Genetic Ablation of CD33 in HSC to Broaden the Therapeutic Index of CD33-directed Immunotherapy in Patients With AML

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

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NCT-Nummer:
NCT05662904

Studienbeginn:
Dezember 2023

Letztes Update:
23.12.2022

Wirkstoff:
Donor-derived CD34+ HSC with CRISPR/Cas9-mediated CD33 deletion, Gemtuzumab Ozogamicin

Indikation (Clinical Trials):
Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
German Cancer Research Center

Collaborator:
University Hospital Heidelberg, University Hospital Dresden,

Studienleiter

Tim Sauer, Dr. med.
Principal Investigator
University Hospital Heidelberg

Kontakt

Tim Sauer, Dr. med.
Kontakt:
Phone: +49 6221 56 38010
E-Mail: tim.sauer@med.uni-heidelberg.de» Kontaktdaten anzeigen

Carsten Müller-Tidow, Prof. Dr. med.
Kontakt:
E-Mail: carsten.mueller-tidow@med.uni-heidelberg.de» Kontaktdaten anzeigen

Studienlocations
(2 von 2)

University Hospital Dresden, Department of Medicine I
01307 Dresden
(Sachsen)
Germany» Google-Maps
Ansprechpartner:
Martin Bornhäuser, Prof. Dr. med.» Ansprechpartner anzeigen

University Hospital Heidelberg, Internal Medicine V
69120 Heidelberg
(Baden-Württemberg)
Germany» Google-Maps
Ansprechpartner:
Tim Sauer, Dr. med.» Ansprechpartner anzeigen

Studien-Informationen

Detailed Description:

CRISPR/Cas9-mediated inactivation of CD33 in hematopoietic stem cells (HSC) may broaden the

therapeutic index of CD33-directed immunotherapy for patients with AML by rendering healthy

hematopoietic stem and progenitor cells (HSPC) resistant to escalating doses and/or shorter

dosing intervals of the CD33-specific antibody-drug conjugate (ADC) Gemtuzumab-ozogamicin

(GO).

In this proof of concept trial, we will develop a platform for genome editing of CD34+ HSC

and demonstrate the feasibility, safety and efficacy of this approach for targeted therapy of

AML.

Upon implementation, the platform shall be used for innovative clinical trials in diverse

types of cancer. Outside of leukemias, autologous HSC could be used to ease the procedure.

Patients with relapsed AML after allogeneic hematopoietic stem cell transplantation will be

transplanted with CD33-deleted CD34+ HSC derived from the initially matched family donor.

Upon HSC engraftment, patients will be treated with escalating doses of the anti-CD33

antibodydrug conjugate Gemtuzumab-Ozogamicin (GO). A conditioning regimen containing GO

(d-14, d-11, d-8),Fludarabine 30 mg/m2 (d-6 to d-3) and Melphalan 140mg/m2 (d-2) is used

prior to transplantation.

The clinical trial will be conducted at two trial sites in the University Hospitals in

Heidelberg and Dresden.

25 patients will be assessed for eligibility and 12 patients will be allocated into the

trial.

Ein-/Ausschlusskriterien

Key Inclusion Criteria:

- confirmed AML according to the WHO classification

- relapsed disease after allo-SCT from an HLA-identical family donor (≥ 2 months after

allo-SCT at time of inclusion)

- ≤ 29% of bone marrow blasts as detected by cytomorphology or immunohistochemistry

- age ≥ 18 years

- confirmed CD33 expression on leukemic blasts at current relapse (as detected by flow

cytometry)

- adequate organ function:

- Renal function defined as: serum creatinine of ≤ 2x ULN or eGFR ≥ 30 mL/min/1.73

m2

- Liver function defined as:

- ALT ≤ 3 times the ULN for the respective age

- Bilirubin ≤ 2.0 mg/dl with the exception of patients with hyperbilirubinemia

explained by Gilbert-Meulengracht syndrome (may be included if total

bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN) or extrahepatic

disease (e.g. chronic hemolytic anemia)

- Minimum level of pulmonary reserve defined as ≤ grade 1 dyspnea and pulse oxygenation

> 90% on room air

- Hemodynamic stability and LVEF ≥ 40% as confirmed by echocardiogram

- Absolute lymphocyte count (ALC) ≥ 100/mm3

Key Exclusion Criteria:

- ECOG performance status >2

- Confirmed CNS involvement

- Acute or chronic Graft versus Host disease (GvHD)

- Availability of other curative standard treatment options

- Prior treatment with GO

- Prior hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS)

- Uncontrolled active hepatitis B or C

- HIV-positivity

- Uncontrolled bacterial, viral or fungal infection

- Participation in another clinical trial at the time of screening

- Organ dysfunction (liver, kidney, lung, heart) that is a contraindication for

conditioning therapy

- Severe concomitant disease (e.g. uncontrolled arterial hypertension, heart failure

NYHA III-IV, uncontrolled diabetes mellitus, uncontrolled hyperlipidemia)

- Unstable angina and/or myocardial infarction within 3 months prior to screening

- Pregnant or nursing (lactating) women

Studien-Rationale

Primary outcome:

1. engraftement of gene edited CD34+HSC (Time Frame - on day 28):
successful engraftement of gene edited CD34+HSC in the bone marrow

2. dose-limiting toxicity (Time Frame - until EOS (day 90)):
dose-limiting toxicity (DLT) of Gemtuzumab-Ozogamicin

3. toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0) (Time Frame - until EOS (day 90)):
frequency and grade of AEs with gene-edited HSC transplantation

Secondary outcome:

1. Anti-tumor efficacy of study treatment in patients with dCD33+ relapsed AML after allo-SCT (Time Frame - until EOS (day 90)):
overall response rate (ORR), complete response (CR), partial response (PR)) at day 90 (EOS) after last GO application)

2. Time to response (Time Frame - until EOS (day 90)):
Time to response (at least partial response) after the last GO application

3. Overall response (Time Frame - until EOS (day 90)):
Duration of overall response (DOR) after the last GO application

4. Progression-free survival (Time Frame - until EOS (day 90)):
Progression-free survival (PFS) after the last GO application

5. Overall survival (Time Frame - until EOS (day 90)):
Overall survival (OS) after the last GO application

6. Number of circulating gene edited cells (Time Frame - at screening and days 14, 28, 56, 90):
Number of circulating gene edited cells in the bone marrow and peripheral blood as determined by flow cytometry

Geprüfte Regime

Donor-derived CD34+ HSC with CRISPR/Cas9-mediated CD33 deletion:
CD33-deleted CD34+ hematopoietic stem cells derived from the initially matched family donor
Gemtuzumab Ozogamicin:
Intrapatient intra-individual dose escalation Level 0: GO day 1 Level 1: GO day 1, day 4 Level 2: GO day 1, day 4, day 7 with repetition after 21 to 28 days up to 84 days.

Quelle: ClinicalTrials.gov

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