Study of CTO1681 for the Prevention and Treatment of CRS in DLBCL Patients Receiving CAR T-Cell Therapy

This is an interventional study to evaluate the use of CTO1681 in preventing or reducing CAR T-cell-induced toxicities like cytokine release syndrome (CRS). This study will enroll adult patients with DLBCL who are scheduled to receive CD19-directed CAR T-cell therapy.

The first phase of the study will be open label with dose escalation. Participants will start taking CTO1681 just prior to receiving their CAR T-cell therapy and continue to take the study drug three times daily for a total of 15 days.

The first phase of the study will be an open-label, dose escalation, safety assessment in a group of patients, and will also collect data to investigate the potential benefit of CTO1681, initiated prior to CAR T-cell therapy, in preventing or reducing certain toxicities or side effects associated with CAR T-cell therapy, such as cytokine release syndrome (CRS).

Participants will start taking CTO1681 just prior to receiving their CAR T-cell therapy and continue to take the study drug three times daily for a total of 15 days.

Participants will provide blood samples at specified points throughout the study. In addition, urine samples, ECGs, scans, and other medical evaluations will be performed that are associated with the CAR T-cell therapy and/or necessary to verify study eligibility. Participants will be monitored for safety and efficacy for 43 days, and then will have follow-up to continue to monitor for safety and monitor for tumor response for up to 6 months for phase 1.

Eligibility Criteria:
Inclusion Criteria:

1. Age 18 years or older.
2. Undergone leukapheresis and is scheduled to receive protocol-specified commercially available axicabtagene ciloleucel CD19-directed CAR T-cell therapy for DLBCL without corticosteroid prophylaxis for CRS and/or ICANS. Patients eligible for study must have relapsed or refractory DLBCL after at least one prior line of systemic therapy.
3. Met all inclusion criteria for CAR T-cell therapy per institutional guidelines.
4. Adequate organ function defined as:

   1. Estimated Creatinine Clearance per Cockroft Gault formula ≥ 60 mL/min.
   2. Serum alanine aminotransferase/aspartate aminotransferase ≤ 2.5 × ULN.
   3. Total bilirubin ≤ 1.5 × ULN.
   4. Left ventricular ejection fraction ≥ 40% on echocardiogram or multigated acquisition and no clinically significant pericardial effusion.
   5. Platelets ≥ 50,000/mm3.
   6. Absolute neutrophil count \> 1000/μL.
   7. Absolute lymphocyte count \> 100/μL.
5. Documented measurable lymphoma disease adequate to judge by Lugano Criteria.
6. Eastern Cooperative Oncology Group performance status 0 to 1.
7. Female participants of childbearing potential and all male participants must agree to use Investigator-approved methods of birth control while on study drug and for 30 days thereafter.
8. Patients who are willing to provide written informed consent before the predose procedures, or patients who have a legal representative capable of providing informed consent on their behalf.

Exclusion Criteria:

1. Any cytotoxic chemotherapy within 14 days prior to leukapheresis.
2. Clinically significant malabsorption syndromes and swallowing difficulties which are inadequately controlled with medication (eg, odynophagia, dysphagia, gastroesophageal reflux disease) as per Investigator assessment.
3. Grade 2 or greater electrolyte imbalance, per CTCAE v5.0:

   1. Potassium \< 3.0 or \> 5.5 mmol/L
   2. Sodium \< 130 or \> 150 mmol/L
   3. Calcium \< 8.0 or \> 11.5 mg/dL
   4. Magnesium \< 0.5 or \> 1.23 mmol/L
4. Clinically significant ECG abnormality at Screening or Baseline (Day -1), including but not limited to, a confirmed QTcF value \> 470 msec. Patients with QTcF readings that are borderline or difficult to interpret because of a condition such as bundle branch block, or in those where the end of the T wave is difficult to measure will be excluded. This also includes any Grade 2 or greater conduction block disorder, atrial, or ventricular arrythmia.
5. History of clinically significant arrhythmia and/or requiring anticoagulation/antiplatelet treatment at therapeutic dose.
6. Any clinically significant (ie, active) cardiovascular disease, including cerebral vascular accident/stroke (\< 6 months before enrollment), myocardial infarction (\< 6 months before enrollment) or unstable angina, and congestive heart failure ≥ New York Heart Association Classification Class III.
7. Uncontrolled thromboembolic events or recent severe hemorrhage within the last 6 months.
8. Known history of any bleeding disorder.
9. Requirement for ongoing therapeutic doses of anticoagulant therapy, antiplatelet or fibrinolytic agents (low molecular weight heparin prophylaxis is allowed).
10. Baseline systolic blood pressure \<100 mmHg.
11. History of autoimmune disease/ graft versus host disease requiring immunosuppressive therapy within the last 2 years. However, physiologic steroids (prednisone equivalent) may be given at a dose of 5 mg or less.
12. Patients who, in the opinion of the Investigator, would be unlikely to comply with study procedures or are otherwise unsuitable for enrollment.