UCD19 CAR T Therapy in Adults With B-ALL and MRD Positivity in CR1

Phase 1/1b Safety and Tolerability Trial of CD19 Directed CAR T Cells in Adult Patients With B-Cell Acute Lymphoblastic Leukemia (B-ALL) With Minimal Residual Disease (MRD) Positivity at First Complete Remission

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.

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 exclusion criteria #4, there must be no evidence of rapidly progressive disease prior to LD chemotherapy initiation per Investigator assessment.

Bridging disease directed antineoplastic therapy is allowed with progressive disease after enrollment but before initiation of lymphodepleting chemotherapy will be removed from the study.

The following assessments will be used to confirm that the participant is able to initiate lymphodepleting chemotherapy (within 72 hours of starting chemotherapy):

• Medical history and Baseline Abnormalities

  • Medical history (defined as ongoing medical conditions identified before the subject's first study-specific intervention (i.e., initiation of LD Chemotherapy on Day -5).
  • Baseline abnormalities refer to abnormal clinical findings (e.g., laboratory values, vital signs, ECG results, etc.) identified before the start of LD Chemotherapy that may or may not be related to the subject's underlying disease.
  • All medical history and baseline abnormalities should be entered in the eCRF. Events should be assessed within 30 days prior to enrollment until LD Chemotherapy. Grading per CTCAE v5.0 should reflect the patient's status at the time of LD Chemotherapy.

• Physical exam

UCD19 CAR T Cell Infusion Eligibility

Participants must meet the following criteria in order for cells to be infused (based on labs obtained within 24 hours of cell infusion):

• UCD19 CAR T Cells must have met release criteria.
• Performance status determination (ECOG must be ≤ 2).
• Participant remains clinically stable without evidence of vital sign instability.
• Must not have ALT/SGPT and AST/SGOT > 10x the ULN or bilirubin >2x the ULN, (unless history of Gilberts syndrome where bilirubin must not be >3x ULN).
• Adequate renal function as defined in the Inclusion Criteria.
• No evidence of uncontrolled infection within 48 hours prior to cell infusion as determined by the PI or sub-investigator. If these criteria are not met, measures will be taken to resolve the underlying condition(s). If successful, cells may be infused up to (and including) 7 days following the time of the planned infusion with no additional lymphodepletion. If the UCD19 CAR T Cell infusion is delayed greater than 7 days, lymphodepleting chemotherapy MAY be repeated. Prior to commencing a second round of lymphodepletion, participants must meet lymphodepletion criteria described above.

Prior to moving to the treatment portion of this study, participants must meet limited eligibility criteria as specified above.

UCD19 CAR T cells may be infused on an inpatient or outpatient basis at the discretion of the treating investigator. Following discharge, participants will continue with once-a-week evaluation until Day 42. If UCD19 CAR T cells are infused on an outpatient basis or following discharge after being inpatient, the participant will need to stay within 1 hour of the Anschutz Medical Campus for at least 4 weeks from date of CAR T cell infusion for monitoring by the treating investigator.

TKI Therapy Post ICD19 CAR T Cell Infusion Eligibility

Participants must meet the following criteria in order to receive TKI therapy:

• Disease classified as Ph+ B-ALL.
• Must be past the DLT period (Day 42).
• Platelet count > 50,000/μL.
• ANC > 1000/μL.