Isatuximab in Adult Patients With Cytologic or Molecular Relapsed/Refractory CD38 Positive T-cell Acute Lymphoblastic Leukemia

A Multicenter, Single-arm Phase II Study to Assess the Safety, Tolerability, and Efficacy of Isatuximab in Adult Patients With Cytologic or Molecular Relapsed/Refractory CD38 Positive T-cell Acute Lymphoblastic Leukemia (GMALL-Isatuximab)

The planned trial offers treatment cohorts for patients with full cytologic relapse (R/R ALL - Cohort 1), as well as for patients with molecular failure/relapse (MRD+ ALL - Cohort 2). Basically, the study aims to develop data for optimization of first-line therapy of T-ALL, either by modification of standard induction with Isatuximab or by establishing a post-induction therapy for eradication of MRD and thereby evaluates in parallel two different strategies.

Study Overview

• Status: Recruiting
• Conditions: T-ALL
• Intervention / Treatment: Drug: Isatuximab; Drug: Isatuximab

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Nicola Goekbuget, MD; Phone Number: 0049-6963016365; Email: goekbuget@em.uni-frankfurt.de

Study Locations

• Germany
  • Augsburg, Germany, 86156
    • Recruiting
    • University Hospital Augsburg, II. Medizinischen Klinik, Hämatologie, internistische Onkologie und Hämostaseologie
    • Contact: Andreas Rank, MD
    • Principal Investigator: Andreas Rank, MD
  • Berlin, Germany, 12203
    • Recruiting
    • Charité Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology and Tumorimmunologyt Hämatologie
    • Contact: Stefan Schwartz, MD
    • Principal Investigator: Stefan Schwartz, MD
  • Dresden, Germany, 01307
    • Recruiting
    • Klinikum Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik I
    • Contact: Lisa Heberling, MD
    • Principal Investigator: Lisa Heberling, MD
  • Düsseldorf, Germany, 40225
    • Recruiting
    • University Hospital Düsseldorf, Department of Hematology, Oncology and Clinical Immunology
    • Contact: Kathrin Nachtkamp, MD
    • Principal Investigator: Kathrin Nachtkamp, MD
  • Erlangen, Germany, 91054
    • Recruiting
    • University Hospital Erlangen AöR, Department of Medicine 5
    • Contact: Bernd Spriewald, MD
    • Principal Investigator: Bernd Spriewald, MD
  • Frankfurt am Main, Germany, 60580
    • Recruiting
    • Goethe University Hospital Frankfurt, Department of Medicine, Hematology and Oncology
    • Contact: Nicola Goekbuget, MD; Phone Number: 0049-6963016365; Email: goekbuget@em.uni-frankfurt.de
    • Principal Investigator: Anjali Cremer, MD
  • Hamburg, Germany, 20251
    • Recruiting
    • University Hospital Hamburg-Eppendorf, Department of Medicine II
    • Contact: Walter Fiedler, MD
    • Principal Investigator: Walter Fiedler, MD
  • Heidelberg, Germany, 69120
    • Recruiting
    • University Hospital Heidelberg, Department V, Hematology, Oncology and Rheumatology
    • Contact: Simon Raffel, MD
    • Principal Investigator: Simon Raffel, MD
  • Kiel, Germany, 24105
    • Recruiting
    • University Hospital Schleswig-Holstein, Campus Kiel, Medical Department II
    • Contact: Lars Fransecky, MD
    • Principal Investigator: Lars Fransecky, MD
  • Leipzig, Germany, 04103
    • Recruiting
    • University Hospital Leipzig; Klinik für Hämatologie, Zelltherapie, Hämostaseologie und Infektiologie, Bereich Hämatologie und Zelltherapie
    • Contact: Georg-Nikolaus Franke, MD
    • Principal Investigator: Georg-Nikolaus Franke, MD
  • München, Germany, 81377
    • Recruiting
    • University Hospital München-Großhadern, Medizinische Klinik und Poliklinik III
    • Contact: Veit Bücklein, MD
    • Principal Investigator: Veit Bücklein, MD
  • Münster, Germany, 48149
    • Recruiting
    • University Hospital Münster, Medizinische Klinik A / KMT-Zentrum
    • Contact: Matthias Stelljes, MD
    • Principal Investigator: Matthias Stelljes, MD
  • Oldenburg, Germany, 26135
    • Recruiting
    • Klinikum Oldenburg AöR, Universitätsklinik für Innere Medizin - Onkologie und Hämatologie
    • Contact: Andreas Voß, MD
    • Principal Investigator: Andreas Voß, MD
  • Stuttgart, Germany, 70376
    • Recruiting
    • Robert-Bosch-Krankenhaus; Abteilung für Hämatologie, Onkologie und Palliativmedizin
    • Contact: Sonja Martin, MD
    • Principal Investigator: Sonja Martin, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

- Patients with CD38 positive T-ALL fitting either to the definitions for cohort 1 or cohort 2:

Cohort 1: In relapse or with primary refractory disease defined as ≥5% blasts in bone marrow after at least three chemotherapy cycles (induction I-II, consolidation I) with the following additional specifications:

• early relapse within 12 months from first achievement of CR or
• late relapse later than 12 months from first achievement of CR or
• primary refractory disease without any CR or
• any relapse after stem cell transplantation or
• any refractory relapse, defined as no response to at least one salvage therapy or
• any second or later relapse and
• Availability of patient material with blast cells (bone marrow or peripheral blood) for central MRD assessment or availability of respective predefined marker.

Cohort 2: In complete hematological remission (defined as less than 5% blasts in bone marrow and no evidence of extramedullary disease) after at least three chemotherapy cycles (induction I-II, consolidation I)

• Detection of quantifiable MRD at a level of ≥10-4, either as molecular failure without prior achievement of molecular remission or molecular relapse after prior achievement of molecular remission
• MRD assay at the central reference lab with at least one marker a minimum sensitivity of 10-4
• MRD detection for study inclusion after an interval of at least 2 weeks from last systemic chemotherapy including antibody therapy
• (in patients without clonal molecular MRD marker, MRD testing can be based on flow-cytometry established in reference laboratory)

ECOG status:

• Cohort 1: 0-2
• Cohort 2: 0-1

Age ≥ 18 years Evidence of a personally signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures

Regeneration from last chemotherapy defined as follows:

Cohort 1:

• Platelets ≥10.000/uL (platelet transfusion allowed)
• Hemoglobin ≥ 7.5 g/dl (red blood cell transfusion allowed)

Cohort 2:

• Neutrophils ≥1.000/uL
• Platelets ≥50.000/uL
• Hemoglobin ≥9 g/dl

Adequate liver function defined as follows:

• Bilirubin ≤ 1.5 ULN (unless Gilbert Meulengracht disease or classified as result of liver infiltration by investigator)
• AST and ALT ≤ 2.5 x ULN (unless classified as result of liver infiltration by investigator)

Adequate renal function defined as follows:

• Serum creatinine ≤ 2 x ULN
• Any serum creatinine level associated with a calculated creatinine clearance ≤ 40 mL/min
• Negative pregnancy test in women of childbearing potential (WOCBP)
• WOCBP must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously.
• Men who are sexually active with a WOCBP must agree to use a barrier method of contraception
• Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Exclusion Criteria:

• Extramedullary involvement except for non-bulky (<7.5 cm) lymph node involvement, splenomegaly, or hepatomegaly
• Patients who have received prior antileukemic immunotherapy within 2 weeks prior to start of Isatuximab treatment
• Patients who have received treatment for leukemia with chemotherapy as follows:

Cohort 1:

• Patients who have received treatment for leukemia with chemotherapy within 2 weeks prior to start of Isatuximab treatment (exception: pre-phase therapy with 5-7 days of Dexamethasone, 3 days of Cyclophosphamide; intrathecal prophylaxis)
• Patients who are candidates for a treatment with Nelarabine

Cohort 2:

• Any chemotherapy or antibody therapy after the MRD assay leading to study inclusion (exception: intrathecal prophylaxis)
• Patients must have recovered from acute non-hematologic toxicity from previous therapies to ≤ grade I unless signs or symptoms are correlated to leukemia involvement
• Prior SCT ≤ 3 months from start of study treatment
• Acute GvHD ≥ grade II or active chronic GvHD requiring systemic treatment
• Any systemic GvHD prophylaxis or treatment within 2 weeks from start of study treatment
• Known HIV positivity, known hepatitis B surface antigen positivity or known history of hepatitis C
• Unstable or severe uncontrolled medical condition e.g. unstable cardiac function or unstable pulmonary condition
• Treatment with an investigational agent within 4 weeks from start of study treatment (safety follow-up period of respective study)
• Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been treated with radiation or surgery; patients with previous malignancies are eligible if they have been disease free for ≥ 2 years and do not require any antitumor therapy.
• Evidence of uncontrolled current serious active infection or recent history (within 4 months) of deep tissue infections such as fasciitis or osteomyelitis
• Known allergies, hypersensitivity, or intolerance to boron or Mannitol, corticosteroids, mAb (including Isatuximab) or human proteins, or their excipients (refer to respective Summary of Product Characteristics), or known sensitivity to mammalian-derived products.
• Active infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator
• Pregnant or breastfeeding females
• Vaccination with live attenuated vaccines within 4 weeks of first study agent administration.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgement of the investigator, would make the patient inappropriate for entry into this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: GMALL-Isatuximab; Cohort 1: In this Cohort, Isatuximab shall be implemented as part of a combination therapy for patients with R/R T-ALL, defined as bone marrow infiltration of ≥5% (R/R T-ALL). Cohort 2: In this Cohort, Isatuximab shall be implemented as single drug treatment for patients with molecular failure/relapse. Cohort 2 will include patients with hematologic remission (bone marrow blast count <5%) of T-cell ALL, but with molecular failure or molecular relapse (MRD+ T-ALL).

Drug: Isatuximab; Cohort 1: All patients will receive two cycles of induction therapy with standard chemotherapy, Bortezomib and Isatuximab. Isatuximab maintenance may be administered in patients with CR until SCT, progression/relapse, unacceptable toxicity, physicians' decision to change treatment or withdrawal of consent.; Other Names: Bortezomib; Drug: Isatuximab; Cohort 2: All patients will receive at least one cycle with Isatuximab. Each cycle will be 4 weeks in duration. Isatuximab will be administered until SCT, hematologic relapse including extramedullary, unacceptable toxicity, physicians' decision, or withdrawal of consent.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with complete hematologic response (ORR= CR and CRi)	Cohort 1: Proportion of patients with complete hematologic response (ORR= CR and CRi) after 2 cycles of induction therapy including Isatuximab.	Day 22, Week 9, per SoC
Overall incidence and severity of adverse events	Cohort 1: Overall incidence and severity of adverse events (CTCAE 5.0).	Day 22, Week 9, month 3, month 6 (depends on duration of therapy which is variable)
Proportion of patients with molecular response (MolCR)	Cohort 2: Proportion of patients with molecular response (MolCR) after one cycle of Isatuximab.	Day 22, Week 9, per SoC

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with CR and CRi, MolCR and cMolCR in R/R	Cohort 1: Proportion of patients with CR and CRi, MolCR and cMolCR in R/R (cohort 1) after 1 or 2 cycles of induction (best response)	Day 22, Week 9, per SoC
Probability of continuous complete remission	Probability of continuous complete remission (remission duration) at 18 months	at 18 months
Probability of overall survival	Probability of overall survival at 18 months	at 18 Months
Probability of relapse-free survival	Probability of relapse-free survival at 18 months	at 18 Months
Probability of event-free survival	Probability of event-free survival at 18 months	at 18 Months
Incidence of relapses and proportion of relapse localisations	Incidence of relapses and proportion of relapse localisations	Day 22, Week 9, per SoC
Incidence of GvHD in patients with prior SCT	Incidence of GvHD in patients with prior SCT	until end of trial
Duration of molecular remission (mimimal residual disease by PCR)	Status is evaluated at distinct timepoints to calculate the duration of molecular remission	Day 22, Week 9, per SoC
Treatment realization for Isatuximab	Dosing of Isatuximab as scheduled per protocol	d22, week 9, per maintenance cycle, end of treatment at month 6
Probability of continuous MolCR and cMolCR and duration of MolCR and cMolCR	Probability of continuous MolCR and cMolCR and duration of MolCR and cMolCR	Day 22, Week 9, per SoC
Time to MolCR and cMolCR	Time to MolCR and cMolCR measured by time-point of first achievement.	Day 22, Week 9, per SoC
Conduct of SCT in patients with CR (ORR), MolCR, cMolCR	The conduct of SCT will be assessed in patients with CR (ORR), MolCR, cMolCR, SCT parameters and outcome	Through completion of the trial, average 18 months
Measurement of Quality of Life	Measurement of Quality of Life with EORTC instruments (e.g. EORTC QLQ-C30) at different time-points during treatment	Day 22, Week 9
Hospitalisation days	Hospitalisation days	Day 22, Week 9, month 3 and 6 (depending on treatment duration which is individual)

Collaborators and Investigators

• Sponsor: Goethe University
• Collaborators: Sanofi
• Investigators: Principal Investigator: Anjali Cremer, MD, Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany; Study Director: Nicola Goekbuget, MD, Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2024
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: July 15, 2024
• First Submitted That Met QC Criteria: October 17, 2024
• First Posted (Actual): October 18, 2024

Study Record Updates

• Last Update Posted (Actual): January 15, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: R/R or MRD CD38-positive T-ALL
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hemic and Lymphatic Diseases; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Inorganic Chemicals; Boronic Acids; Acids, Noncarboxylic; Acids; Boron Compounds; Pyrazines; Bortezomib; isatuximab
• Other Study ID Numbers: GMALL-Isatuximab; 2023-507899-47-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No