CD45BE-HSPC + CART-45 Cells

Официальное название

Phase 1 Study of Autologous Anti-CD45 CAR T Cells in Combination With CD45 Base Edited HSPCs in Patients With Relapsed or Refractory Hematologic Malignancies

Обзор

This is a phase 1, open-label, dose-finding study to assess the safety, feasibility, pharmacokinetics and preliminary efficacy of autologous base edited anti-CD45 CAR T cells (referred to as "CART-45 cells") following an autologous transplant of CD45 base edited hematopoietic stem and progenitor cells (referred to as "CD45BE-HSPC") in patients with relapsed or refractory hematologic malignancies.

Вмешательства

• Биопрепарат CART-45 cells
  Autologous base edited anti-CD45 CAR T cells
• Биопрепарат CD45BE-HSPC
  CD45 base edited hematopoietic stem and progenitor cells

Первичные конечные точки

• Incidence of Adverse Events as assessed by CTCAE v6.0 [Срок оценки: Up to 15 years post infusion]
• Occurrence of dose-limiting toxicities (DLTs) [Срок оценки: 28 days post-CART-45 infusion]
• Identification of the maximum tolerated dose (MTD) [Срок оценки: 28 days post-CART-45 infusion]
• Identification of a recommended dose for expansion (RDE) [Срок оценки: 3 months post-CART-45 infusion]

Вторичные конечные точки (11)

• Proportion of CD45BE-HSPC products that fail to meet the product release criteria [Срок оценки: 3 months]
• Proportion of CART-45 products that fail to meet the product release criteria [Срок оценки: 3 months]
• Proportion of CD45BE-HSPC products that fail to meet the protocol-defined dose [Срок оценки: 3 months]
• Proportion of CART-45 products that fail to meet the assigned dose. [Срок оценки: 3 months]
• Evaluate study feasibility [Срок оценки: 3 months]
• Engraftment of CD45BE-HSPC [Срок оценки: 28 days after treatment]
• Overall survival (OS) [Срок оценки: Up to 15 years after last CART-45 Cells administration]
• Overall Response/Remission Rate (ORR) [Срок оценки: Up to 12 months following CART-45 administration]
• Best Overall Response (BOR) [Срок оценки: Up to 12 months following CART-45 administration]
• Duration of Response (DOR) [Срок оценки: Up to 12 months following CART-45 administration]
• Progression-Free Survival (PFS) [Срок оценки: Up to 15 years after product administration]

Критерии участия

Критерии включения

1\. Signed informed consent form 2. Male or females age ≥ 18 years 3. Disease-Specific Criteria

a. B-cell Non-Hodgkin Lymphoma (B-cell NHL)- including the following sub-types:

i. Patients with any of the following large B-cell lymphoma diagnoses who meet the prior treatment criteria outlined below: Diffuse Large B-cell Lymphoma not otherwise specified (DLBCL NOS); Primary Cutaneous DLBCL; Primary Mediastinal (thymic) Large B-cell Lymphoma; ALK+ Anaplastic Large B-cell Lymphoma; High-Grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements (i.e., "Double or Triple Hit"); High-grade B-cell Lymphoma, NOS; T-cell Rich B-cell Lymphoma; Transformed Follicular Lymphoma; or any aggressive B-cell lymphoma arising from indolent lymphoma.

1\. Patients must have either failed/relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND 2. Relapsed/refractory disease after at least 2 prior lines of appropriate therapy.

ii. Follicular Lymphoma

• Patients must have either failed/relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND
• Relapsed/refractory disease after at least 2 prior lines of systemic therapy (not including a single agent monoclonal antibody therapy).

iii. Mantle Cell Lymphoma

• Patients must have either failed/relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND
• Relapsed/refractory disease after at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (TKI) inhibitor. Single-agent monoclonal antibody therapy does not count towards prior lines of therapy.

iv. Marginal Zone Lymphoma- relapsed/refractory disease after at least 2 prior lines of appropriate therapy, including a Bruton tyrosine kinase (TKI) inhibitor. Note: Single-agent monoclonal antibody therapy does not count towards prior lines of therapy.

b. T-cell Non-Hodgkin Lymphoma (T-cell NHL)

i. Histologically or cytologically confirmed relapsed or refractory (r/r) mature aggressive T- and NK-cell neoplasms as defined in the 5th edition of the WHO Classification of Hematolymphoid tumors, which includes any of the following diagnoses:

• Peripheral T-cell Lymphoma, NOS (PTCL-NOS);

• Nodal T-cell Lymphomas with T Follicular Helper \[TFH\] Phenotype, including Follicular T cell Lymphoma, Angioimmunoblastic Lymphoma, or Anaplastic Large Cell Lymphoma (ALCL);

• ALK+ or ALK-, Enteropathy-Associated T-cell Lymphoma (EATL);

• Monomorphic Epitheliotropic Intestinal T-cell Lymphoma (MEITL);

• Extranodal NK/T-cell Lymphoma;

• Primary Cutaneous T-cell Lymphoma (CTCL);

• Transformed Mycosis Fungoides (tMF) without blood involvement;

• Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-Cell Lymphoma;

• Subcutaneous Panniculitis-like T-cell Lymphoma.

ii. Must have received at least one prior line of systemic therapy for their lymphoma. Additional prior treatment provisions required for the following indications:

1\. Participants with Anaplastic Large Cell Lymphoma (ALCL) must have received prior Brentuximab vedotin, unless contraindicated.

2\. Participants with Subcutaneous Panniculitis-like T-cell Lymphoma or Transformed Mycosis Fungoides (tMF) must have received at least 2 prior lines of systemic therapy.

c. Hodgkin Lymphoma (HL)

i. Patients with histologically proven classical Hodgkin Lymphoma that is CD45 positive by IHC or flow cytometry by a CLIA certified laboratory; AND

ii. Relapsed/refractory disease after at least 2 prior lines of therapy which must include the following:

• Brentuximab vedotin and immune checkpoint inhibitors (unless contraindicated); AND
• Autologous stem cell transplant (unless patient has chemorefractory disease to salvage treatment) d. Large Cell Transformation of CLL (Richter's Transformation) i. Patients must be primary refractory or received at least 1 prior line of treatment for Richter's Transformation.

4\. Patients are appropriate candidates for autologous HSCT as per physician-investigator clinical discretion

5\. Patients with relapsed disease after prior allogeneic SCT must meet the following criteria:

a. Have no active GVHD and require no immunosuppression

b. Are more than 6 months from transplant at the time of physician-investigator confirmation of eligibility

6\. Adequate organ function defined as:

• Serum creatinine ≤ 1.5x ULN or estimated creatinine clearance ≥ 35 mL/min and not on dialysis
• ALT/AST ≤ 3 x ULN
• Direct bilirubin ≤ 2.0 mg/dl; for patients with Gilbert's syndrome direct bilirubin must be ≤ 3.0 mg/dl
• Left Ventricular Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA
• DLCO > 45% predicted value; adjusted for level of hemoglobin
• Must have minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air 7. ECOG Performance Status 0-1

Критерии исключения

• Active hepatitis B or hepatitis C infection
• Any active, uncontrolled infection.
• Class III/IV cardiovascular disability according to the New York Heart Association Classification.
• Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
• Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study.
• Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
• Active acute or chronic GVHD requiring systemic therapy.
• Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications.
• Active CNS involvement. Patients with a history of CNS involvement that was successfully treated are eligible. A CNS evaluation is only required for eligibility if a subject is experiencing signs/symptoms of CNS involvement.
• Patients with evidence of a circulating T-cell malignancy as measured by flow cytometry.
• History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
• Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
• Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods.

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• University of Pennsylvania — Philadelphia

Идентификаторы

NCT: NCT07451054 · 50425

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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