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NKTR-255 in Combination With CAR-T Cell Therapy for the Treatment of Relapsed or Refractory Large B-cell Lymphoma

Primary Purpose

Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, Recurrent Grade 3b Follicular Lymphoma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
Fludarabine
Lisocabtagene Maraleucel
Polymer-conjugated IL-15 Receptor Agonist NKTR-255
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent Diffuse Large B-Cell Lymphoma

Eligibility Criteria

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

Inclusion Criteria:

  • Adult subjects with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving liso-cel
  • Male or female >= 18 years of age at the time of consent
  • Patients with LBCL (including diffuse large B-cell lymphoma [DLBCL] not otherwise specified [including DLBCL arising from indolent lymphoma], high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B) with a Food and Drug Administration (FDA)-approved indication for treatment with liso-cel
  • Fludeoxyglucose F-18 (FDG)-avid disease on positron emission tomography (PET) imaging or pathology evidence of active disease
  • Evidence of CD19 expression on any prior or current tumor specimen or a high likelihood of CD19 expression based on disease histology
  • Karnofsky performance status >= 60%
  • Absolute neutrophil count (ANC) >= 1000 cells/mm^3 in the absence of bone marrow involvement by lymphoma
  • Platelets >= 50,000 cells/mm^3 in the absence of bone marrow involvement by lymphoma
  • Hemoglobin >= 8 g/dL in the absence of bone marrow involvement by lymphoma
  • Calculated creatinine clearance (Cockcroft/Gault) > 30 mL/min/1.73 m^2
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (or < 5 x ULN for subjects with lymphomatous infiltration of the liver)
  • Total bilirubin =< 2 (or < 3.0 for subjects with Gilbert's syndrome or lymphomatous infiltration of the liver)
  • Common Terminology Criteria for Adverse Events (CTCAE) Grade =< 1 dyspnea
  • Saturation of oxygen (Sa02) >= 92% on room air
  • Patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing and must have a forced expiratory volume in 1 second (FEV1) of >= 50% of predicted value
  • Patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing and must have a diffusing capacity of the lung for carbon monoxide (DLCO; corrected) >= 40% of predicted value
  • Left ventricular ejection fraction (LVEF) >= 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA)
  • Patients with Fridericia's corrected QT interval (QTcF) > 450 ms for men and > 470 ms for women will require clearance by a cardiologist
  • Women of reproductive potential (defined as all women physiologically capable of becoming pregnant) must agree to use suitable methods of contraception for 1 month after the last dose of study therapy (NKTR-255)
  • Males who have partners of reproductive potential must agree to use an effective barrier contraceptive method for 1 month after the last dose of study therapy (NKTR-255)
  • Ability to understand and provide informed consent
  • Able and willing to comply with study visit schedule and procedures, including tumor biopsy where feasible and with acceptable risk

Exclusion Criteria:

  • Planned use of therapeutic doses of corticosteroids (> 20 mg/day prednisone or equivalent) or other systemic immunosuppression within 7 days prior to leukapheresis or within 72 hours prior to liso-cel infusion. Topical and/or inhaled steroids are permitted
  • Prior treatment with any CD19 CAR-T cell therapy
  • For allogeneic hematopoietic cell transplant (HCT) recipients, active graft versus host disease (GVHD) and/or systemic GVHD therapy within 30 days prior to planned leukapheresis
  • Known active hepatitis B (detectable hepatitis B deoxyribonucleic acid [DNA]) or hepatitis C (detectable hepatitis C ribonucleic acid [RNA])
  • Known human immunodeficiency virus (HIV) infection
  • Pregnant or breastfeeding women
  • Prior treatment with any IL-2 or IL-15 agonist and/or biosimilar agents
  • Active autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., ulcerative colitis, Crohn's disease], celiac disease, or other serious chronic gastrointestinal conditions associated with diarrhea, autoimmune vasculitis, systemic lupus erythematosus, Wegener syndrome [granulomatosis with polyangiitis], myasthenia gravis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.) within 1 year prior to the planned start of treatment. The following are exceptions to this criterion:

    • Vitiligo.
    • Alopecia.
    • Hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement.
    • Type 1 diabetes mellitus.
    • Psoriasis not requiring systemic treatment.
    • Conditions considered to be low risk of serious deterioration by the principal investigator (PI).
  • History of any one of the following cardiovascular conditions within the past 6 months: class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, or unstable angina; unless clearance by a cardiologist is obtained. History of other clinically significant cardiac disease that, in the opinion of the PI or designee, is a contraindication to study treatment is also excluded
  • History or presence of clinically relevant central nervous system (CNS) pathology, such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, or psychosis that in the opinion of the PI is a contraindication to study treatment.

    • Patients with active parenchymal CNS involvement by malignancy will be excluded. Patients with prior or current secondary leptomeningeal CNS disease are eligible. CNS disease prophylaxis must be stopped at least 1 week prior to liso-cel infusion
  • History of solid organ transplantation
  • Active, serious, and uncontrolled infection(s)

Sites / Locations

  • Fred Hutch/University of Washington Cancer ConsortiumRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (lymphodepletion, liso-cel, NKTR-255)

Arm Description

Patients receive standard of care lymphodepletion therapy consisting of cyclophosphamide and fludarabine on days -5 to -3 followed by liso-cel CAR-T cell infusion on day 0. Patients then receive NKTR-255 IV over 30 minutes every 3 weeks starting on day 10 or 14 for up to 3 doses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Incidence of adverse events (AEs)
Grade ≥ 3 AEs considered related to NKTR-255 will be listed and summarized. Summaries of grade ≥ 3 laboratory data will include, at a minimum, treatment-emergent laboratory abnormalities. Summaries of AEs and laboratory abnormalities will be based on the safety evaluable population.
Dose-limiting toxicity (DLT) rates
Observed DLT rates will be summarized based on the DLT evaluable population. Final DLT rates at each dose level will be estimated by isotonic regression by applying the pooled adjacent violators algorithm.
Optimal biological dose (OBD)
A composite of clinical information will be utilized to determine the OBD based on safety and tolerability, confirmation of maximum target engagement, optimal biological effects without undesirable clinical effects, pharmacokinetic parameters, and biological response data.
Complete response (CR) rate
The CR rate will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence interval based on the efficacy evaluable population.

Secondary Outcome Measures

Complete response (CR) and overall response (OR) rates
The CR and OR rates will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence interval based on the efficacy evaluable population.
Duration of response (DOR)
Will be assessed among responders. If a patient does not have an event for the DOR analyses, the patient will be censored at the date of the last adequate disease assessments or prior to the earliest censoring event. The censoring reason can include last contact/follow-up, discontinuation or completion of the study, receipt of another anticancer treatment with the exception of consolidation therapy with hematopoietic cell transplantation (HCT), and at least two consecutive missed scheduled disease assessments. Kaplan-Meier (KM) method will be used to analyze DOR.
Progression free survival (PFS)
Will be assessed among responders. If a patient does not have an event for the PFS analyses, the patient will be censored at the date of the last adequate disease assessments or prior to the earliest censoring event. The censoring reason can include last contact/follow-up, discontinuation or completion of the study, receipt of another anticancer treatment with the exception of consolidation therapy with HCT, and at least two consecutive missed scheduled disease assessments. KM method will be used to analyze PFS.
Overall survival (OS)
Analyses of OS will be performed in the safety population. For assessment of OS, data from surviving patients will be censored at the last time that the patient is known to be alive. KM method will be used to analyze OS.

Full Information

First Posted
April 28, 2022
Last Updated
May 4, 2023
Sponsor
Fred Hutchinson Cancer Center
Collaborators
Nektar Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT05359211
Brief Title
NKTR-255 in Combination With CAR-T Cell Therapy for the Treatment of Relapsed or Refractory Large B-cell Lymphoma
Official Title
A Phase Ib Open-Label Study Evaluating the Safety and Efficacy of NKTR-255 in Combination With CD19-Directed CAR-T Cell Therapy in Patients With Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 8, 2022 (Actual)
Primary Completion Date
January 31, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
Nektar Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase Ib trial studies the effects of NKTR-255 in combination with chimeric antigen (CAR)-T cell therapy and to see how well they work in treating patients with large B-cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). NKTR-255 is an investigational IL-15 receptor agonist designed to boost the immune system's natural ability to fight cancer. T cells are infection fighting blood cells that can kill tumor cells. Lisocabtagene maraleucel is a CAR-T cell product that consists of genetically engineered T cells, modified to recognize CD19, a protein on the surface of cancer cells. These CD19-specific T cells may help the body's immune system identify and kill CD19-positive cancer cells. Giving NKTR-255 together with lisocabtagene maraleucel may work better in treating large B-cell lymphoma than either drug alone.
Detailed Description
OUTLINE: Patients receive standard of care lymphodepletion therapy consisting of cyclophosphamide and fludarabine on days -5 to -3 followed by liso-cel CAR-T cell infusion on day 0. Patients then receive NKTR-255 intravenously (IV) over 30 minutes every 3 weeks starting on day 10 or 14 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 30 days for 3 months, then every 3 months up to 12 months after the CAR-T cell infusion.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, Recurrent Grade 3b Follicular Lymphoma, Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, Refractory Grade 3b Follicular Lymphoma, Refractory Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Transformed Indolent B-Cell Non-Hodgkin Lymphoma to Diffuse Large B-Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (lymphodepletion, liso-cel, NKTR-255)
Arm Type
Experimental
Arm Description
Patients receive standard of care lymphodepletion therapy consisting of cyclophosphamide and fludarabine on days -5 to -3 followed by liso-cel CAR-T cell infusion on day 0. Patients then receive NKTR-255 IV over 30 minutes every 3 weeks starting on day 10 or 14 for up to 3 doses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fluradosa
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Lisocabtagene Maraleucel
Other Intervention Name(s)
Anti-CD19-CAR Genetically Engineered Autologous T Lymphocytes JCAR017, Anti-CD19-CAR Genetically Engineered Autologous T-lymphocytes JCAR017, Autologous Anti-CD19-EGFRt-4-1BB-zeta-modified CAR CD8+ and CD4+ T-lymphocytes JCAR017, Breyanzi, JCAR 017, JCAR017
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Polymer-conjugated IL-15 Receptor Agonist NKTR-255
Other Intervention Name(s)
IL-15 Receptor Agonist NKTR-255, Long-acting Polymer-conjugated IL-15, NKTR 255, NKTR-255, NKTR255
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Incidence of adverse events (AEs)
Description
Grade ≥ 3 AEs considered related to NKTR-255 will be listed and summarized. Summaries of grade ≥ 3 laboratory data will include, at a minimum, treatment-emergent laboratory abnormalities. Summaries of AEs and laboratory abnormalities will be based on the safety evaluable population.
Time Frame
30 days after the last dose of NKTR-255 or until a new antitumor therapy has been initiated
Title
Dose-limiting toxicity (DLT) rates
Description
Observed DLT rates will be summarized based on the DLT evaluable population. Final DLT rates at each dose level will be estimated by isotonic regression by applying the pooled adjacent violators algorithm.
Time Frame
Up to 21 days after the first NKTR-255 infusion
Title
Optimal biological dose (OBD)
Description
A composite of clinical information will be utilized to determine the OBD based on safety and tolerability, confirmation of maximum target engagement, optimal biological effects without undesirable clinical effects, pharmacokinetic parameters, and biological response data.
Time Frame
Up to 12 months after the CAR-T cell infusion
Title
Complete response (CR) rate
Description
The CR rate will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence interval based on the efficacy evaluable population.
Time Frame
Up to 3 months after the CAR-T cell infusion
Secondary Outcome Measure Information:
Title
Complete response (CR) and overall response (OR) rates
Description
The CR and OR rates will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence interval based on the efficacy evaluable population.
Time Frame
Up to 12 months after the CAR-T cell infusion
Title
Duration of response (DOR)
Description
Will be assessed among responders. If a patient does not have an event for the DOR analyses, the patient will be censored at the date of the last adequate disease assessments or prior to the earliest censoring event. The censoring reason can include last contact/follow-up, discontinuation or completion of the study, receipt of another anticancer treatment with the exception of consolidation therapy with hematopoietic cell transplantation (HCT), and at least two consecutive missed scheduled disease assessments. Kaplan-Meier (KM) method will be used to analyze DOR.
Time Frame
Up to 12 months after the CAR-T cell infusion
Title
Progression free survival (PFS)
Description
Will be assessed among responders. If a patient does not have an event for the PFS analyses, the patient will be censored at the date of the last adequate disease assessments or prior to the earliest censoring event. The censoring reason can include last contact/follow-up, discontinuation or completion of the study, receipt of another anticancer treatment with the exception of consolidation therapy with HCT, and at least two consecutive missed scheduled disease assessments. KM method will be used to analyze PFS.
Time Frame
Up to 12 months after the CAR-T cell infusion
Title
Overall survival (OS)
Description
Analyses of OS will be performed in the safety population. For assessment of OS, data from surviving patients will be censored at the last time that the patient is known to be alive. KM method will be used to analyze OS.
Time Frame
Up to 12 months after the CAR-T cell infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female >= 18 years of age at the time of consent Patients with LBCL (including diffuse large B-cell lymphoma [DLBCL] not otherwise specified [including DLBCL arising from indolent lymphoma], high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B) with a Food and Drug Administration (FDA)-approved indication for treatment with liso-cel Fludeoxyglucose F-18 (FDG)-avid disease on positron emission tomography (PET) imaging or pathology evidence of active disease Evidence of CD19 expression on any prior or current tumor specimen or a high likelihood of CD19 expression based on disease histology Karnofsky performance status >= 60% Absolute neutrophil count (ANC) >= 1000 cells/mm^3 in the absence of bone marrow involvement by lymphoma Platelets >= 50,000 cells/mm^3 in the absence of bone marrow involvement by lymphoma Hemoglobin >= 8 g/dL in the absence of bone marrow involvement by lymphoma Calculated creatinine clearance (Cockcroft/Gault) > 30 mL/min/1.73 m^2 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (or < 5 x ULN for subjects with lymphomatous infiltration of the liver) Total bilirubin =< 2 (or < 3.0 for subjects with Gilbert's syndrome or lymphomatous infiltration of the liver) Common Terminology Criteria for Adverse Events (CTCAE) Grade =< 1 dyspnea Saturation of oxygen (Sa02) >= 92% on room air Patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing and must have a forced expiratory volume in 1 second (FEV1) of >= 50% of predicted value Patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing and must have a diffusing capacity of the lung for carbon monoxide (DLCO; corrected) >= 40% of predicted value Left ventricular ejection fraction (LVEF) >= 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA) Patients with Fridericia's corrected QT interval (QTcF) > 450 ms for men and > 470 ms for women will require clearance by a cardiologist Women of reproductive potential (defined as all women physiologically capable of becoming pregnant) must agree to use suitable methods of contraception for 1 month after the last dose of study therapy (NKTR-255) Males who have partners of reproductive potential must agree to use an effective barrier contraceptive method for 1 month after the last dose of study therapy (NKTR-255) Ability to understand and provide informed consent Able and willing to comply with study visit schedule and procedures, including tumor biopsy where feasible and with acceptable risk Exclusion Criteria: Planned use of therapeutic doses of corticosteroids (> 20 mg/day prednisone or equivalent) or other systemic immunosuppression within 7 days prior to leukapheresis or within 72 hours prior to liso-cel infusion. Topical and/or inhaled steroids are permitted Prior treatment with any CD19 CAR-T cell therapy For allogeneic hematopoietic cell transplant (HCT) recipients, active graft versus host disease (GVHD) and/or systemic GVHD therapy within 30 days prior to planned leukapheresis Known active hepatitis B (detectable hepatitis B deoxyribonucleic acid [DNA]) or hepatitis C (detectable hepatitis C ribonucleic acid [RNA]) Known human immunodeficiency virus (HIV) infection Pregnant or breastfeeding women Prior treatment with any IL-2 or IL-15 agonist and/or biosimilar agents Active autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., ulcerative colitis, Crohn's disease], celiac disease, or other serious chronic gastrointestinal conditions associated with diarrhea, autoimmune vasculitis, systemic lupus erythematosus, Wegener syndrome [granulomatosis with polyangiitis], myasthenia gravis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.) within 1 year prior to the planned start of treatment. The following are exceptions to this criterion: Vitiligo. Alopecia. Hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement. Type 1 diabetes mellitus. Psoriasis not requiring systemic treatment. Conditions considered to be low risk of serious deterioration by the principal investigator (PI). History of any one of the following cardiovascular conditions within the past 6 months: class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, or unstable angina; unless clearance by a cardiologist is obtained. History of other clinically significant cardiac disease that, in the opinion of the PI or designee, is a contraindication to study treatment is also excluded History or presence of clinically relevant central nervous system (CNS) pathology, such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, or psychosis that in the opinion of the PI is a contraindication to study treatment. Patients with active parenchymal CNS involvement by malignancy will be excluded. Patients with prior or current secondary leptomeningeal CNS disease are eligible. CNS disease prophylaxis must be stopped at least 1 week prior to liso-cel infusion History of solid organ transplantation Active, serious, and uncontrolled infection(s)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
SCCA Immunotherapy Intake
Phone
206-606-4668
Email
immunotherapy@seattlecca.org
First Name & Middle Initial & Last Name or Official Title & Degree
SCCA Immunotherapy Intake
Phone
855-557-0555
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexandre Hirayama
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
SCCA Immunotherapy Intake
Phone
206-606-4668
Email
immunotherapy@seattlecca.org
First Name & Middle Initial & Last Name & Degree
SCCA Immunotherapy Intake
Phone
855-557-0555
First Name & Middle Initial & Last Name & Degree
Alexandre Hirayama

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

NKTR-255 in Combination With CAR-T Cell Therapy for the Treatment of Relapsed or Refractory Large B-cell Lymphoma

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