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

Phase 1B/2A Study of CTO1681 for the Prevention and Treatment of Cytokine Release Syndrome in Patients Receiving Chimeric Antigen Receptor 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 lymphoma or multiple myeloma who are scheduled to receive CAR T-cell therapy.

The first phase of the study is open label with dose escalation. Participants will start taking CTO1681 either the day before starting lymphodepleting chemotherapy or just prior to receiving their CAR T-cell therapy, depending on their cohort assignment. In both cases participants will continue to take the study drug three times daily until 13 days after their CAR T-cell infusion.

Study Overview

• Status: Recruiting
• Conditions: Cytokine Release Syndrome
• Intervention / Treatment: Drug: CTO1681 20 μg; Drug: CTO1681 30 μg; Drug: CTO1681 10 µg; Drug: CTO1681 10 µg Run-in / 20 µg Treatment; Drug: CTO1681 20 µg Run-in / 30 µg Treatment

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Heather Nottingham, PhD; Email: heather@tekteam.net
• Study Contact Backup: Name: Gail Brown, MD; Phone Number: 650-868-2182; Email: gail@tekteam.net

Study Locations

• United States
  • California
    • Orange, California, United States, 92868
      • Recruiting
      • University of California, Irvine - Chao Family Comprehensive Cancer Center
      • Contact: Blake Johnson; Phone Number: 714-456-3476; Email: blakej@hs.uci.edu
      • Principal Investigator: Stefan Ciurea, MD
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Recruiting
      • Georgia Cancer Center at Augusta University
      • Principal Investigator: Yenny Moreno, MD
      • Contact: Rebecca Paynter, MSN, RN; Phone Number: 7064465177; Email: rpaynter@augusta.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Beth Israel Deaconess Medical Center
      • Contact: Jon Arnason, MD; Phone Number: 617-667-9920; Email: jarnason@bidmc.harvard.edu
      • Principal Investigator: Jon Arnason, MD
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Recruiting
      • Duke Cancer Institute
      • Principal Investigator: Chenyu Lin, MD
      • Contact: Jennifer Tichon, BSN, RN; Phone Number: 919-660-7262; Email: jennifer.tichon@duke.edu
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Recruiting
      • University of Pittsburgh Medical Center
      • Principal Investigator: Alison Sehgal, MD
      • Contact: Linda Elias, BSN, RN; Phone Number: 4126236037; Email: eliaslj@upmc.edu
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutchinson Cancer Center
      • Principal Investigator: Jordan Gauthier, MD, MSc
      • Contact: Immunotherapy Intake; Phone Number: 206-606-4668; Email: immunotherapy@fredhutch.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18 years or older.
2. 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.
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. Disease specification must match the indication described in the product label of the planned CAR T-cell product.
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 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.
5. Active central nervous system (CNS) lymphoma (history of CNS involvement may be allowable only after approval by the Medical Monitor and Sponsor).
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 may be given at a dose of 5 mg or less (prednisone equivalent).
12. Patients who, in the opinion of the Investigator, would be unlikely to comply with study procedures or are otherwise unsuitable for enrollment.
13. Planned prophylactic treatment for CRS or ICANS with corticosteroids or any immunomodulatory or anticytokine therapies (including but not limited to tocilizumab and anakinra).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CTO1681 30 μg Total Daily Dose; Participants receive 10 μg CTO1681 orally 3 times daily (total daily dose of 30 μg) for 15 days.	Drug: CTO1681 10 µg; Administered 3 times daily for 15 days (initial cohort).
Experimental: CTO1681 60 μg Total Daily Dose; Participants receive 20 μg CTO1681 orally 3 times daily (total daily dose of 60 μg) for 15 days.	Drug: CTO1681 20 μg; Administered 3 times daily for 15 days (successive cohort).
Experimental: CTO1681 90 μg Total Daily Dose; Participants receive 30 μg CTO1681 orally 3 times daily (total daily dose of 90 μg) for 15 days.	Drug: CTO1681 30 μg; Administered 3 times daily for 15 days (successive cohort).
Experimental: CTO1681 30 µg Run-in Daily Dose / 60 µg Treatment Daily Dose; Participants receive 10 µg CTO1681 orally 3 times daily (total daily dose of 30 µg) during the run-in period and then 20 µg CTO1681 orally 3 times daily (total daily dose of 60 µg) during the treatment period. The total dosing duration is up to 21 days.	Drug: CTO1681 10 µg Run-in / 20 µg Treatment; Administered 3 times daily for up to 21 days (successive cohort).
Experimental: CTO1681 60 µg Run-in Daily Dose / 90 µg Treatment Daily Dose; Participants receive 20 µg CTO1681 orally 3 times daily (total daily dose of 60 µg) during the run-in period and then 30 µg CTO1681 orally 3 times daily (total daily dose of 90 µg) during the treatment period. The total dosing duration is up to 21 days.	Drug: CTO1681 20 µg Run-in / 30 µg Treatment; Administered three times daily for up to 21 days (successive cohort).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events (AEs)	AEs graded by CTCAE v5.0	6 months following start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of CRS (any grade)	CRS graded by ASTCT Consensus Grading	6 months following the start of treatment
Incidence of ICANS (any grade)	ICANS graded by ASTCT Consensus Grading	6 months following the start of treatment
Incidence of hospitalizations	Unplanned hospitalizations	6 months following the start of treatment
Use of other anticytokine therapies	Use of cytokine mitigating therapies other than CTO1681	6 months following the start of treatment
Proinflammatory cytokine levels	Concentration of proinflammatory cytokines in the blood	6 months following the start of treatment
Concentration of CTO1681	Concentration of CTO1681 in the blood	Baseline, Day 0, Day 2, Day 4, Day 6, Day 13
CAR T-cell concentration in blood	Concentration of CAR T-cell measured using ddPCR	6 months following the start of treatment
CAR T-cell antitumor response	Antitumor response assessment using the Lugano or International Myeloma Working Group (IMWG) Criteria	6 months following the start of treatment

Collaborators and Investigators

• Sponsor: CytoAgents, Inc.
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Mike Howell, PhD, CytoAgents, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2023
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: April 28, 2023
• First Submitted That Met QC Criteria: June 6, 2023
• First Posted (Actual): June 15, 2023

Study Record Updates

• Last Update Posted (Actual): August 31, 2026
• Last Update Submitted That Met QC Criteria: August 27, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: CAR T-cell therapy; Cytokine storm; Cytokine release syndrome; Immunotoxicity; Hypercytokinemia
• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Pathological Conditions, Signs and Symptoms; Cytokine Release Syndrome; Therapeutics
• Other Study ID Numbers: CTA-2101; R44CA295189 (U.S. NIH Grant/Contract)

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