Phase I Dose Escalation Study of Anti-CRLF2-R/TSLPR Chimeric Antigen Receptor T Cells (TSLPR-CART) in Participants With Recurrent or Refractory CRLF2-R/TSLPR-Overexpressing B-cell Acute Lymphoblastic Leukemia (B-ALL)

NCT07572136 | Not Yet Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10001555001555-C
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• gPhiladelphia (Ph)-like h acute lymphoblastic leukemia (ALL) is a high-risk subgroup of B-ALL associated with high rates of chemotherapy resistance and relapse. Ph-like ALL is defined by an activated cytokine receptor and kinase signaling profile similar to that of Philadelphia chromosome-positive (Ph+) ALL yet lacking BCR-ABL1 rearrangement.
• Approximately half of childhood and adult Ph-like ALL cases have rearrangement in cytokine receptor like factor-2 (CRLF2), which encodes one subunit of the thymic stromal lymphopoietin receptor (TSLPR) and heterodimerizes with the interleukin-7 receptor alpha (IL7Ra) subunit. Its ligand, TSLP, is a cytokine that plays a critical role in regulation of the immune response and in the differentiation of hematopoietic cells. TSLP binding to the TSLPR in B-ALL induces constitutive Janus kinases and signal transducers and activators of transcription (JAK/STAT) pathway signaling.
• Most CRLF2-rearranged (CRLF2-R) Ph-like ALL cases can be readily identified by increased TSLPR surface expression by flow cytometric immunophenotyping, and specific CRLF2 rearrangements can then be confirmed by genetic testing. Given the prevalence of CRLF2 rearrangements and the poor clinical outcomes of patients with Ph-like ALL, TSLPR is a promising target for new immunotherapies.
• Chimeric antigen receptor-expressing T cells (CAR) have proven highly successful in patients with cancer with dramatic responses in \>70% of patients with relapsed/refractory B-ALL treated with CD19-redirected CAR T cells, resulting in Food and Drug Administration (FDA) approval of a CD19 CAR T-cell immunotherapy in children and young adults. A trial of CAR T cells targeting CD22 is currently ongoing at the NCI and has demonstrated comparable efficacy and toxicity results as the CD19 CAR.
• Emerging data have indicated that not all patients respond, and up to 50% of those who achieve remission will subsequently relapse. The most common cause of relapse is the target antigen loss, which is likely multi-factorial in etiology and for which this mechanism of escape is under active investigation. Novel targets are needed.
• This will be the first in human testing of anti-CRLF2-R/TSLPR CAR T cell (TSLPRCART) adoptive cell therapy. Objective:
• To assess the safety of administering escalating doses of autologous anti-CRLF2-R/TSLPR-CAR engineered T cells (TSLPR-CART) containing a truncated epidermal growth factor (tEGFR) suicide switch to determine a maximum tolerated dose (MTD) in participants with recurrent or refractory CRLF2/TSLPR-overexpressing B-cell acute lymphoblastic leukemia (ALL) following a cyclophosphamide/fludarabine lymphodepletion regimen. Eligibility:
• Age \>= 18 years
• Participants must have confirmed diagnosis of a B-cell ALL with TSLPR+ expression on flow cytometry who have relapsed or refractory disease after at least one standard chemotherapy regimen and one salvage regimen, with no alternative curative options. Design:
• This is a first-in-human Phase I trial aimed to determine the safety of TSLPR-CART in participants with recurrent or refractory B-cell ALL.
• Participants will undergo apheresis and TSLPR-CART will be manufactured from the enriched T-cell product
• Participants will receive LD preparative regimen of fludarabine and cyclophosphamide followed by an infusion of TSLPR-CART.
• The MTD of autologous TSLPR-CAR T cells using a 3 + 3 dose escalation design will be determined. Additional participants in an expansion cohort will be treated at an MTD dose to evaluate the rate of response to TSLPR-CAR T cells. Participants will be evaluated for toxicity, anti-tumor response, CAR expansion and persistence, and other biologic correlatives....

Conditions

B-All; Acute Lymphoblastic Leukemia

Keywords

Adoptive Immunotherapy; CRLF2-R/TSLPR Expressing Tumor; Acute Lymphoblastic Leukemia; B-All

Outcome Measures

Primary Outcomes (1)

• To assess the safety of administering escalating doses of TSLPR-CART containing a tEGFR suicide switch to determine an MTD

  Safety analyses will consist of tabulations of grades of toxicity by type of toxicity

  28 days post cell infusion

Secondary Outcomes (2)

• Efficacy of TSLPR-CART

  2 years post cell infusion

• 1-year and 2-year OS (overall survival)

  2 years post cell infusion

Study Arms (2)

1

EXPERIMENTAL

TSLPR-CART at escalating doses

Biological: TSLPR-CART; Drug: Cyclophosphamide; Drug: Fludarabine

2

EXPERIMENTAL

TSLPR-CART at MTD or highest dose administered

Biological: TSLPR-CART; Drug: Cyclophosphamide; Drug: Fludarabine

Interventions

TSLPR-CART BIOLOGICAL

TSLPR CAR transduced T cells on D0 after lymphodepleting preparative regimen

1; 2

Cyclophosphamide DRUG

Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 500 mg/m\^2/dose after fludarabine infusion on days -3 and -2.

1; 2

Fludarabine DRUG

Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes on days -5 through -2. To prevent undue toxicity the dose will be based on BSA (30 mg/m\^2/dose).

1; 2

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documentation of pathologic confirmation of a diagnosis of B-Cell acute lymphoblastic leukemia (ALL).
• TSLPR+ expression must be detected on . 80% of the malignant cells by NSR device. Note: TSLPR+ expression does not need to be repeated by NSR device if there is a documentation of TSLPR surface expression by flow cytometry from a Clinical Laboratory Improvement Amendments (CLIA) approved laboratory.
• Participants must have a disease that is relapsed or refractory after initial systemic therapy and at least one salvage treatment, and must either be ineligible for, cannot access in a timely manner, or declined alternative curative options (including commercial CAR Tcell
• constructs\*, and/or have relapsed after allogeneic HSCT).
• \*Individuals that are CD19 positive will be considered for this study, However, these individuals should be ineligible for, unable to obtain in a timely manner, cannot access, unwilling to undergo, or have failed prior FDA approved CD19 CAR constructs.
• Participants must have measurable or evaluable disease at the screening, defined by any evidence of MRD or positron emission tomography (PET)-avid extramedullary disease
• Age \>= 18 years
• Clinical performance status: Karnofsky \>= 50%. Participants who are unable to walk because of paralysis, but who are upright in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.
• Participants must have adequate organ and marrow function as defined below:
• Leukocytes \>= 750/mcL\*
• Platelets \>= 50,000/mcL\*
• Total bilirubin \<= 2 x upper limit of normal (ULN) (except in the case of participants
• with documented Gilbert fs disease \> 3 X ULN)
• Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) \<= 5 X institutional ULN
• Creatinine \< 1.5X ULN OR Creatinine clearance \>= 60 mL/min/1.73m\^2 for participants with creatinine levels above max listed above

You may not qualify if:

• <!-- -->
• Recurrent or refractory leukemia limited to isolated testicular or isolated CNS disease
• Hyperleukocytosis (\>=50,000 blasts/mcL)
• Positive serum or urine beta-human chorionic gonadotropin (beta-HCG) pregnancy test performed in WOCBP at screening.
• Washout criteria (time prior to apheresis or prior to start of LD if apheresis is not done on this protocol):
• ====
• Therapy: Systemic chemotherapy, antineoplastic investigational agents, or antibody-based therapies, any investigational therapy
• Washout\*: \>= 2 weeks
• Exceptions: 6 weeks for clofarabine or nitrosoureas No washout for prior intrathecal chemotherapy, steroid therapy, hydroxyurea (no dose increases within prior 2 weeks) or ALL maintenance type chemotherapy (vincristine, 6- mercaptopurine, oral methotrexate, or a tyrosine kinase for participants with Ph+ or Ph-like ALL) provided there is recovery from any acute toxic effects
• ====
• Therapy: Radiation therapy
• Washout\*: \>= 3 weeks
• Exceptions: No time restriction with radiation therapy if the volume of bone marrow treated is less than 10% and the participant has measurable/evaluable disease outside the radiation window.
• ====
• Therapy: History of allogeneic HSCT

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Cyclophosphamide; fludarabine

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Nirali N Shah, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

NCI Pediatric Leukemia, Lymphoma Transpl

CONTACT

(240) 760-6970; ncilltct@mail.nih.gov

Nirali N Shah, M.D.

CONTACT

(240) 760-6970; shahnn@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2026
• First Posted: May 7, 2026
• Study Start (Estimated): May 12, 2026
• Primary Completion (Estimated): June 30, 2030
• Study Completion (Estimated): June 30, 2032
• Last Updated: May 7, 2026

Record last verified: 2026-05-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be made available as soon as possible or at the time of associated publication. Data not published in a manuscript will be shared via public source once the data set completes QC.
• Access Criteria: Clinical data will be made available upon request and with the permission of the study PI. Genomic data are made available via dbGAP through requests to the data custodians.

Locations

US (1)