Clinical trial NCT07007117: PHOX2B PC-CAR T Cells for Relapsed Neuroblastoma
Official title: Phase 1 Trial of PHOX2B Peptide-Centric Chimeric Antigen Receptor Autologous T Cells (PHOX2B PC-CAR T) for Relapsed Neuroblastoma
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Refractory Neuroblastoma
Relapsed Neuroblastoma
High-Risk Neuroblastoma
Keywords: Neuroblastoma
PHOX2B PC-CAR T Cells
Cell Therapy
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
Collaborators: name: Children's Hospital of Philadelphia
name: Alliance for Cancer Gene Therapy
name: Children's Cancer Research Fund
First posted: 2025-06-05
Enrollment: 38
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a first in human dose escalation trial to determine the safety of administering PHOX2B PC-CAR T cells in patients with advanced, high-risk neuroblastoma.

Detailed description: Neuroblastoma is a tumor of childhood arising from neural crest-derived cells of the developing sympathetic nervous system. While neuroblastomas in young infants often spontaneously regress, children diagnosed with advanced disease after 18 months of age experience poor overall survival despite intensive therapy.

Neuroblastoma is a heterogenous disease, but approximately 50% of patients have a "high-risk" clinical phenotype defined by well-established clinical signs and molecular biomarkers. Over 50% of patients ultimately relapse and survivors are often burdened with significant long-term therapy related morbidities. There is no known cure for patients with relapsed high-risk neuroblastoma. PHOX2B as a therapeutic target for neuroblastoma Paired like homeobox 2B (PHOX2B) is a homeodomain transcription factor that promotes differentiation of neural crest cell derived sympathetic nervous system precursor cells. The PHOX2B protein is so specifically expressed in neuroblastoma that it is used an immunohistochemical confirmation of diagnosis. While PHOX2B is expressed during fetal development, PHOX2B expression is silenced in the vast majority of normal tissues after birth.

To therapeutically leverage this differential expression, an HLA restricted PHOX2B PC-CAR T cell was developed and showed potent inhibition of the growth of neuroblastoma patient-derived xenografts. This investigation will be a single institution, open-label first in human, dose escalation and expansion study designed to assess the safety, tolerability, and manufacturing feasibility of PHOX2B- PC CAR T Cells.

Eligibility criteria: Inclusion Criteria:

* 1. Patients must be ≥ 1 years of age
* 2. Patients must demonstrate expression of at least one of the following HLA alleles by HLA genotyping (conducted at CHOP) to be eligible.

HLA-A\*24:02 HLA-A\*24:03 HLA-A\*24:04 HLA-A\*24:07 HLA-A\*24:124 HLA-A\*24:143 HLA-A\*24:17 HLA-A\*24:242 HLA-A\*24:305 HLA-A\*24:314 HLA-A\*24:33 HLA-A\*24:353 HLA-A\*24:41 HLA-A\*24:51 HLA-A\*24:63 HLA-A\*24:87 HLA-A\*24:92 HLA-A\*23:01 HLA-A\*23:17 HLA-A\*23:25 HLA-A\*23:39

3. Patients must have high-risk neuroblastoma according to COG risk classification at the time of study enrollment. Patients who were initially considered low- or intermediate-risk, but then reclassified as high-risk are also eligible.

4. Patients must have a previously histologically confirmed diagnosis of neuroblastoma That is recurrent/relapsed or refractory/persistent according to INRC AND For which standard curative measures do not exist or are no longer effective. Patients at first relapse are eligible as no known curative therapies exist for relapsed high-risk neuroblastoma.

5. Patients must have evaluable or measurable disease at enrollment. 5. The patient must have experienced at least one of the following:

a. New disease site documented on at least one of the following: i. 123I-meta-iodobenzylguanidine (MIBG) or 18F-mFBG (meta-fluorobenzylguanidine) scan; OR ii. CT/MRI; OR iii. FDG or Ga-68 Dotatate PET (in patients known to have MIBG non-avid tumor) and MRI findings consistent with tumor (i.e., bone lesions), OR iv. Biopsy confirmed neuroblastoma for any new or progressing lesion. b. Greater than 20% increase in a least one dimension of soft tissue mass documented by CT/MRI and a minimum absolute increase of 5 mm in longest dimension in existing lesion(s). Previously irradiated lesions may be included.

c. Bone marrow biopsy shows progressive disease according to the revised INRC.61 d. Stable persistent disease, such that response at the completion of upfront therapy or salvage therapy is less than partial response AND has a biopsy of at least one site showing viable neuroblastoma.

e. Responding persistent disease, defined as at least a partial response to frontline therapy (i.e., at least a partial response to frontline therapy but still has residual disease by MIBG scan, CT/MRI, or bone marrow aspirations/biopsies). Patients in this category are required to have histologic confirmation of viable neuroblastoma from at least one residual site (tumor seen on routine bone marrow morphology is sufficient)

6. Patients must have a Lansky (≤ 16 years) or Karnofsky (\> 16 years) score of ≥ 60.

7. Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 ULN for age: Age Male Female 12 months to \< 2 years 0.6 0.6 2 to \< 6 years 0.8 0.8 6 to \< 10 years 1.0 1.0 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.4

* 16 years 1.7 1.4

  8. Liver Function as follows:
  1. Total bilirubin ≤ 1.5 x ULN (exception: total bilirubin ≤ 3 ULN for patients with Gilbert's Disease or liver metastases).
  2. Alanine aminotransferase (ALT) ≤ 3.0 ULN (exception: ALT ≤ 5 x ULN for patients with liver metastases).
  3. Aspartate aminotransferase (AST) ≤ 3.0 ULN (exception: ALT ≤ 5 x ULN for patients with liver metastases).

     9. Pulmonary Function as follows:

  a. Patients need to have a baseline pulse oximetry of at least 92% on room air and DLCO ≥ 60% (corrected for anemia) if PFTs are clinically appropriate as determined by the treating investigator.

  8. Cardiac Function as follows:

  a. Left ventricular shortening fraction (LVSF) ≥28% or ejection fraction (LVEF) ≥ 50% confirmed by Echo, or adequate ventricular function documented by a scan or a cardiologist.

  10. Patients of child-bearing potential ( patients who have reached menarche and have not experienced treatment-related premature ovarian failure) must have a negative serum pregnancy test performed at the time of screening It is recommended that all patients of reproductive potential use at least one medically acceptable form of contraception for at least 1 year after their last infusion of PHOX2B PC-CAR T cells. Investigators shall counsel patients on the importance of pregnancy prevention and the implications of an unexpected pregnancy.

Exclusion Criteria:

* 1. Patients with active hepatitis B or active hepatitis C. 2. Patients with active HIV infection (patients undergoing anti-retroviral therapy with undetectable HIV viral load are eligible).

  3. Patients with uncontrolled active infection 4. Patients with primary or acquired immunodeficiency disorder. 5. Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well.

  6. Patients with actively progressing CNS metastases, including parenchymal or leptomeningeal involvement. (Note: CNS imaging at screening is only required if there is a clinical indication of suspected CNS metastasis) 7. Active medical disorder that, in the opinion of the investigator, would substantially increase the risk of uncontrollable CRS and/or neurotoxicity.

  8. Patients who have received any live vaccines within 30 days prior to enrollment.

  9. Pregnant or nursing (lactating) patients.

Primary outcomes:
measure: Determine the Maximum Tolerated Dose of PHOX2B PC-CAR T Cells
timeFrame: 5 years
measure: Frequency of Adverse Events Following PHOX2B PC-CAR T cell administration
timeFrame: 5 years
Secondary outcomes:
measure: Manufacturing Feasibility of PHOX2B PC-CAR T cells
timeFrame: 5 years
measure: Persistence of PHOX2B PC-CAR T cells
timeFrame: 5 years
measure: Preliminarily define the clinical activity of PHOX2B PC-CAR T cells in patients with relapsed or refractory neuroblastoma
timeFrame: 5 years
measure: Severity of Adverse Events Following Repeated dosing of PHOX2B PC-CAR T Cells
timeFrame: 5 years
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Jacquelyn Crane, MD
role: STUDY_DIRECTOR
affiliation: Children's Hospital of Philadelphia
name: Stephan A. Grupp, MD, PhD
role: STUDY_DIRECTOR
References: