Phase I/II Evaluation of CD7-CART01, Cyclophosphamide, and Fludarabine Phosphate in Pediatric and Young Adult Relapsed/Refractory CD7+ T-ALL/Lymphoblastic Lymphoma
- Trial ID
- 2023-508355-39-00
- Protocol
- CD7-CAR01
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase I/II study is to evaluate the **safety** and establish the recommended dose of CD7-CART01 cells in pediatric patients and young adults with relapsed/refractory CD7+ T-cell Acute Lymphoblastic Leukemia/Lymphoma. This is crucial for determining the appropriate dosage that minimizes adverse effects while maintaining therapeutic potential. The Phase II extension aims to assess the **efficacy** of the treatment at the optimal dose identified in Phase I, which is essential for understanding the treatment's potential to improve clinical outcomes in this patient population.
Participants
The clinical trial involves a study population comprising pediatric patients and young adults aged **6 months to 25 years** diagnosed with **relapsed/refractory CD7+ T-cell Acute Lymphoblastic Leukemia/Lymphoma**. The trial includes both male and female participants, and the population is considered vulnerable due to the age range and health conditions involved. The sponsor has not provided the total number of participants. Participants were selected based on specific eligibility criteria, including a diagnosis of CD7 expressing T-ALL or LL, and the presence of measurable or evaluable disease. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have adequate venous access for apheresis and a potential allogeneic hematopoietic stem cell donor available. The study aims to evaluate the safety and establish the recommended dose of CD7-CART01 cells in this demographic.
Plans and Procedures
The clinical trial is designed to evaluate the safety and efficacy of **CD7-CART01** cells in pediatric patients and young adults with relapsed or refractory CD7+ T-cell Acute Lymphoblastic Leukemia or Lymphoma. This is a Phase I/II trial, structured as a randomized, double-blind, controlled study. The trial is expected to commence in April 2024 and conclude by September 2028. Participants will be involved in the study for a duration that includes initial screening, treatment, and follow-up visits, with the total involvement period varying based on individual response and treatment outcomes.
The study begins with a screening visit to assess eligibility, which includes confirming the diagnosis of CD7+ T-cell malignancies and ensuring adequate venous access for apheresis. Following successful screening, participants will undergo a series of study visits. The initial phase involves dose-escalation to determine the recommended dose of CD7-CART01 cells, with safety and dose-limiting toxicity as primary endpoints. Participants will receive the investigational product via **intravenous** infusion, with follow-up visits scheduled to monitor safety and efficacy outcomes.
Subsequent visits will focus on assessing the antitumor effect of the treatment, with primary endpoints including morphological response and minimal residual disease (MRD) negativity at day 28 post-infusion. Secondary endpoints will evaluate the overall response rate and confirm the safety of the recommended dose. The end-of-study visit will occur after the final follow-up assessments, marking the completion of the participant's involvement in the trial.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in the participant's best interest. The trial's design ensures rigorous monitoring and adherence to ethical standards, with informed consent obtained from all participants or their legal guardians. The study aims to provide valuable insights into the potential therapeutic benefits of CD7-CART01 cells for this patient population.
Treatment
The clinical trial involves the administration of **Cyclophosphamide**, a chemotherapeutic agent, provided in the form of a **solution for injection**. The product, marketed as Cyclophosphamide Injection 1 g, is manufactured by Baxter Healthcare Ltd. It is administered via **solution for injection or infusion**. The specific dosage, frequency, and administration schedule are determined based on the trial protocol and patient-specific factors. Participant compliance is monitored through regular assessments and documentation of administration.
**Fludarabine Phosphate** is another chemotherapeutic agent used in this study, provided as a powder for solution for injection or infusion, under the brand name Fludara 50 mg. This product is manufactured by Genzyme Europe B.V. and is administered as a **solution for injection or infusion**. The dosing regimen is tailored according to the trial's requirements and patient response, with compliance monitored through scheduled follow-ups and adherence checks.
The experimental treatment in this trial is **CD7-CART01**, a cell therapy product provided as a **cell suspension for injection**. This investigational product is developed by IRCCS Ospedale Pediatrico Bambino Gesù and is administered intravenously. The primary objective of the trial is to evaluate the safety and establish the recommended dose of CD7-CART01 cells in pediatric patients and young adults with relapsed or refractory T-cell Acute Lymphoblastic Leukemia or lymphoblastic lymphoma. The administration schedule and dosing are determined during the trial's phase I, with efficacy assessed in phase II. Compliance is ensured through rigorous monitoring and documentation of each administration.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Phase I include evaluating the safety of the infusion of **CD7-CART01** at two escalating doses and establishing the dose-limiting toxicity (DLT) of the cellular product. For Phase II, the primary endpoint is to assess the antitumor effect of **CD7-CART01** at day 28 post-infusion by determining bone marrow (BM), peripheral blood (PB), and cerebrospinal fluid (CSF) morphological response and minimal residual disease (MRD). The primary endpoint will focus on the proportion of patients achieving either morphological complete remission (CR) or CR with incomplete blood count recovery (CRi) and MRD negativity at day 28, defined as a value less than 1x10-4.
Secondary endpoints for both Phase I and II include confirming the safety of the approach using the recommended dose defined during Phase I and assessing the Overall Response Rate (ORR) at day 28. This includes MRD-negative CR, CR, and CRi. For patients with lymphoblastic lymphoma (LL), the percentage of responders will be defined by a reduction of tumor masses greater than 35% at day 33, a blast percentage of less than 5% in the BM, and the absence of blasts in the CSF. These efficacy parameters will be measured and analyzed at specified time points to determine the treatment's effectiveness in achieving the desired clinical outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients will be screened for eligibility criteria at procurement (i.e. before apheresis) and before treatment. Procurement eligibility Inclusion Criteria 1. Diagnosis of CD7 expressing (> 98% CD7 expression on blast cells) T-ALL or LL and one of the following: 1. Patients with T-ALL in 1st or subsequent relapse, after at least one standard frontline chemotherapy with BM involvement (MRD >1% in 2 consecutive determinations or evidence of morphological relapse, i.e. >5% blasts in BM) 2. Relapse after allogeneic HSCT, if at least 100 days post-transplant, if there is no evidence of active GVHD and if the patient is no longer taking immunosuppressive agents for at least 30 days prior to enrollment 3. CNS disease as defined as > 5 WBCs/ L in CSF with morphological/flow-cytometry evidence of blasts or biopsy proven recurrence in the eye or brain 4. Extramedullary relapse as defined by morphological evidence of blasts in the testis or any other extramedullary sites 5. Refractory disease, defined as MRD ≥ 1% or <1% but persistently positive (i.e. a positive MRD value confirmed by PCR at 2 subsequent evaluations performed at least 2 weeks apart), at the end of consolidation blocks in newly diagnosed patients 2. Age: 6 months – 25 years. 3. Adequate venous access for apheresis or eligible for appropriate catheter placement, and no other contraindications for leukapheresis 4. Voluntary informed consent is given. For subjects <18-year-old, or below the age required by each Country regulation, their legal guardian must give informed consent. Pediatric subjects will be included in age-appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate, or to sign age-adapted informed consent, according to the regulatory requirement of each Country. 5. Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients < 16 years of age: Lansky scale greater than or equal to 60%. Treatment eligibility Patient Inclusion Criteria 6. Diagnosis of CD7 expressing (> 98% CD7 expression on blast cells) T-ALL or LL and one of the following: 1. Patients with T-ALL in 1st or subsequent relapse, after at least one standard frontline chemotherapy with BM involvement (MRD >1% in 2 consecutive determinations or evidence of morphological relapse, i.e. >5% blasts in BM) 2. Relapse after allogeneic HSCT, if at least 100 days post-transplant, if there is no evidence of active GVHD and if the patient is no longer taking immunosuppressive agents for at least 30 days prior to enrollment 3. CNS disease as defined as > 5 WBCs/ L in CSF with morphological or flow-cytometry evidence of blasts or biopsy proven recurrence in the eye or brain 4. Extramedullary relapse as defined by morphological evidence of blasts in the testis or any other extramedullary sites 5. Refractory disease, defined as MRD ≥1% or <1% but persistently positive (i.e. a positive MRD value confirmed by PCR at 2 subsequent evaluations performed at least 2 weeks apart), at the end of consolidation blocks in newly diagnosed patients 7. Measurable or evaluable disease at the time of enrollment, which may include any evidence of disease, including MRD detected by flow-cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis. 8. Age: 6 months – 25 years. 9. Before enrollment for treatment, patients must have a potential allogeneic hematopoietic stem cell (HSC) donor (matched related, matched unrelated or haploidentical) available. 10. Voluntary informed consent is given. For subjects <18-year-old, or below the age required according to each Country regulation, their legal guardian must give informed consent. Pediatric subjects will be included in age-appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate, or to sign age-adapted informed consent, according to the regulatory requirement of the Country.
Exclusion Criteria
- Severe, uncontrolled active intercurrent infections 2. HIV, or active HCV (<12 weeks between achievement of a sustained virological response to the specific treatment and apheresis) and/or HBV infection (either positive for Hepatitis B core antibody [HBcAb] or positive hepatitis B surface antigen [HBsAg] AND NAT tests), defined according to the American Association for the Study of Liver Diseases guidelines. 3. Blast contamination in peripheral blood >5% and/or CD3+ cells < 300/mcL by flow-cytometry, at the time of leukapheresis collection 4. Concurrent or recent prior therapies, before apheresis: i. Systemic steroids (at a dose equivalent to or greater than 2 mg/kg prednisone) in the 2 weeks before apheresis collection. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary. ii. Systemic chemotherapy in the 2 weeks preceding apheresis collection. iii. Nelarabine, daratumomab, clofarabine exposure in the 3 weeks preceding apheresis collection. iv. Anti-thymocyte globulin (ATG) or Alemtuzumab (Campath®) in the 8 weeks preceding apheresis collection. v. Immunosuppressive agents in the 2 weeks preceding apheresis collection. vi. Radiation therapy must have been completed at least 2 weeks prior to apheresis. vii. Donor lymphocytes infusion in the 4 weeks preceding apheresis collection. viii. Other anti-neoplastic investigational agents currently administered or within 30 days prior to apheresis (i.e. start of protocol therapy); ix. Exceptions: 1. There is no time restriction with regard to prior intrathecal chemotherapy, provided that there is complete recovery from any acute toxic effects of such; 2. Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study provided they meet all other eligibility criteria; 3. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis. Treatment eligibility: 1. Pregnant or lactating women 2. Severe, uncontrolled active intercurrent infections 3. HIV, or active HCV (<12 weeks between achievement of a sustained virological response to the specific treatment and apheresis) and/or HBV infection (either positive for Hepatitis B core antibody [HBcAb] or positive hepatitis B surface antigen [HBsAg] AND NAT tests), defined according to the American Association for the Study of Liver Diseases guidelines 4. Life-expectancy < 6 weeks 5. Hepatic function: Inadequate liver function defined as total bilirubin > 3x upper limit of normal (ULN) or transaminase (ALT and AST) > 5 x ULN 6. Renal function: Creatinine clearance calculated using the Schwartz formula1, or radioisotope glomerular filtration rate (GFR) <70 mL/min/1.73 m2. 7. Blood oxygen saturation < 90%. 8. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO. 9. Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject. 10. Uncontrolled seizures or status epilepticus; increased intra-cranial pressure as evidenced by papilledema and CSF opening pressure > 20 cm water; decreased conscious state (any cause) 11. Contamination of either the apheresis collection or the CD7-CART01 drug product with >5% blasts 12. Presence of active, grade 2-4 acute or extensive chronic GvHD 13. Evidence of concomitant clinically significant disorder, condition or disease that, in the investigator’s judgement, would interfere with the patient’s safety or with study procedures or completion.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 01 Apr 2024 | 26 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Fludara 50 mg powder for solution for injection or infusion. | Other | POWDER FOR SOLUTION FOR INJECTION OR INFUSION. | SOLUTION FOR INJECTION OR INFUSION | — | — | PRD440781 |
Cyclophosphamide Injection 1 g. | Other | INJECTION | SOLUTION FOR INJECTION OR INFUSION | — | — | PRD347230 |