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

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). This study will enroll adult patients with lymphoma or multiple myeloma who are scheduled to receive commercially available, protocol specified CAR T-cell therapy.

Participants who are assigned to cohorts not receiving run-in dosing will start taking CTO1681 the day prior to receiving their CAR T-cell therapy and continue to take the study drug three times daily until 13 days after the CAR T-cell infusion (total of 15 days). Participants assigned to cohorts the do receive run-in dosing will start taking CTO1681 the day before starting lymphodepleting chemotherapy and continue to take the study drug three times daily until 13 days after the CAR T-cell infusion (approximately 20 days total).

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 from the start of dosing until 41 days after CAR T-cell infusion, 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.

Inclusion criteria

• Age 18 years or older.
• Undergone leukapheresis and is scheduled to receive protocol-specified CAR T-cell therapy (axicabtagene ciloleucel, lisocabtagene maraleucel, idecabtagene vicleucel, or ciltacabtagene autoleucel) for relapsed or refractory lymphoma or multiple myeloma. All patients must have relapsed or refractory disease to at least one prior line of systemic therapy. Prior CAR T-cell therapy is allowable with approval from the Sponsor and Medical Monitor.
• Met all inclusion criteria for CAR T-cell therapy per institutional guidelines.
• Adequate organ function defined as:

• Estimated Creatinine Clearance per Cockroft Gault formula ≥ 60 mL/min.
• Serum alanine aminotransferase/aspartate aminotransferase ≤ 2.5 × ULN.
• Total bilirubin ≤ 1.5 × ULN.
• Left ventricular ejection fraction ≥ 40% on echocardiogram or multigated acquisition and no clinically significant pericardial effusion.
• Platelets ≥ 50,000/mm3.
• Absolute neutrophil count > 1000/μL.
• Absolute lymphocyte count > 100/μL.
• Disease specification must match the indication described in the product label of the planned CAR T-cell product.
• Eastern Cooperative Oncology Group performance status 0 to 1.
• 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.
• 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

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

• Potassium < 3.0 or > 5.5 mmol/L
• Sodium < 130 or > 150 mmol/L
• Calcium < 8.0 or > 11.5 mg/dL
• Magnesium < 0.5 or > 1.23 mmol/L
• Clinically significant ECG abnormality at Screening or Baseline (Day -1), including but not limited to, a confirmed QTcF value > 470 msec. Patients to be excluded included those 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. This also includes any Grade 2 or greater conduction block disorder, atrial, or ventricular arrythmia. A patient with an ECG abnormality may be enrolled only after approval by the Medical Monitor and Sponsor.
• Active central nervous system (CNS) lymphoma (history of CNS involvement may be allowable only after approval by the Medical Monitor and Sponsor).
• 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.
• Uncontrolled thromboembolic events or recent severe hemorrhage within the last 6 months.
• Known history of any bleeding disorder.
• Requirement for ongoing therapeutic doses of anticoagulant therapy, antiplatelet or fibrinolytic agents (low molecular weight heparin prophylaxis is allowed).
• Baseline systolic blood pressure <100 mmHg.
• History of autoimmune disease/ graft versus host disease requiring immunosuppressive therapy within the last 2 years. However, physiologic steroids may be given at a dose of 5 mg or less (prednisone equivalent).
• Patients who, in the opinion of the Investigator, would be unlikely to comply with study procedures or are otherwise unsuitable for enrollment.
• Planned prophylactic treatment for CRS or ICANS with corticosteroids or any immunomodulatory or anticytokine therapies (including but not limited to tocilizumab and anakinra).