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Duvelisib Following Chimeric Antigen Receptor T-Cell Therapy

Primary Purpose

Non-hodgkin Lymphoma, Acute Lymphocytic Leukemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Duvelisib
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-hodgkin Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Meets FDA-approved criteria for treatment of non-Hodgkin lymphoma (NHL) with axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), lisocabtagene maraleucel (Breyanzi) or brexucabtagene autoleucel (Tecartus). Subjects receiving breuxacabtagene autoleucel for treatment of B-cell acute lymphoblastic leukemia (ALL) are not eligible.
  • At least 18 years of age.
  • The effects of duvelisib on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for at least 3 months after the last dose of duvelisib, as well as conform to institutional CAR T-cell guidelines. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and for at least 3 months after the last dose of duvelisib.
  • Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

  • Receiving axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, or brexucabtagene autoleucel for the treatment of B-cell acute lymphoblastic leukemia.
  • Known allergy or intolerance to duvelisib or another PI3K inhibitor. Previous treatment with duvelisib or other PI3K inhibitor is permitted unless therapy was discontinued due to toxicity or intolerance of therapy.
  • Receiving therapy with a strong CYP3A inducer or inhibitor that cannot be discontinued during duvelisib therapy. Subjects receiving a strong CYP3A inducer or inhibitor at screening are eligible to participate if the drug can be discontinued the longest of the following time periods prior to initiation of duvelisib: 7 days (for strong CYP3A inhibitors), 14 days (for strong CYP3A inducers) or 4-5 half-lives (either inducer or inhibitor).
  • Active CNS involvement by hematologic malignancy under treatment
  • Evidence of uncontrolled infection of any origin (viral, bacterial, or fungal)
  • Active bacterial, fungal or mycobacterial infection tuberculosis requiring treatment within the two years prior to study enrollment
  • Known HIV infection, untreated hepatitis C or hepatitis B infection. Untreated hepatitis B is not an exclusion if hepatitis B is undetectable.
  • Acute or chronic GVHD requiring systemic therapy
  • Concurrent use of chronic systemic steroids or immunosuppressant medications
  • Known history of immunologic/autoimmune disease affecting the CNS unrelated to diagnosis of hematologic malignancy under treatment
  • Clinically significant venous thromboembolic disease, defined deep vein thrombosis or pulmonary embolism occurring in the last 3 months or requiring ongoing anticoagulation at time of study screening
  • Clinically significant pulmonary disease, defined as grade 2 or greater dyspnea or grade 2 or greater hypoxia
  • Clinically significant cardiac disease, defined as unstable angina, acute myocardial infarction in the last 6 months, and NYHA class II or IV heart failure. Subjects with unstable arrhythmias that are not stable with medical management in 2 weeks prior to day -2 are also excluded.
  • Clinically significant hepatic disease, defined as ALT, AST or alkaline phosphatase ≥ 3x ULN or total bilirubin > 1.5x ULN (unless related to Gilbert's or Meulengracht's syndrome). Subjects with a history of chronic liver disease, previous veno-occlusive disease, active alcohol abuse or history of alcohol abuse within the past 6 months are also excluded.
  • Clinically significant renal disease, defined as calculated or measured creatinine clearance < 50 mL/min
  • Currently breastfeeding or pregnant. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry.
  • Inability to swallow and retain oral medication or prior surgery or GI dysfunction that may affect drug absorption (i.e. gastric bypass surgery, gastrectomy)
  • Receipt of a prior investigational agent within 4 weeks before Day -3 or currently receiving any other investigational agents.
  • Unable to receive prophylactic treatment for pneumocystis, HSV or VZV at screening
  • Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of medication, attendance of study visits, elevated risk of complications or interference with interpretation of the study data
  • A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease. Non-metastatic, non-melanoma skin cancers are not considered exclusionary.

Sites / Locations

  • Washington University School of MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Dose Escalation Stage: Duvelisib

Cohort A Dose Expansion Stage: Duvelisib

Cohort B Dose Expansion Stage: Duvelisib

Arm Description

Duvelisib is an oral medication taken on a twice daily basis on all dosing days. Doses being explored in this study are 15 mg BID (starting dose), 25 mg BID, and 15 mg QD. In the dose escalation stage, patients will receive duvelisib from Day -2 through Day 28. CAR T-cells will be given per standard of care.

Patients in Cohort A will receive duvelisib from Day -2 to Day 28. The dose that will be given will be determined in the dose escalation stage (the maximum tolerated dose). CAR T-cells will be given per standard of care.

Patients in Cohort B will receive duvelisib from Day -2 to Day 180. The dose that will be given will be one dose level below the maximum tolerated dose determined in the dose escalation stage. CAR T-cells will be given per standard of care.

Outcomes

Primary Outcome Measures

Toxicity as measured by number of adverse events
Toxicity is graded using NCI CTCAE v 5.0

Secondary Outcome Measures

Cumulative incidence of cytokine release syndrome (CRS)
-Any and grade 3-4 per ASTCT criteria
Cumulative incidence of immune effector cell-associated neurotoxicity syndrome (ICANS)
-Any and grade 3-4 per ASCT criteria
Number of participants who receive anti-IL-6 agents for treatment of cytokine release syndrome (CRS)
Number of participants who receive steroids for treatment of cytokine release syndrome (CRS)
Number of participants with complete response (CR)
Best overall response rate
-Defined as proportion of subjects with complete response (CR) or partial response (PR) by Lugano criteria
Best overall response rate
-Defined as proportion of subjects with complete response (CR) or partial response (PR)
Best overall response rate
-Defined as proportion of subjects with complete response (CR) or partial response (PR)
Progression-free survival (PFS)
Overall survival (OS)
Proportion of participants with partial response (PR) on Day 30 with improved response on Day 90
Proportion of participants with partial response (PR) on Day 30 with improved response on Day 180

Full Information

First Posted
September 3, 2021
Last Updated
February 12, 2023
Sponsor
Washington University School of Medicine
Collaborators
SecuraBio, The Foundation for Barnes-Jewish Hospital, National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT05044039
Brief Title
Duvelisib Following Chimeric Antigen Receptor T-Cell Therapy
Official Title
Phase I Dose Escalation and Dose Expansion Study of Duvelisib Following Chimeric Antigen Receptor T-Cell Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 28, 2022 (Actual)
Primary Completion Date
May 31, 2025 (Anticipated)
Study Completion Date
October 31, 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
SecuraBio, The Foundation for Barnes-Jewish Hospital, National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
While chimeric antigen receptor T-cell (CAR T-cell) therapy produces impressive response rates in heavily pre-treated patients, early loss of response remains a barrier. One potential mechanism of relapse is limited CAR T-cell persistence. Pre-clinical research shows that PI3K inhibition represents an intriguing mechanism for increasing CAR T-cell persistence that is easily reversible and CAR T-cell agnostic. The investigators hypothesize that PI3K inhibition with duvelisib would be safe, may provide effective prophylaxis against cytokine release syndrome (CRS), and may enhance the persistence and efficacy of CAR T-cells in the treatment of hematologic malignancies.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-hodgkin Lymphoma, Acute Lymphocytic Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
43 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dose Escalation Stage: Duvelisib
Arm Type
Experimental
Arm Description
Duvelisib is an oral medication taken on a twice daily basis on all dosing days. Doses being explored in this study are 15 mg BID (starting dose), 25 mg BID, and 15 mg QD. In the dose escalation stage, patients will receive duvelisib from Day -2 through Day 28. CAR T-cells will be given per standard of care.
Arm Title
Cohort A Dose Expansion Stage: Duvelisib
Arm Type
Experimental
Arm Description
Patients in Cohort A will receive duvelisib from Day -2 to Day 28. The dose that will be given will be determined in the dose escalation stage (the maximum tolerated dose). CAR T-cells will be given per standard of care.
Arm Title
Cohort B Dose Expansion Stage: Duvelisib
Arm Type
Experimental
Arm Description
Patients in Cohort B will receive duvelisib from Day -2 to Day 180. The dose that will be given will be one dose level below the maximum tolerated dose determined in the dose escalation stage. CAR T-cells will be given per standard of care.
Intervention Type
Drug
Intervention Name(s)
Duvelisib
Intervention Description
Patients should take duvelisib at approximately the same time every day, with or without food.
Primary Outcome Measure Information:
Title
Toxicity as measured by number of adverse events
Description
Toxicity is graded using NCI CTCAE v 5.0
Time Frame
Through Day 56 for dose expansion and Cohort A and Through Day 210 for Cohort B
Secondary Outcome Measure Information:
Title
Cumulative incidence of cytokine release syndrome (CRS)
Description
-Any and grade 3-4 per ASTCT criteria
Time Frame
By Day 28
Title
Cumulative incidence of immune effector cell-associated neurotoxicity syndrome (ICANS)
Description
-Any and grade 3-4 per ASCT criteria
Time Frame
By Day 28
Title
Number of participants who receive anti-IL-6 agents for treatment of cytokine release syndrome (CRS)
Time Frame
Through completion of follow-up (estimated to be 6 months)
Title
Number of participants who receive steroids for treatment of cytokine release syndrome (CRS)
Time Frame
Through completion of follow-up (estimated to be 6 months)
Title
Number of participants with complete response (CR)
Time Frame
Through completion of follow-up (estimated to be 6 months)
Title
Best overall response rate
Description
-Defined as proportion of subjects with complete response (CR) or partial response (PR) by Lugano criteria
Time Frame
At 1 month
Title
Best overall response rate
Description
-Defined as proportion of subjects with complete response (CR) or partial response (PR)
Time Frame
At 3 months
Title
Best overall response rate
Description
-Defined as proportion of subjects with complete response (CR) or partial response (PR)
Time Frame
At 6 months
Title
Progression-free survival (PFS)
Time Frame
Through completion of follow-up (estimated to be 5 years)
Title
Overall survival (OS)
Time Frame
Through completion of follow-up (estimated to be 5 years)
Title
Proportion of participants with partial response (PR) on Day 30 with improved response on Day 90
Time Frame
Day 90
Title
Proportion of participants with partial response (PR) on Day 30 with improved response on Day 180
Time Frame
Day 180

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Meets FDA-approved criteria for treatment of non-Hodgkin lymphoma (NHL) with axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), lisocabtagene maraleucel (Breyanzi) or brexucabtagene autoleucel (Tecartus). Subjects receiving breuxacabtagene autoleucel for treatment of B-cell acute lymphoblastic leukemia (ALL) are not eligible. At least 18 years of age. The effects of duvelisib on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for at least 3 months after the last dose of duvelisib, as well as conform to institutional CAR T-cell guidelines. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and for at least 3 months after the last dose of duvelisib. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Receiving axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, or brexucabtagene autoleucel for the treatment of B-cell acute lymphoblastic leukemia. Known allergy or intolerance to duvelisib or another PI3K inhibitor. Previous treatment with duvelisib or other PI3K inhibitor is permitted unless therapy was discontinued due to toxicity or intolerance of therapy. Receiving therapy with a strong CYP3A inducer or inhibitor that cannot be discontinued during duvelisib therapy. Subjects receiving a strong CYP3A inducer or inhibitor at screening are eligible to participate if the drug can be discontinued the longest of the following time periods prior to initiation of duvelisib: 7 days (for strong CYP3A inhibitors), 14 days (for strong CYP3A inducers) or 4-5 half-lives (either inducer or inhibitor). Active CNS involvement by hematologic malignancy under treatment Evidence of uncontrolled infection of any origin (viral, bacterial, or fungal) Active bacterial, fungal or mycobacterial infection tuberculosis requiring treatment within the two years prior to study enrollment Known HIV infection, untreated hepatitis C or hepatitis B infection. Untreated hepatitis B is not an exclusion if hepatitis B is undetectable. Acute or chronic GVHD requiring systemic therapy Concurrent use of chronic systemic steroids or immunosuppressant medications Known history of immunologic/autoimmune disease affecting the CNS unrelated to diagnosis of hematologic malignancy under treatment Clinically significant venous thromboembolic disease, defined deep vein thrombosis or pulmonary embolism occurring in the last 3 months or requiring ongoing anticoagulation at time of study screening Clinically significant pulmonary disease, defined as grade 2 or greater dyspnea or grade 2 or greater hypoxia Clinically significant cardiac disease, defined as unstable angina, acute myocardial infarction in the last 6 months, and NYHA class II or IV heart failure. Subjects with unstable arrhythmias that are not stable with medical management in 2 weeks prior to day -2 are also excluded. Clinically significant hepatic disease, defined as ALT, AST or alkaline phosphatase ≥ 3x ULN or total bilirubin > 1.5x ULN (unless related to Gilbert's or Meulengracht's syndrome). Subjects with a history of chronic liver disease, previous veno-occlusive disease, active alcohol abuse or history of alcohol abuse within the past 6 months are also excluded. Clinically significant renal disease, defined as calculated or measured creatinine clearance < 50 mL/min Currently breastfeeding or pregnant. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry. Inability to swallow and retain oral medication or prior surgery or GI dysfunction that may affect drug absorption (i.e. gastric bypass surgery, gastrectomy) Receipt of a prior investigational agent within 4 weeks before Day -3 or currently receiving any other investigational agents. Unable to receive prophylactic treatment for pneumocystis, HSV or VZV at screening Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of medication, attendance of study visits, elevated risk of complications or interference with interpretation of the study data A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease. Non-metastatic, non-melanoma skin cancers are not considered exclusionary.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Armin Ghobadi, M.D.
Phone
314-454-8304
Email
arminghobadi@wustl.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Armin Ghobadi, M.D.
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Armin Ghobadi, M.D.
Phone
314-454-8304
Email
arminghobadi@wustl.edu
First Name & Middle Initial & Last Name & Degree
Armin Ghobadi, M.D.
First Name & Middle Initial & Last Name & Degree
John F Dipersio, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Michael Slade, M.D.
First Name & Middle Initial & Last Name & Degree
Feng Gao, Ph.D.

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://www.siteman.wustl.edu
Description
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Learn more about this trial

Duvelisib Following Chimeric Antigen Receptor T-Cell Therapy

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