Phase I/II study of anti-CD7 Chimeric Antigen Receptor-Expressing T cells in pediatric patients/young adult affected by relapsed/refractory CD7+ T-cell Acute Lymphoblastic Leukemia/Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ospedale Pediatrico Bambino Gesu'

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

20 Apr 2024 → ongoing

Decision date (initial)

2024-04-18

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

National Center for Gene Therapy and Drug RNA 2022 PNRR_CN41_FL

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective of this phase I study is to evaluate the safety and to establish the recommended dose of CD7-CART01 cells infused in pediatric patients and young adults affected by relapsed/refractory T-ALL or lymphoblastic lymphoma (LL). The phase II extension is aimed at testing the efficacy of the treatment at the optimal dose defined in the phase I.

Conditions and MedDRA coding

Relapsed/refractory CD7+ T-cell Acute Lymphoblastic Leukemia/Lymphoma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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 1

1. 1. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I primary end-points • To evaluate the safety of the infusion of CD7-CART01 at 2 different escalating doses (1.0 x 106 and 3.0 x 106 cells/kg recipient total body weight of CAR+ T cells) and establish the dose-limiting toxicity (DLT) of the cellular product. DLT will be defined as any of the following that is not pre-existing, due to infection or to underlying malignancy, occurring in the first 28 days after infusion, and that may be considered possibly, probably or definitely related to t
2. Phase II primary end-points 1. To assess the antitumor effect of CD7-CART01 at day 28 post-infusion by determining BM, PB and CSF morphological response and MRD. In particular, the primary end-point will be the proportion of patients achieving either morphological complete remission (CR) or CR with incomplete blood count recovery (CRi) and with minimal residual disease (MRD) negativity at day 28 (defined as a value < 1x10-4).

Secondary endpoints 1

1. Phase I and II secondary end-points: 1. To confirm the safety of the approach, using the recommended dose defined during the Phase I portion of the study. 2. To assess the Overall Response Rate (ORR) at day 28, which includes MRD-negative CR, CR and CR with incomplete blood count recovery (CRi). Only for patients with LL, the percentage of responders will be defined by a reduction of the tumor masses >35% at day+33 and blasts percentage <5% in the BM and absence of blasts in the CSF.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ospedale Pediatrico Bambino Gesu'

Sponsor organisation

Ospedale Pediatrico Bambino Gesu'

Address

Piazza Sant'onofrio 4

City

Rome

Postcode

00165

Country

Italy

Scientific contact point

Organisation

Ospedale Pediatrico Bambino Gesu'

Contact name

Franco Locatelli

Public contact point

Organisation

Ospedale Pediatrico Bambino Gesu'

Contact name

Francesca Del Bufalo

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

3 submissions — initial application plus substantial / non-substantial modifications