination mit bis zu drei oNKord®-Infusionen. Diese Prüfbehandlung insgesamt wird Teil der Sicherheitsprüfung in dieser Studie sein.
Das Dosierungsregime von oNKord® nach einer vorhergehenden nicht-myeloablativen Konditionierung wurde in der Phase-I-Studie PMLA25 mit oNKord®-Einzelinfusionen von bis zu 30 x 106 NK-Zellen/kg festgelegt.
Es ist geplant, bis zu drei Wiederholungsdosen im Abstand von vier Tagen zu infundieren, was eine maximale kumulative Dosis von 3 x 325 – 1.000 x 106 viablen NK-Zellen ergibt.
Es wird erwartet, im Zielkollektiv einen klinischen Nutzen im Zusammenhang mit einer anhaltenden Exposition gegenüber den in oNKord® enthaltenen NK-Zellen zu erzielen, insbesondere in Bezug auf die MRD, einem Surrogatendpunkt für die Bewertung des Überlebens. Das Zielkollektiv besteht aus AML-Patienten in CMR mit MRD, bei denen eine allogene HSCT keine geeignete oder keine bevorzugte Option ist. Bei den Patienten dieser Gruppe besteht ein erheblicher medizinischer Bedarf, da ihr Rezidivrisiko hoch ist, eine allogene HSCT, die derzeit einzige verfügbare kurative Behandlung bei AML, bei ihnen aber nicht infrage kommt. Ein adoptiver Transfer unter Verwendung von seriell hergestellten Effektor-Immunzellen, also z. B. NK-Zellen, ist ein vielversprechender Ansatz bei der AML, da er eine Erweiterung der Optionen für eine zelluläre Immuntherapie über eine HSCT hinaus ermöglicht.

Interventions (Data source: WHO)


Product Name: oNKord®
Pharmaceutical Form: Infusion
INN or Proposed INN: ALLOGENEIC EX VIVO-GENERATED NATURAL KILLER CELLS FROM CD34+ UMBILICAL CORD BLOOD PROGENITOR CELLS
Other descriptive name: ALLOGENEIC EX VIVO-GENERATED NATURAL KILLER CELLS FROM CD34+ UMBILICAL CORD BLOOD PROGENITOR CELLS
Concentration unit: Other
Concentration type: range
Concentration number: 325000000-1000000000

Criteria for participation in trial (Data source: BASEC)

Patienten
1. mit diagnostizierter akuter myeloischer Leukämie( AML) die nach einem oder zwei Zyklen einer Remissionsinduktionschemotherapie eine vollständiger morphologischer Remission erreicht haben, mit Dokumentation einer messbare Resterkrankung beim Screening
2. älter als 18 Jahre sein und eine Restlebenszeit von mindestens 6 Monaten haben
3. über funktionierende Nieren und eine funktionierende Leber verfügen

Exclusion criteria (Data source: BASEC)

1. Patienten, bei denen eine Blutstammzelltransplantation geplant ist,
2. Patienten, die bereits eine Blutstammzelltransplantation erhalten haben.
3. Patienten mit akuter Promyelozytenleukämie.

Inclusion/Exclusion Criteria (Data source: WHO)

Inclusion criteria:
To be eligible to participate in this trial, subjects must meet ALL of the following eligibility criteria:
1.Male or female subjects = 18 years old
2.Subjects with a diagnosis of AML and related precursor neoplasms according to the WHO 2016 classification (excluding acute promyelocytic leukaemia), including secondary AML after an antecedent haematological disease (e.g. myelodysplastic syndrome) and therapy-related AML
3.Subjects who have achieved CMR, including CRi and complete clinical remission, with MRD documented at screening, as assessed by centralized MFC, after one or two courses of remission induction chemotherapy and who have completed consolidation chemotherapy or who achieved CMR with documented MRD with hypomethylating agents or other relevant appropriate therapies
4.Life expectancy = 6 months at screening
5.Adequate renal and hepatic functions within 14 days of study screening, unless clearly disease related, as indicated by the following laboratory values:
a.Serum creatinine = 3 times the upper limit of normal (ULN) and estimated glomerular filtration rate (eGFR) = 30 ml/min/1.73m2
b.Serum total bilirubin < 2.0 mg/dl, unless due to Gilbert’s syndrome
c.Alanine transaminase (ALT) = 2.5 x ULN
6.Karnofsky Status = 50%
7.Male subjects with partners who are women of childbearing potential must use an effective contraceptive method during the trial and for a minimum of 6 months after trial treatment, or have undergone successful vasectomy at least 6 months prior to entry into the trial (confirmed by semen analysis).
8.Female subjects of childbearing potential must have a negative serum pregnancy test at screening and agree to use an effective contraceptive method during the trial and for a minimum of 6 months after trial treatment.
9. Able to understand and willing to provide written informed consent
to participate in the trial
10. Affiliation to a national health insurance scheme (according to
applicable local requirements)

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 17
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 16

Exclusion criteria:
Subjects who meet any of the following criteria at screening will be excluded from trial entry:
1.Subjects proceeding to allogeneic HSCT, i.e. subject is a suitable candidate for allogeneic HSCT according to the investigator's assessment and donor is expected to be available in a timely manner
2.Subjects having received prior allogeneic HSCT
3.Subjects with acute promyelocytic leukaemia
4.Diagnosis of any previous or concomitant malignancy is an exclusion criterion, except when the subject completed treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 6 months prior to enrolment
5.Blast crisis of chronic myeloid leukaemia
6.Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, uncontrolled hypertension, active or uncontrolled infection) including abnormal laboratory values, that could compromise compliance with the trial protocol or cause unacceptable safety risks
7.Antibodies against HLA (anti-HLA) present
8.Seronegativity for Epstein-Barr Virus (EBV)
9.Known allergy to any of the components of oNKord® (e.g., dimethyl sulfoxide [DMSO]) or to any of the drugs to be administered in the preparative regimen to oNKord® infusion
10.Contraindication to any of the drugs to be administered in the conditioning regimen or oNKord® infusion. This includes Cy, Flu, and medications associated with prophylaxis of AEs
11.Cardiac dysfunction as defined by:
a.Myocardial infarction within the last 3 months of trial entry, or
b.Reduced left ventricular function with an ejection fraction < 40% as measured by multi-gated acquisition (MUGA) scan or echocardiogram (echo) within 28 days before screening, or
c.Unstable angina, or
d.New York Heart Association (NYHA) Class IV congestive heart failure, or
e.Unstable cardiac arrhythmias
12.Pulmonary dysfunction as defined by oxygen saturation < 90% on room air. Pulmonary function test (PFT) is required only in the case of symptomatic or prior known impairments within 28 days before screening - with pulmonary function < 50% corrected diffusing capacity of the lung for carbon monoxide (DLCO) and forced expiratory volume in 1 second (FEV1)
13.Major surgery within 4 weeks prior to screening or a major wound that has not fully healed
14.Vaccination with live, attenuated vaccines within 4 weeks prior to screening
15.Immunosuppressive drugs for concomitant disease. Subject must be able to be off prednisone or other immunosuppressive medications for at least 3 days prior to the start of Cy/Flu regimen
16.History of stroke or intracranial haemorrhage within 6 months prior to screening
17.Active infections (viral, bacterial or fungal) that requires specific therapy. Acute anti-infectious therapy must have been completed within 14 days prior to trial treatment
18.History of human immunodeficiency virus (HIV) or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
19.Current concomitant chemotherapy, radiation therapy, or immunotherapy
20.Positive pregnancy test or breastfeeding for women of childbearing potential
21.Participation in another interventional clinical trial within 4 weeks prior to trial enrolment or participation in a concomitant interventional clinical trial
22.Any serious concomitant medical condition, medication or therapy which could, in the opinion of the Investigator, compromise participation in the trial
23. Subjects under legal protection measure (guardianship,

Further information on the trial in WHO primary registry

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-003686-17

Further information on the trial from WHO database (ICTRP)

http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2019-003686-17-DE

Further information on trial

Date trial registered

27.04.2020

Incorporation of the first participant

27.08.2020

Recruitment status

Authorised-recruitment may be ongoing or finished

Academic title (Data source: WHO)

A prospective phase I/IIa, open-label, multicentre trial to evaluate the safety and efficacy of oNKord®, an off-the-shelf, ex vivo-cultured allogeneic NK cell preparation, in subjects with acute myeloid leukaemia who are in complete morphologic remission with measurable residual disease and without a strong indication for stem cell transplantation.

Type of trial (Data source: WHO)

Interventional clinical trial of medicinal product

Design of the trial (Data source: WHO)

Controlled: no
Randomised: no
Open: yes
Single blind: no
Double blind: no
Parallel group: no
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: no
Placebo: no
Other: no
Number of treatment arms in the trial: 1

Phase (Data source: WHO)

Human pharmacology (Phase I): yesTherapeutic exploratory (Phase II): yesTherapeutic confirmatory - (Phase III): noTherapeutic use (Phase IV): no

Primary end point (Data source: WHO)

Main Objective: The primary objectives are:
•The primary safety objective is to evaluate the safety and tolerability of up to three infusions of oNKord®
•The primary efficacy objective is to assess the cumulative incidence of MRD response, following the infusion of oNKord® at the RP2D


;Secondary Objective: The secondary objectives are:
•In Stage A, to determine the RP2D of oNKord®
•To evaluate the safety and tolerability of the overall trial treatment (combination of the Cy/Flu conditioning regimen and up to three oNKord® infusions)
•To further assess the efficacy of the overall trial treatment (combination of the Cy/Flu conditioning regimen and oNKord® at RP2D) on EFS, duration of MRD response, CIR and OS
•To evaluate the effect of the overall trial treatment (combination of the Cy/Flu conditioning regimen and oNKord® at RP2D) on quality of life (QoL)

;Primary end point(s): Safety and Tolerability:
To evaluate the safety and tolerability of oNKord® using the cumulative incidence of the adverse events of special interest (AESI), including:
•Grade 3-to 4 infusion-related toxicity of oNKord®, as rated by the National Cancer Institute (NCI)’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
•Acute GVHD grade III and IV
•CRS = Grade 2, as rated by the ASTCT Consensus Grading for Cytokine Release Syndrome
•ICANS = Grade 2, as rated by the ASTCT Consensus Grading for Neurologic Toxicity Associated with Immune Effector Cells (see Appendix C)
Efficacy:
To evaluate the efficacy of oNKord® using:
•The cumulative incidence of MRD response as assessed by multiparameter flow cytometry (MFC) in bone marrow at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord® infusion. Subjects with responses are defined as MRD negative subjects still in CMR at any time during the follow-up period of the trial after receiving oNKord® at RP2D
;Timepoint(s) of evaluation of this end point: Safety & tolerability: at screening, D-6 D-5, D-4, D-3, D0, D1, (D5, D8,) D9, D14 + each follow-up visit
Efficacy: The cumulative incidence of MRD response at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord® infusion.

Secundary end point (Data source: WHO)

Secondary end point(s): Safety and Tolerability:
To evaluate the safety and tolerability of the overall trial treatment (Cy/Flu in combination with up to three oNKord® infusions) using the cumulative incidence of AESIs, including:
•Grade 3-to 4 infusion-related toxicity of the overall trial treatment, as rated by CTCAE v5.0
•Acute GVHD grade III and IV / Extensive chronic GVHD
•CRS = Grade 2, as rated by the ASTCT Consensus Grading for Cytokine Release Syndrome
•ICANS = Grade 2, as rated by the ASTCT Consensus Grading for Neurologic Toxicity Associated with Immune Effector Cells
•Haemorrhagic cystitis
•Death related to the overall trial treatment
•Incidence and severity of viral, fungal, and bacterial infections with onset during the first two months following conditioning initiation, including viral reactivations, and Infection Related Mortality (IRM) defined as death due to infectious disease
Efficacy:
To evaluate the efficacy of the overall trial treatment (Cy/Flu in combination with oNKord® at RP2D) by assessing:
•EFS, defined as the time from enrolment until disease relapse (morphologic and/or clinical relapse) after CMR or death due to any cause, whichever occurs first
•CIR, defined as the cumulative incidence of relapse throughout the course of the trial
•Duration of MRD response, defined as duration between MRD negativity to returning to MRD positivity, as assessed by MFC
•OS, defined as the time from enrolment until death from any cause
•Changes in QoL using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and SF-36 questionnaires, assessed at 1, 3 and 12 months post-treatment compared to baseline
Exploratory Endpoints
•Analysis of biomarkers predictive of response may include:
oAnalysis of responders and non-responders, as assessed by the efficacy primary endpoint, in relation to secondary efficacy endpoints
oTargeted DNA sequencing of commonly mutated genes in AML, performed by next generation sequencing (NGS) on bone marrow samples, compared to diagnosis tumour genetic profiling (if available), and associated to response/ non-response
oAssessment of oNKord® immunogenicity
oNumber of oNKord® infusions and corresponding enumeration of oNKord®-derived NK-cells in combination with relevant cytokine levels, including chimerism as determined by genomic assays and/or flow cytometry
oMRD negativity, baseline physical and functional conditions associated to occurrence of relapse and survival
•Determination of the biological parameters related to oNKord® derived NK-cells may include analysis of the in-vivo lifespan (immunophenotyping), cytolytic activity (persistence of oNKord® derived NK-cell functionality after infusions), and extent of oNKord® derived NK-cell expansion at multiple time points after oNKord® infusion(s)
•Cumulative incidence of molecular response on MRD as assessed by error-corrected NGS at various timepoints post oNKord® infusion(s) in bone marrow and peripheral blood
;Timepoint(s) of evaluation of this end point: Safety & tolerability: at screening, D-6 D-5, D-4, D-3, D0, D1, (D5, D8,) D9, D14 + each follow-up visit
Efficacy:
- QOL: assessed at 1, 3 and 12 months post-treatment compared to baseline
-OS: until death
-Duration MRD response at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord® infusion.
-CIR; throughout the course of the trial
-EFS: enrolment until disease relapse

Contact information (Data source: WHO)

Glycostem Therapeutics BV

Trial results (Data source: WHO)

Results summary

A prospective phase I/IIa, open-label, multicentre trial to evaluate the safety and efficacy of oNKord®, an off-the-shelf, ex vivo-cultured allogeneic NK cell preparation, in subjects with acute myeloid leukaemia who are in complete morphologic remission with measurable residual disease and without a strong indication for stem cell transplantation.

Link to the results in the primary register

no information available yet

Information on the availability of individual participant data

no information available yet

Trial sites

Trial sites in Switzerland (Data source: BASEC)

Basel, Zurich

Countries (Data source: WHO)

Belgium, France, Germany, Netherlands, Switzerland

Contact for further information on the trial

Details of contact in Switzerland (Data source: BASEC)

wink
+31 20 4350 580
regulatory@sms-oncology.com

Contact for general information (Data source: WHO)

Pavlina Topalova
Walaardt Sacréstraat 401-403
SMS-oncology
00310204350580
regulatory@sms-oncology.com

Contact for scientific information (Data source: WHO)

Pavlina Topalova
Walaardt Sacréstraat 401-403
SMS-oncology
00310204350580
regulatory@sms-oncology.com

Principal Sponsor/Investigator

Principal sponsor (Data source: WHO)

Glycostem Therapeutics BV

Authorisation by the ethics committee (Data source: BASEC)

Name of the authorising ethics committee (for multicentre studies only the lead committee)

Ethikkommission Nordwest- und Zentralschweiz EKNZ

Date of authorisation by the ethics committee

15.06.2020

Further trial identification numbers

Trial identification number of the ethics committee (BASEC-ID) (Data source: BASEC)

2020-00698

Secondary ID (Data source: WHO)

WiNK
SMS-0341