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

NCT ID: NCT05662904

Last Updated: 2025-03-14

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2028-01-31
• Study Completion Date: 2030-01-31

Brief Summary

The study "GALAXY33" is an open-label, prospective, nonrandomized, one arm phase I clinical trial in which 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.

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.

Conditions

Relapsed/Refractory Acute Myeloid Leukemia (AML)

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Donor-derived CD33-deleted CD34+ HSC combined with Gemtuzumab-Ozogamicin (GO)

Patients 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 antibodydrugconjugate 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.

Group Type: EXPERIMENTAL

Donor-derived CD34+ HSC with CRISPR/Cas9-mediated CD33 deletion

Intervention Type: BIOLOGICAL

CD33-deleted CD34+ hematopoietic stem cells derived from the initially matched family donor

Gemtuzumab Ozogamicin

Intervention Type: DRUG

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.

Interventions

Donor-derived CD34+ HSC with CRISPR/Cas9-mediated CD33 deletion

CD33-deleted CD34+ hematopoietic stem cells derived from the initially matched family donor

Intervention Type: BIOLOGICAL

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.

Intervention Type: DRUG

Eligibility Criteria

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital Heidelberg

OTHER

Sponsor Role: collaborator

University Hospital Dresden

OTHER

Sponsor Role: collaborator

German Cancer Research Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Tim Sauer, Dr. med.

Role: PRINCIPAL_INVESTIGATOR

University Hospital Heidelberg

Locations

University Hospital Dresden, Department of Medicine I

Dresden, , Germany

University Hospital Heidelberg, Internal Medicine V

Heidelberg, , Germany

Countries

Germany

Central Contacts

Tim Sauer, Dr. med.

Role: CONTACT

tim.sauer@med.uni-heidelberg.de

+49 6221 56 38010

Carsten Müller-Tidow, Prof. Dr. med.

Role: CONTACT

carsten.mueller-tidow@med.uni-heidelberg.de

Facility Contacts

Martin Bornhäuser, Prof. Dr. med.

Role: primary

Tim Sauer, Dr. med.

Role: primary

Other Identifiers

2022-002

Identifier Type: -

Identifier Source: org_study_id