A Study of TAK-007 in Adults With Relapsed or Refractory (r/r) B-cell Non-Hodgkin Lymphoma (NHL)

Phase 2

Active, not recruiting

• Conditions: Relapsed or Refractory (r/r) B-cell Non-Hodgkin Lymphoma (NHL)
• Interventions: Biological: TAK-007; Drug: Chemotherapy Agents

• Registration Number: NCT05020015
• Lead Sponsor: Takeda

Brief Summary

This study has 2 parts.

The main aim of Part 1 is to check for side effects from TAK-007 in adults with relapsed or refractory (r/r) B-cell Non-Hodgkin Lymphoma (NHL),

The main aim of Part 2 is to learn whether lymphoma disease responds to treatment with TAK-007 in adults with r/r B-cell NHL or iNHL.

Participants will receive 3 days of chemotherapy to reduce a type of white blood cells called lymphocytes, in the blood. This is called lymphodepleting chemotherapy (LDC) or lymphodepletion. After LDC, patients will receive a single injection of TAK-007 or three weekly injections of TAK-007 (multi-dose injection). After this, participants will regularly visit the clinic for check-ups.

Detailed Description

The product being tested in this study is called TAK-007. TAK-007 is being tested to evaluate the safety and tolerability in adult participants with r/r B-cell NHL. The study will include 2 parts: Part 1 (Dose escalation and dose expansion) and Part 2.

The study will enroll approximately 265 participants.

In Part 1, dose escalation cohorts' participants will receive TAK-007 as follows:

Part 1 dose escalation:

* Part 1: Dose escalation: TAK-007 - 200×10\^6 CD19-CAR+ Viable NK (Natural Killer) Cells (±30%)

* Part 1: Dose escalation: TAK-007 - 800×10\^6 CD19-CAR+ Viable NK Cells (±25%)

In Part 1 dose expansion phase, separate expansion cohorts for LBCL and iNHL (Cohorts 1A \[LBCL 3L+\] and 2A \[iNHL 3L+\]) and two additional dose expansion cohorts with a multi-dose regimen will be added (i.e., Cohort 1B and 1C) to evaluate more than 1 doses of TAK-007 after a 3-day regimen of lymphodepleting chemotherapy.

Part 1 dose expansion cohorts' participants will receive TAK-007 as follows:

* Part 1: Dose expansion: Cohort 1A (LBCL 3L+): TAK-007 - 200×10\^6/ 800×10\^6 CD19-CAR+ Viable NK Cells on Day 0 of the study.

* Part 1: Dose expansion: Cohort 2A (iNHL 3L+): TAK-007 - 200×10\^6/ 800×10\^6 CD19-CAR+ Viable NK Cells on Day 0 of the study.

* Part 1: Dose Expansion: Cohort 1B (LBCL 3L+): TAK-007- 800×10\^6 CD19-CAR+ Viable NK Cells on Days 0, 7 and 14 of the study.

* Part 1: Dose Expansion: Cohort 1C (LBCL 2L): TAK-007- 800×10\^6 CD19-CAR+ Viable NK Cells on Days 0, 7 and 14 of the study.

Based on the data in Part 1, a single TAK-007 dose level will be selected by the sponsor and investigators as the recommended phase 2 dose (RP2D).

Once RP2D is determined, participants will be enrolled in Part 2 of the study in the following cohorts:

* Cohort 1: TAK-007 (LBCL)

* Cohort 2: TAK-007 (iNHL)

This multi-center trial will be conducted worldwide. Part 1 of the study will be conducted in the US, and Part 2 will be conducted worldwide. The overall time to participate in this study is 5 years. Participants will make multiple visits to the clinic and will enroll in a separate, long-term, follow-up study for continued safety assessments for up to 15 years after TAK-007 administration.

Study Timeline

• Study First Submitted: 2021-08-20
• Study First Submitted QC: 2021-08-20
• Study First Posted: 2021-08-25
• Study Start: 2021-11-12
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-27
• Last Update Posted: 2024-05-29
• Primary Completion: 2025-10-14
• Study Completion: 2030-06-20

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 27

Inclusion Criteria

1. Participants who have a life expectancy ≥12 weeks.

2. Participants who have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

3. Participants with a diagnosis of previously treated r/r histologically proven Cluster of Differentiation (CD)19 expressing disease of the following types:

   a. LBCL, including the following subtypes defined by the World Health Organization (WHO): i. Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS). ii. High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangement iii. HGBL NOS without translocations. iv. DLBCL arising from iNHL including follicular lymphoma (FL) or marginal zone lymphoma (MZL).

   v. T-cell/histiocyte-rich LBCL. vi. DLBCL associated with chronic inflammation. vii. Epstein-Barr virus-positive DLBCL-NOS. viii. Primary cutaneous DLBCL, leg type. ix. Primary mediastinal large B-cell lymphoma (PMBCL). x. FL Grade 3B. b. iNHL, including the following subtypes defined by the WHO: i. FL Grades 1, 2, 3A. ii. MZL (nodal, extranodal, and splenic).

4. Participants who have measurable disease, defined as at least 1 lesion per the Lugano classification. Lesions situated in a previously irradiated area are considered measurable if radiographic progression has been documented in such lesions following completion of radiation therapy. LBCL should have positron emission tomography (PET) -positive disease per the Lugano classification.

5. Participants who have r/r LBCL or r/r iNHL after ≥2 prior lines of systemic therapy: (Expansion Cohorts 1A and 1B [LBCL 3L+], and 2A [iNHL 3L +]) or r/r LBCL after 1 prior line of systemic therapy (Expansion Cohort 1C [LBCL 2L]):

   1. Participants with r/r LBCL must have received an anti-CD20 monoclonal antibody (mAb) and an anthracycline containing chemotherapy regimen and failed or be ineligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT).

   2. Participants with iNHL must have received an anti-CD20 mAb and an alkylating agent (eg, bendamustine or cyclophosphamide).

   3. Preinduction salvage chemotherapy and ASCT should be considered 1 line of therapy.

   4. Any consolidation/maintenance therapy after a chemotherapy regimen (without intervening relapse) should be considered 1 line of therapy with the preceding combination therapy. Maintenance antibody therapy should not be considered a line of therapy.

   5. Single-agent anti-CD20 mAb therapy should not be considered a line of therapy.

   6. Bridging chemotherapy given just prior to CAR-T cell therapy treatment should be considered one line of therapy together with cell therapy.

   7. Participants who have received prior CD19-targeting CAR-T cell therapy must have achieved at least a partial response to the most recent CD19-targeting CAR-T cell therapy.

   8. Participants with 1 prior line of therapy in Part 1 Cohort 1C must have either:

      • refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy OR
      • relapsed or refractory disease and be ineligible for intensive chemoimmunotherapy and/or high-dose chemotherapy followed by ASCT due to comorbidities and/or age.

6. Participants who have adequate bone marrow function defined as follows:

   1. Absolute neutrophil count >500/μL.
   2. Platelet count of >50,000/μL at screening. Participants with transfusion-dependent thrombocytopenia are excluded.

7. Participants who have adequate renal, hepatic, cardiac, and pulmonary function as defined in the study protocol:

   1. Estimated glomerular filtration rate (GFR; Modification of Diet in Renal Disease equation [MDRD]) ≥30 mL/min.
   2. Serum alanine aminotransferase/aspartate aminotransferase ≤5 times the upper limit of normal range (ULN), as long as participant is asymptomatic.
   3. Total bilirubin ≤2 mg/dL. Participants with Gilbert's syndrome may have a bilirubin level >2 × ULN, per discussion between the investigator and the medical monitor.
   4. Left ventricular ejection fraction (LVEF) ≥40% as determined by an echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed within 1 month of determination of eligibility.
   5. No evidence of clinically relevant pericardial effusion, and no acute clinically significant electrocardiogram (ECG) findings.
   6. Absence of Grade ≥2 pleural effusion. Grade 1 stable pleural effusions are allowed.
   7. Baseline oxygen saturation >92% on room air.

8. Participants are required to consent to provide either sufficient archived formalin-fixed paraffin embedded (at least 10 unstained slides, ideally 20 unstained slides) or fresh tumor tissue obtained after the last relapse (see laboratory manual for details). Exception may be granted by sponsor medical monitor per discussion with investigator.

Read More

Exclusion Criteria

1. Participants with total body weight of <40 kg.
2. Participants with primary or secondary central nervous system (CNS) involvement by lymphoma. Participants with a history of secondary CNS involvement by lymphoma without evidence of CNS involvement at screening may be included.
3. Participants with Burkitt lymphoma, mantle cell lymphoma, lymphoplasmocytic lymphoma, or transformation from CLL/small lymphocytic lymphoma (Richter transformation).
4. Participants with a history of malignancy other than nonmelanoma skin cancer, carcinoma in situ (eg, cervix, bladder, breast), low-grade tumors deemed to be cured and not treated with systemic therapy (eg, by gastro-endoscopy curatively removed gastric cancer) or unless disease free for ≥3 years at screening.
5. Participants who have undergone autologous or allogeneic transplant or Chimeric antigen receptor T cells (CAR-T) or Chimeric antigen receptor Natural Killer cells (CAR-NK) therapy within 3 months of planned enrollment. Participants after allogeneic transplant have to be off systemic immunosuppressive therapy and without the evidence of clinically relevant acute or chronic graft-versus-host disease (GvHD) at the time of enrollment.
6. Treatment with any investigational products or any systemic anticancer treatment within 14 days or 2 half-lives of the treatment (whichever is longer) before conditioning therapy. For rituximab, a half-life of 22 days should be considered.
7. Participants with active infection, including fungal, bacterial, viral, or other infection that is uncontrolled or requires IV antimicrobials for management within 3 days before enrollment.
8. Participants with a history or presence of active or clinically relevant CNS disorder, such as seizure, encephalopathy, cerebrovascular ischemia/hemorrhage, severe dementia, cerebellar disease, or any autoimmune disease with CNS involvement. For CNS disorders that recover or are in remission, participants without recurrence within 2 years of planned study enrollment may be included.
9. Participants with any of the following within 6 months of enrollment: myocardial infarction, cardiac angioplasty or stenting, unstable angina, symptomatic congestive heart failure (ie, New York Heart Association Class II or greater), clinically significant arrythmia (including uncontrolled atrial fibrillation), or any other clinically significant cardiac disease.
10. Participants who have received a live vaccine ≤6 weeks before the start of the conditioning regime.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1: Dose Expansion: Cohort 2A (iNHL 3L+): TAK-007 - 200×10^6/ 800×10^6 CD19-CAR+ Viable NK Cells	TAK-007	Participants with r/r Indolent Non-Hodgkin Lymphoma (iNHL) will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 - 200×10\^6/ 800×10\^6 CD19-CAR+ viable NK cells, single-dose, intravenously, once on Day 0 to determine RP2D.
Part 1: Dose Escalation: TAK-007 - 800×10^6 CD19-CAR+ Viable NK Cells	Chemotherapy Agents	Participants will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 - 800×10\^6 CD19-CAR+ viable NK cells, single-dose, intravenously, once on Day 0.
Part 1: Dose Escalation: TAK-007 - 200×10^6 CD19-CAR+ Viable NK Cells	TAK-007	Participants will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 200×10\^6 anti-CD19 chimeric antigen receptor (CD19-CAR+) viable NK cells, single-dose, intravenously, once on Day 0.
Part 1: Dose Escalation: TAK-007 - 800×10^6 CD19-CAR+ Viable NK Cells	TAK-007	Participants will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 - 800×10\^6 CD19-CAR+ viable NK cells, single-dose, intravenously, once on Day 0.
Part 2: Cohort 2- iNHL	Chemotherapy Agents	Participants with iNHL will be enrolled in this cohort to receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 at the RP2D, intravenously.
Part 1: Dose Expansion: Cohort 1A (LBCL 3L+): TAK-007 - 200×10^6/ 800×10^6 CD19-CAR+ Viable NK Cells	TAK-007	Participants with r/r Large B-cell Lymphoma (LBCL) will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 - 200×10\^6/ 800×10\^6 CD19-CAR+ viable NK cells, single-dose, intravenously, once on Day 0 to determine RP2D.
Part 1: Dose Escalation: TAK-007 - 200×10^6 CD19-CAR+ Viable NK Cells	Chemotherapy Agents	Participants will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 200×10\^6 anti-CD19 chimeric antigen receptor (CD19-CAR+) viable NK cells, single-dose, intravenously, once on Day 0.
Part 1: Dose Expansion: Cohort 1B (LBCL 3L+): TAK-007- 800×10^6 CD19-CAR+ Viable NK Cells	TAK-007	Participants with r/r Large B-cell Lymphoma (LBCL) will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 - 800×10\^6 CD19-CAR+ viable NK cells, intravenously, once on Days 0, 7 and 14 to determine RP2D.
Part 1: Dose Expansion: Cohort 1C (LBCL 2L): TAK-007- 800×10^6 CD19-CAR+ Viable NK Cells	TAK-007	Participants with r/r Large B-cell Lymphoma (LBCL) will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 - 800×10\^6 CD19-CAR+ viable NK cells, intravenously, once on Days 0, 7 and 14 to determine RP2D.
Part 2: Cohort 1- LBCL	Chemotherapy Agents	Participants with LBCL will be enrolled in this cohort to receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 at the RP2D, intravenously.
Part 2: Cohort 2- iNHL	TAK-007	Participants with iNHL will be enrolled in this cohort to receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 at the RP2D, intravenously.
Part 1: Dose Expansion: Cohort 1A (LBCL 3L+): TAK-007 - 200×10^6/ 800×10^6 CD19-CAR+ Viable NK Cells	Chemotherapy Agents	Participants with r/r Large B-cell Lymphoma (LBCL) will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 - 200×10\^6/ 800×10\^6 CD19-CAR+ viable NK cells, single-dose, intravenously, once on Day 0 to determine RP2D.
Part 1: Dose Expansion: Cohort 1B (LBCL 3L+): TAK-007- 800×10^6 CD19-CAR+ Viable NK Cells	Chemotherapy Agents	Participants with r/r Large B-cell Lymphoma (LBCL) will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 - 800×10\^6 CD19-CAR+ viable NK cells, intravenously, once on Days 0, 7 and 14 to determine RP2D.
Part 1: Dose Expansion: Cohort 2A (iNHL 3L+): TAK-007 - 200×10^6/ 800×10^6 CD19-CAR+ Viable NK Cells	Chemotherapy Agents	Participants with r/r Indolent Non-Hodgkin Lymphoma (iNHL) will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 - 200×10\^6/ 800×10\^6 CD19-CAR+ viable NK cells, single-dose, intravenously, once on Day 0 to determine RP2D.
Part 2: Cohort 1- LBCL	TAK-007	Participants with LBCL will be enrolled in this cohort to receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 at the RP2D, intravenously.
Part 1: Dose Expansion: Cohort 1C (LBCL 2L): TAK-007- 800×10^6 CD19-CAR+ Viable NK Cells	Chemotherapy Agents	Participants with r/r Large B-cell Lymphoma (LBCL) will receive lymphodepleting chemotherapy per day intravenously for 3 days followed by TAK-007 - 800×10\^6 CD19-CAR+ viable NK cells, intravenously, once on Days 0, 7 and 14 to determine RP2D.

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants with Clinically Significant Changes in Vital Signs	Up to 60 months	Vital signs will include body temperature (oral or tympanic measurement), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse rate (bpm).
Part 1: Number of Participants with Adverse Events (AEs)	Up to 60 months	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.
Part 1: Number of Participants with Clinically Significant Changes in Laboratory Parameters	Up to 60 months	Laboratory parameters will include hematology, clinical chemistry, serum immunoglobulin and urinalysis tests.
Part 2: Overall Response Rate (ORR) per Independent Review Committee (IRC)	Up to 60 months	ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) as best response to treatment, determined by the IRC per the Lugano 2014 criteria after TAK-007 administration.

Secondary Outcome Measures

Name	Time	Method
Part 2: Complete Response (CR) Per IRC	Up to 60 months	CR will be defined per Lugano criteria as percentage of participants with target nodes/nodal masses must regress to ≤1.5 cm in the longest transverse diameter of all lesions and no extralymphatic sites of disease.
Part 2: Duration of Response (DOR) per IRC	Up to 60 months	DOR is defined as the time from the date of first documented objective response to the date of first documented disease progression, determined by the IRC Lugano 2014 criteria classification or death, whichever comes first, for participants who experience an objective response.
Part 2: Progression-free Survival (PFS) per IRC	Up to 60 months	PFS is defined as time from enrolment date to the date of disease progression, determined by the IRC per Lugano 2014 criteria classification or death from any cause, whichever comes first.
Part 2: Number of Participants with Clinically Significant Changes in Vital Signs	Up to 60 months	Vital signs will include body temperature (oral or tympanic measurement), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm).
Parts 1 and 2: AUClast - Area Under the Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration of TAK-007	Predose (Day 0) and at multiple timepoints postdose (up to 60 months)
Percentage of Participants with B-cell Aplasia Before and After TAK-007 Administration	Up to 24 months
Percentage of Participants with Positive Replication Competent Retrovirus (RCR) Test Results Before (Prevalence) and After (Incidence) TAK-007 Administration Over Time	Up to 60 months
Parts 1 and 2: Overall Survival (OS)	Up to 60 months	OS is defined as time from enrolment to the date of death from any cause.
Parts 1 and 2: Tlast - Time of Last Measurable Concentration Above the Lower Limit of Quantitation of TAK-007	Predose (Day 0) and at multiple timepoints postdose (up to 60 months)
Part 1 and Part 2: ORR per Investigator	Up to 60 months	ORR is defined as the percentage of participants with CR or PR as best response to treatment, determined by the investigator per the Lugano 2014 criteria after TAK-007 administration.
Part 1 and Part 2: Complete Response (CR) per Investigator	Up to 60 months	CR will be defined per Lugano 2014 criteria as percentage of participants with target nodes/nodal masses must regress to ≤1.5 cm in the longest transverse diameter of all lesions and no extralymphatic sites of disease.
Part 1 and Part 2: Duration of Response (DOR) per Investigator	Up to 60 months	DOR is defined as the time from the date of first documented objective response to the date of first documented disease progression, determined by investigator per Lugano 2014 criteria classification or death, whichever comes first, for participants who experience an objective response.
Part 1 and Part 2: Progression-free Survival (PFS) per Investigator	Up to 60 months	PFS is defined as time from enrolment date to the date of disease progression, determined by the investigator per Lugano 2014 criteria classification or death from any cause, whichever comes first.
Part 2: Number of Participants with Adverse Events (AEs)	Up to 60 months	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable or unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.
Part 2: Number of Participants with Clinically Significant Changes in Laboratory Parameters	Up to 60 months	Laboratory parameters will include hematology, clinical chemistry, serum immunoglobulin and urinalysis tests.
Parts 1 and 2: Cmax - Maximum Observed Blood Concentration of TAK-007	Predose (Day 0) and at multiple timepoints postdose (up to 60 months)
Part 1 and Part 2: Concentration of Interleukin (IL)-15 and Other Soluble Immune Factors in Plasma Over Time	Up to 24 months	Concentration of IL-15 and soluble immune factors (eg, Interferon (IFN)-gamma (γ), IL-1 beta (β), IL- 2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, Tumor necrosis factor (TNF) alpha (α), Granulocyte-macrophage colony-stimulating factor (GM-CSF)) in plasma over time will be reported.
Parts 1 and 2: Tmax - Time of First Occurrence of Cmax of TAK-007	Predose (Day 0) and at multiple timepoints postdose (up to 60 months)
Percentage of Participants with Detectable Anti-human Leukocyte Antigen (HLA) and Anti-chimeric Antigen Receptor (CAR) Antibodies Before (Prevalence) and After (Incidence) TAK-007 Administration Over Time	Up to 24 months

Trial Locations

Locations (15)

Cedars Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute; 🇺🇸 Los Angeles, California, United States

Northside Hospital; 🇺🇸 Atlanta, Georgia, United States

Northwestern Memorial Hospital; 🇺🇸 Chicago, Illinois, United States

Thomas Jefferson University Sidney Kimmer Cancer Center, Clinical Research Organization; 🇺🇸 Philadelphia, Pennsylvania, United States

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

MedStar Georgetown University Medical Center; 🇺🇸 Washington, District of Columbia, United States

University of Michigan Comprehensive Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

DUHS Duke Blood Cancer Center; 🇺🇸 Durham, North Carolina, United States

University of Virginia Comprehensive Cancer Center; 🇺🇸 Charlottesville, Virginia, United States

University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Sylvester Comprehensive Cancer Center University of Miami Hospitals and Clinics; 🇺🇸 Miami, Florida, United States

Saint Davids South Austin Medical Center; 🇺🇸 Austin, Texas, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Montefiore Medical Center; 🇺🇸 Bronx, New York, United States