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

Relapsed/Refractory Acute Myeloid Leukemia (AML) Clinical Trial

— GALAXY33  

Official title:

Genetic Ablation of CD33 in Hematopoietic Stem Cells to Broaden the Therapeutic Index of CD33-directed Immunotherapy in Patients With Acute Myeloid Leukemia (AML)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05662904
• Other study ID #: 2022-002
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: December 2023
• Est. completion date: February 2025

Study information

• Verified date: December 2022
• Source: German Cancer Research Center
• Contact: Tim Sauer, Dr. med.
• Phone: +49 6221 56 38010
• Email: tim.sauer[@]med.uni-heidelberg.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 12
• Est. completion date: February 2025
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Relapsed/Refractory Acute Myeloid Leukemia (AML)

Intervention

Biological:
• Donor-derived CD34+ HSC with CRISPR/Cas9-mediated CD33 deletion
CD33-deleted CD34+ hematopoietic stem cells derived from the initially matched family donor

Drug:
• 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.

Locations

Country	Name	City	State
Germany	University Hospital Dresden, Department of Medicine I	Dresden
Germany	University Hospital Heidelberg, Internal Medicine V	Heidelberg

Sponsors (3)

Lead Sponsor	Collaborator
German Cancer Research Center	University Hospital Dresden, University Hospital Heidelberg

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	engraftement of gene edited CD34+HSC	successful engraftement of gene edited CD34+HSC in the bone marrow	on day 28
Primary	dose-limiting toxicity	dose-limiting toxicity (DLT) of Gemtuzumab-Ozogamicin	until EOS (day 90)
Primary	toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0)	frequency and grade of AEs with gene-edited HSC transplantation	until EOS (day 90)
Secondary	Anti-tumor efficacy of study treatment in patients with dCD33+ relapsed AML after allo-SCT	overall response rate (ORR), complete response (CR), partial response (PR)) at day 90 (EOS) after last GO application)	until EOS (day 90)
Secondary	Time to response	Time to response (at least partial response) after the last GO application	until EOS (day 90)
Secondary	Overall response	Duration of overall response (DOR) after the last GO application	until EOS (day 90)
Secondary	Progression-free survival	Progression-free survival (PFS) after the last GO application	until EOS (day 90)
Secondary	Overall survival	Overall survival (OS) after the last GO application	until EOS (day 90)
Secondary	Number of circulating gene edited cells	Number of circulating gene edited cells in the bone marrow and peripheral blood as determined by flow cytometry	at screening and days 14, 28, 56, 90