Safety and Efficacy of ThisCART19A Bridging Hematopoietic Stem Cell Transplantation in Patients With Refractory or Relapsed B-cell Acute Lymphoblastic Leukemia

A Single Dose-escalation Study to Evaluate the Safety and Efficacy of Allogeneic CAR-T Targeting CD19 Bridging Hematopoietic Stem Cell Transplantation in Patients With Refractory or Relapsed B Cell Acute Lymphoblastic Leukemia

This is a a phase 1, open label study to assess the safety and efficacy of ThisCART19 (Allogeneic CAR-T targeting CD19) Bridging Hematopoietic Stem Cell Transplantation in patients with refractory or relapsed B cell acute lymphoblastic leukemia (r/r B-ALL).

Study Overview

• Status: Not yet recruiting
• Conditions: Allogeneic, CAR-T, Protein Sequestration, Non-gene Edited
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: ThisCART19A; Drug: Fludarabine Oral Tablet; Drug: VP-16; Procedure: HSCT

Detailed Description

This is a phase 1, single-center, nonrandomized, open-label, dose-escalation study to evaluate the safety and efficacy of ThisCART19A Bridging Hematopoietic Stem Cell Transplantation in patients with CD19 positive r/r B-ALL and identify a treatment regimen most likely to result in clinical efficacy while maintaining a favorable safety profile.

• Study Type: Interventional
• Enrollment (Anticipated): 19
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jun Li, Ph.D; Phone Number: +86-18662604088; Email: jli@ctigen.com
• Study Contact Backup: Name: Yongping Song, Ph.D; Phone Number: +86-13521186987; Email: songyongping@medmail.com.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 71 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. All subjects or legal representatives must sign a voluntary letter of consent approved by the IRB in person prior to the commencement of any screening procedure;
2. Patients diagnosed with B-ALL;
3. No gender limitation, Age 14 years to 75 years (both upper and lower limits included);

4. Consistent with the diagnosis of recurrent refractory B-ALL. Recurrence： was defined as the recurrence of lymphoblasts（≥5%） in peripheral blood or bone marrow or extramedullary diseasefor patients who had acquired CR ; Refractory ：was defined as failure to CR or CRi at the end of induction therapy (generally referred to 4-week regimen or Hyper-CVAD regimen);Patients with Ph+ R/R ALL who failed after 2-line TKI treatment, were intolerant to TKI treatment or were not suitable for TKI treatment; The following factors can coexist:

   1. Failure to prepare autologous CAR-T (definition: too few autologous lymphocytes [200/ML] or cannot meet the release standard);
   2. Experienced treatment with auto car-T/berintoomumab/ CD22 antibody conjugation drugs;
   3. ≥100 days after hematopoietic stem cell transplantation;

   4. High-risk patients (High risk was defined as a high white blood cell count ≥30×109/L at diagnosis or with poor cytogenetic prognosis);

      • Hypodiploid (<44 chromosomes);
      • KMT2A rearrangement: t (4;11) or otherwise;
      • t (v; 14q32) /IgH
      • t (9; 22) (q34; q11.2) or BCR-ABL1
      • Complex karyotype (≥5 chromosomal abnormalities);
      • BCR-ABL1-like (Ph-like) ALL;
      • JAK-STAT (CRLF2r, EPORr, JAK1/2/3r, TYK2r, mutations of SH2B3, IL7r, Jak1/2/3);
      • ABL class rearrangements (such as ABL1, ABL2, PDGFRA, PDGFRB, FGFR, etc.)
      • Others (NTRKr, FLT3r, LYNr, PTK2Br);
      • Intrachromosomal amplification of chromosome 21 (iAMP21);
      • t (17; 19): TCF3-HLF fusion;
      • Alterations of IKZF1;
   5. Extramedullary lesions.
5. The expected survival time is ≥12 weeks;
6. ECOG score 0-2;
7. Adequate bone marrow, renal, hepatic, pulmonary and cardiac function;
8. CD19 was still expressed in leukemia cells in bone marrow, peripheral blood or biopsy tissue by flow cytometry within one month prior to informed consent (after the last treatment).

Exclusion Criteria:

1. Allergic to preconditioning measures;
2. Diagnosis of chronic myelogenous leukemia lymphoid blast crisis;
3. Isolated extramedullary relapse;
4. Presence of CNS-3 disease or CNS-2 disease with neurological changes;
5. Imaging confirmed the presence of central nervous system involvement;
6. Severe CNS disorders such as a history of frequent epileptic seizures;
7. Patients with other malignancies other than B-cell malignancies within 5 years prior to screening. Patients with cured skin squamous carcinoma, basal carcinoma, non-primary invasive bladder cancer, localized low-risk prostate cancer, in situ cervical/breast cancer can be recruited.
8. Uncontrollable bacterial, fungal and viral infection during screening;
9. Patients had pulmonary embolism (PE) and/or deep vein thrombosis (DVT) within 3 months prior to enrollment;
10. Had intolerant severe cardiovascular and cerebrovascular diseases and hereditary diseases prior to enrollment;
11. Radiation therapy within 2 weeks prior to lymphodepletion chemotherapy (>30% bone marrow exposure);
12. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) or Human immunodeficiency virus (HIV) or Syphilis infection. HBV-DNA < 2000 IU/mL can be enrolled, but should admitted to use anti-virus drugs such as entecavir, tenofovir, etc, and supervisory the relative indication during the treatment;
13. Vaccinated with influenza vaccine within 2 weeks prior to lymphodepleting chemotherapy (Severe Acute Respiratory Syndrome-Corona virus disease 19 can be included, inactivated, live/non-live adjuvant vaccinations allowed to be included) ;
14. Patients who are receiving Graft versus host disease Hepatitis(GvHD) treatment; Patients without GvHD and who had stopped immunosuppressive drugs for at least 1 month were eligible for inclusion;
15. Women who are in pregnant or lactating, and female subjects or partners who plan to be pregnant within 1 year after cell infusion. Male subjects who plan pregnancy within 1 year after infusion;
16. Any ineligibility conditions considered by the investigator that may increase the risk of the subject or interfere with the results of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ThisCART19A cells infusion and HSCT; In this study, allogeneic anti-CD19 CAR T cell (ThisCART19A) infusion is used to treat patients with refractory or relapsed CD19 positive B cell acute lymphoblastic leukemia. After patients achieve MRD- remissions through ThisCART19A, they will subsequently receive hematological stem cell transplantations.	Drug: Cyclophosphamide; Cyclophosphamide is used for lymphodepletion.; Drug: ThisCART19A; ThisCART19A is a new type CAR-T therapy for patients with r/r B-ALL.; Drug: Fludarabine Oral Tablet; Fludarabine is used for lymphodepletion.; Drug: VP-16; VP-16 is used for lymphodepletion.; Other Names: etoposide; Procedure: HSCT; Hematological stem cell transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limited toxicity(DLT) observation in patient with B-ALL in each dose level during dose escalation and dose expansion stage	DLT is defined as the incidence of severe adverse events related to ThisCART19A more than 33% in each dose level.	28 days
Overall Complete Response (OCR) Rate (Complete Remission [CR]+ Complete Remission With Incomplete Hematologic Recovery [CRi]) within 3 months	OCR rate within 3 months: percentage of participants achieving CR+CRi within 3 months after CAR-T cell infusion.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimum Residual Disease (MRD) Negative Remission Rate	MRD was assessed utilizing multicolor flow cytometry to detect residual cancerous cells with a sensitivity of 10^-4. MRD negative remission was defined as MRD < 10^-4 threshold. Percentage of participants with MRD negative remission was reported.	3 months
Duration of response(DOR) during dose escalation stage and expansion stage	DOR was defined as the time from first CR or CRi to relapse or any death in the absence of documented relapse.	24 months
RFS (Relapse-free Survival)	RFS is defined as the time from the date of ThisCART19A infusion to the date of disease relapse or death from any cause.	24 months
EFS (Event-free Survival)	EFS is defined as the time from the date of ThisCART19A infusion to the date of disease relapse, progression, genetic relapse or death from any cause.	24 months
OS (Overall Survival)	OS is defined as the time from the date of ThisCART19A infusion to the date of death from any cause.	24 months

Collaborators and Investigators

• Sponsor: Fundamenta Therapeutics, Ltd.
• Collaborators: The First Affiliated Hospital of Zhengzhou University
• Investigators: Principal Investigator: Yongping Song, Ph.D, The first affiliated hospital of Zhengzhou university

Study record dates

Study Major Dates

• Study Start (Anticipated): October 15, 2022
• Primary Completion (Anticipated): January 22, 2025
• Study Completion (Anticipated): July 22, 2025

Study Registration Dates

• First Submitted: September 23, 2022
• First Submitted That Met QC Criteria: October 8, 2022
• First Posted (Actual): October 12, 2022

Study Record Updates

• Last Update Posted (Actual): October 12, 2022
• Last Update Submitted That Met QC Criteria: October 8, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cyclophosphamide; Etoposide; Fludarabine
• Other Study ID Numbers: ThisCART19 FT400-007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No