Acute Lymphoblastic Leukemia, Acute Lymphoid Leukemia
Conditions
Brief summary
This open-label, single arm Phase 1/1b trial aims to determine the safety and tolerability of anti-CD19 chimeric antigen receptor-expressing (CAR) T cells (UCD19 CAR T) in adults with B-ALL that are in first complete remission with MRD positivity. This trial will enroll 10 patients during Phase 1 for apheresis, treatment with lymphodepleting chemotherapy, and UCD19 CAR T cell infusion. Patients will be assessed for DLTs (within 42 days after CAR T infusion) to determine a maximum tolerated dose (MTD), duration of B cell aplasia, overall response rate (at 1-3-, 6- and 12-months), and overall survival and event free survival (at 12- and 24- months) post UCD19 CAR T infusion. After the initial dose escalation phase, an additional 12 participants will be enrolled in the dose expansion at the MTD to determine preliminary efficacy.
Interventions
DRUGCD19 Directed CAR T Cell
The UCD19 CAR T cells are developed through transfection of autologous peripheral blood mononuclear cells with a lentivirus carrying the DNA that encodes a short chain fragment variable region (scFv) derived from an anti-CD19 monoclonal antibody, among other elements.
Sponsors
University of Colorado, Denver
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age: ≥ 18 years of age with no upper age limit 2. ECOG Performance Status ≤ 2 3. Confirmed B-cell ALL in first complete morphologic remission 4. MRD positivity as defined by: 1. For Ph- ALL: \> 0.01% by FACS or \> 0 clonal sequences by NGS (clonoSEQ). MRD assessment for eligibility must be at least 28 days after the start of SOC induction therapy. Remission-induction therapy must have consisted of multi-agent chemotherapy (≥ 3 systemic anti-leukemia chemotherapy agents). 2. For Ph+ ALL: \> 0.01% by FACS, \> 0 clonal sequences by NGS (clonoSEQ), or less than complete molecular remission (undetectable BCR-ABL1 transcripts by RT-PCR assay with sensitivity of at least 1 in 100,000). MRD assessment for eligibility must be at least 57 days after the start of SOC induction therapy. Remission-induction therapy must have consisted of a BCR-ABL1 directed tyrosine kinase inhibitor and at least one other systemic anti-leukemia chemotherapy agent. 5. Peripheral blood CD3 count must be \> 0.15 x 106 cells/mL within 21 days prior to proceeding with apheresis. 6. Toxicities from prior therapy must be stable and recovered to ≤ Grade 2 (exceptions include non-clinically significant toxicities such as alopecia and the organ function definitions provided in inclusion criteria 7). 7. Adequate organ function as defined by: 1. Absolute neutrophil count (ANC) ≥ 500/μL. 2. Platelet count ≥ 50,000/μL. 3. Renal: Either Creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated by Cockcroft Gault equation) ≥ 60 mL/min. 4. Hepatic: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 upper limit of normal (ULN). 5. Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert's syndrome where a bilirubin \< 3.0 mg/dL will be acceptable. 6. Cardiac: Ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings at the time of screening. 7. Pulmonary: No clinically significant pleural effusion. i. Baseline oxygen saturation \> 92% on room air and; ii. Pulmonary Function Test: Diffuse capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) are all ≥50% of predicted by spirometry after correcting for hemoglobin. 8. Females of childbearing potential must have a negative serum pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential). 9. Subjects of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for 12 months after receiving the UCD19 infusion. 10. Must be able to give informed consent; subjects unable to give informed consent will not be eligible for this study. 11. Be able to consent to long-term follow-up protocol (#20-0188).
Exclusion criteria
1. Previous CAR T therapy. 2. Relapsed or refractory B-cell acute lymphoblastic leukemia, including patients who have evidence of MRD after having previously documented MRD-negative remission. 3. Mixed phenotype acute leukemia or Burkitt's lymphoma 4. Not in hematological remission at time of enrollment (Remission is defined as \< 5% blasts) 5. Signs or symptoms of active CNS disease or detectable evidence of CNS disease on MRI at the time of screening. Subjects who have been previously treated for CNS disease but have no evidence of disease at screening are eligible. 6. History of malignancy unless disease free for at least 3 years. Exceptions include non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast). 7. Uncontrolled fungal, bacterial, viral, or other infection requiring antimicrobials for management; simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment. 8. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (hepatitis B surface antigen \[HBsAg\] positive) or hepatitis C. 9. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment or have cardiac atrial or cardiac ventricular lymphoma involvement. 10. Venous thrombosis or embolism not managed on a stable regimen of anticoagulation. 11. Any medical condition that in the judgement of the Sponsor is likely to interfere with assessment of safety or efficacy of study treatment. 12. History of severe immediate hypersensitivity reaction to any of the agents used in this study. 13. Females planning to become pregnant during the course of the study. Apheresis Eligibility In order to proceed with apheresis, enrolled participants must continue to meet all inclusion criteria within no more than 21 days prior to apheresis, unless otherwise specified. Note: Disease evaluation to meet inclusion criteria must be completed within 30 days prior to apheresis. Screening Eligibility In order to proceed, participants must meet all inclusion criteria. Medical history, blood tests, and assessments may be done as standard of care but must be performed within 14 to 30 days prior to enrollment unless otherwise indicated. Lymphodepleting Chemotherapy Eligibility In order to proceed with lymphodepleting chemotherapy, enrolled participants must have all assessments below completed, and continue to meet all inclusion criteria within 72 hours of initiation of lymphodepletion, with the following clarifications: * Disease restaging studies will be performed as clinically indicated but must be within 14 days prior to initiation of lymphodepletion. * Peripheral blood for CD3 count must be obtained within 21 days prior to apheresis and, therefore, is not applicable for determining lymphodepleting chemotherapy eligibility. * In lieu of
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of UCD19 CAR T in Adults With B-ALL in first complete remission with MRD Positivity: occurrence and frequency of Adverse Events (AEs) | Up to 30 days after last day of study participation | The occurrence and frequency of Adverse Events will be graded using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grading criteria. |
| Safety of UCD19 CAR T in Adults With B-ALL in first complete remission with MRD Positivity: occurrence of Dose Limiting Toxicities (DLTs) | 42 days | Adverse events that are at least possibly related to the UCD19 CAR T cells with onset within the first 42 days following UCD19 CAR T cell infusion and are ≥ Grade 3 in severity will be considered DLTs. With exception to hematological toxicity for subjects with normal, Grade 1 or Grade 2 Hematologic Parameters at baseline (independent of transfusion) and cytopenias NOT due to Bone Marrow Involvement by Disease. However, any Grade 4 hematological toxicity (i.e., neutropenia or thrombocytopenia with the exception of lymphopenia) persisting beyond 42 days after infusion will be considered a DLT unless toxicity is attributed to patient's underlying disease. |
| Preliminary efficacy of UCD19 CAR T infusion at the MTD in adult B-ALL patients at first complete remission with MRD positivity | 12 and 24 months | Determine the Relapse Free Survival (RFS) rate post UCD19 CAR T infusion. RFS will be measured from the date of infusion of the UCD19 CAR T product to the time of relapse or death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) at 1, 3, 6, 12, and 24 months post UCD19 CAR T infusion as measured by MRD. | 1, 3, 6, 12, and 24 months | MRD negativity is defined as bone marrow that has no detectable blasts at or above the sensitivity threshold for the particular assay used (approximately 0.01% for FACS-MRD, 0.001% for BCR-ABL qPCR, 0.0001% for IgH/TCR NGS). MRD positivity post UCD19 CAR T infusion is defined as \> 0.01% by FACS or a rising number of \> 0 clonal sequences by NGS (clonoSEQ) at two timepoints at least 2-4 weeks apart in the bone marrow or peripheral blood for Ph- ALL, and either \> 0.01% by FACS, a rising number of \> 0 clonal sequences by NGS (clonoSEQ), or less than complete molecular remission (undetectable BCR-ABL1 transcripts by quantitative PCR assay with sensitivity of at least 1 in 100,000) at two timepoints at least 2-4 weeks apart in the bone marrow or peripheral blood for Ph+ ALL. |
| Overall Survival (OS) at 12 and 24 months post UCD19 CAR T infusion. | 12 and 24 months | OS defined as measured from the date of infusion to the time of death from any cause. |
| Event Free Survival (EFS) at 12 and 24 months post UCD19 CAR T infusion | 12 and 24 months | EFS is defined as failure to achieve MRD-negativity (approximately 0.01% for FACS-MRD, 0.001% for BCR-ABL qPCR), disease relapse, or death from any cause from the date of infusion |
Countries
United States
Contacts
CONTACTDerek Schatz
CONTACTMathew Angelos, MD
PRINCIPAL_INVESTIGATORMathew Angelos, MD
University of Colorado, Denver
Outcome results
None listed