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

Официальное название

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)

Обзор

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.

Вмешательства

• Препарат 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.
• Препарат 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.

Первичные конечные точки

• Proportion of patients with complete hematologic response (ORR= CR and CRi) [Срок оценки: Day 22, Week 9, per SoC]
• Overall incidence and severity of adverse events [Срок оценки: Day 22, Week 9, month 3, month 6 (depends on duration of therapy which is variable)]
• Proportion of patients with molecular response (MolCR) [Срок оценки: Day 22, Week 9, per SoC]

Вторичные конечные точки (12)

• Proportion of patients with CR and CRi, MolCR and cMolCR in R/R [Срок оценки: Day 22, Week 9, per SoC]
• Probability of continuous complete remission [Срок оценки: at 18 months]
• Probability of overall survival [Срок оценки: at 18 Months]
• Probability of relapse-free survival [Срок оценки: at 18 Months]
• Probability of event-free survival [Срок оценки: at 18 Months]
• Incidence of relapses and proportion of relapse localisations [Срок оценки: Day 22, Week 9, per SoC]
• Incidence of GvHD in patients with prior SCT [Срок оценки: until end of trial]
• Duration of molecular remission (mimimal residual disease by PCR) [Срок оценки: Day 22, Week 9, per SoC]
• Treatment realization for Isatuximab [Срок оценки: d22, week 9, per maintenance cycle, end of treatment at month 6]
• Probability of continuous MolCR and cMolCR and duration of MolCR and cMolCR [Срок оценки: Day 22, Week 9, per SoC]
• Time to MolCR and cMolCR [Срок оценки: Day 22, Week 9, per SoC]
• Conduct of SCT in patients with CR (ORR), MolCR, cMolCR [Срок оценки: Through completion of the trial, average 18 months]

Критерии участия

Критерии включения

\- 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)

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Германия · 15 центров

• University Hospital Augsburg, II. Medizinischen Klinik, Hämatologie, internistische Onkolo — Augsburg
• Charité Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology and Tumorimmu — Berlin
• Gesundheit Nord Klinikverbund Bremen gGmbH, Klinikum Bremen-Mitte, Med. Klinik I — Bremen
• Klinikum Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik I — Dresden
• University Hospital Düsseldorf, Department of Hematology, Oncology and Clinical Immunology — Düsseldorf
• University Hospital Erlangen AöR, Department of Medicine 5 — Erlangen
• Goethe University Hospital Frankfurt, Department of Medicine, Hematology and Oncology — Frankfurt am Main
• University Hospital Hamburg-Eppendorf, Department of Medicine II — Hamburg
• … и ещё 7 центров

Идентификаторы

NCT: NCT06648889 · GMALL-Isatuximab · 2023-507899-47-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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