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

Study Overview
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Brief Summary
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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 B-cell Non-Hodgkin Lymphoma. The main aim of Part 2 is to learn if lymphomas are reduced or gone after treatment withTAK-007 in adults with relapsed or refractory B-cell Non-Hodgkin Lymphoma or indolent non-Hodgkin lymphoma (iNHL). Participants will receive lymphodepleting chemotherapy for 3 days before receiving a single injection of TAK-007. After this, participants will regularly visit the clinic for check-ups.

Detailed Description
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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 242 patients. In Part 1, dose escalation and dose expansion cohorts participants will receive TAK-007 as follows: Part 1: Dose escalation: TAK-007 - 200×10^6 CD19-CAR+ Viable NK Cells (±30%) Part 1: Dose escalation: TAK-007 - 800×10^6 CD19-CAR+ Viable NK Cells (±25%) Part 1: Dose expansion: r/r LBCL: TAK-007 - 200×10^6/800×10^6 Viable NK Cells Part 1: Dose expansion: r/r iNHL: TAK-007 - 200×10^6/ 800×10^6 Viable NK Cells 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. 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.

Official Title
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A Phase 2, Open-label, Multicenter Study of the Safety and Efficacy of TAK-007 in Adult Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Conditions
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Relapsed or Refractory (r/r) B-cell Non-Hodgkin Lymphoma (NHL)

Intervention / Treatment
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* Biological: TAK-007
* Drug: Chemotherapy Agents


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who have a life expectancy ≥12 weeks. Participants who have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 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). 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 -positive disease per the Lugano classification. Participants whose disease is r/r after at least 2 prior lines of systemic therapy: 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). Participants with iNHL must have received an anti-CD20 mAb and an alkylating agent (eg, bendamustine or cyclophosphamide). Preinduction salvage chemotherapy and ASCT should be considered 1 therapy. 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. Single-agent anti-CD20 mAb therapy should not be considered a line of therapy. Participants who have adequate bone marrow function defined as follows: Absolute neutrophil count >500/μL. Platelet count of >50,000/μL at screening. Participants with transfusion-dependent thrombocytopenia are excluded. Participants who have adequate renal, hepatic, cardiac, and pulmonary function as defined in the study protocol: Estimated glomerular filtration rate (GFR; Modification of Diet in Renal Disease equation [MDRD]) ≥30 mL/min. Serum alanine aminotransferase/aspartate aminotransferase ≤5 times the upper limit of normal range (ULN), as long as participant is asymptomatic. 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. 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. No evidence of clinically relevant pericardial effusion, and no acute clinically significant electrocardiogram (ECG) findings. Absence of Grade ≥2 pleural effusion. Grade 1 stable pleural effusions are allowed. Baseline oxygen saturation >92% on room air. 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. Exclusion Criteria: Participants with total body weight of <40 kg. 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. Participants with Burkitt lymphoma, mantle cell lymphoma, lymphoplasmocytic lymphoma, or transformation from CLL/small lymphocytic lymphoma (Richter transformation). 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. Participants who have undergone autologous or allogeneic transplant or Chimeric antigen receptor T cells (CAR-T) 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. 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. 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. 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. 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. Participants who have received a live vaccine ≤6 weeks before the start of the conditioning regimen.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study has 2 Parts: Part 1 is composed of dose escalation followed by dose expansion and Part 2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation: TAK-007 - 200×10^6 CD19-CAR+ Viable NK Cells<br>Participants will receive lymphodepleting chemotherapy per day intravenously followed by TAK-007 200×10^6 anti-CD19 chimeric antigen receptor (CD19-CAR+) viable natural killer (NK) cells, single-dose, intravenously, once on Day 0. | Biological: TAK-007<br>* TAK-007 intravenous injection.<br>Drug: Chemotherapy Agents<br>* Fludarabine and cyclophosphamide as per standard of care.<br>|
| Experimental: Part 1: Dose Escalation: TAK-007 - 800×10^6 CD19-CAR+ Viable NK Cells<br>Participants will receive lymphodepleting chemotherapy per day intravenously followed by TAK-007 - 800×10^6 CD19-CAR+ Viable NK Cells, single-dose, intravenously, once on Day 0. | Biological: TAK-007<br>* TAK-007 intravenous injection.<br>Drug: Chemotherapy Agents<br>* Fludarabine and cyclophosphamide as per standard of care.<br>|
| Experimental: Part 1: Dose Expansion: LBCL: TAK-007 - 200×10^6/ 800×10^6 CD19-CAR+ Viable NK Cells<br>Participants with r/r Large B-cell Lymphoma (LBCL) will receive lymphodepleting chemotherapy per day intravenously 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. | Biological: TAK-007<br>* TAK-007 intravenous injection.<br>Drug: Chemotherapy Agents<br>* Fludarabine and cyclophosphamide as per standard of care.<br>|
| Experimental: Part 1: Dose Expansion: iNHL: TAK-007 - 200×10^6/ 800×10^6 CD19-CAR+ Viable NK Cells<br>Participants with r/r Indolent Non-Hodgkin Lymphoma (iNHL) will receive lymphodepleting chemotherapy per day intravenously 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. | Biological: TAK-007<br>* TAK-007 intravenous injection.<br>Drug: Chemotherapy Agents<br>* Fludarabine and cyclophosphamide as per standard of care.<br>|
| Experimental: Part 2: Cohort 1- LBCL<br>Participants with LBCL will be enrolled in this cohort to receive lymphodepleting chemotherapy per day intravenously followed by TAK-007 at RP2D, intravenously, once on Day 0. | Biological: TAK-007<br>* TAK-007 intravenous injection.<br>Drug: Chemotherapy Agents<br>* Fludarabine and cyclophosphamide as per standard of care.<br>|
| Experimental: Part 2: Cohort 2- iNHL<br>Participants with iNHL will be enrolled in this cohort to receive lymphodepleting chemotherapy per day intravenously followed by TAK-007 at RP2D, intravenously, once on Day 0. | Biological: TAK-007<br>* TAK-007 intravenous injection.<br>Drug: Chemotherapy Agents<br>* Fludarabine and cyclophosphamide as per standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants with Adverse Events (AEs) | 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. | Up to 60 months | 
| Part 1: Number of Participants with Clinically Significant Changes in Laboratory Parameters | Laboratory parameters will include hematology, clinical chemistry, serum immunoglobulin and urinalysis tests. | Up to 60 months | 
| Part 1: Number of Participants with Clinically Significant Changes in Vital Signs | 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). | Up to 60 months | 
| Part 2: Overall Response Rate (ORR) per Independent Review Committee (IRC) | 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. | Up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2: ORR per Investigator | 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. | Up to 60 months | 
| Part 1 and Part 2: Complete Response (CR) per Investigator | 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. | Up to 60 months | 
| Part 2: Complete Response (CR) Per IRC | 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. | Up to 60 months | 
| Part 1 and Part 2: Duration of Response (DOR) per Investigator | 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. | Up to 60 months | 
| Part 2: Duration of Response (DOR) per IRC | 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. | Up to 60 months | 
| Part 1 and Part 2: Progression-free Survival (PFS) per Investigator | PFS is defined as time from enrollment date to the date of disease progression, determined by the investigator per Lugano 2014 criteria classification or death from any cause, whichever comes first. | Up to 60 months | 
| Part 2: Progression-free Survival (PFS) per IRC | PFS is defined as time from enrollment date to the date of disease progression, determined by the IRC per Lugano 2014 criteria classification or death from any cause, whichever comes first. | Up to 60 months | 
| Parts 1 and 2: Overall Survival (OS) | OS is defined as time from enrollment to the date of death from any cause. | Up to 60 months | 
| Part 2: Number of Participants with Adverse Events (AEs) | 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. | Up to 60 months | 
| Part 2: Number of Participants with Clinically Significant Changes in Laboratory Parameters | Laboratory parameters will include hematology, clinical chemistry, serum immunoglobulin and urinalysis tests. | Up to 60 months | 
| Part 2: Number of Participants with Clinically Significant Changes in Vital Signs | 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). | Up to 60 months | 
| Parts 1 and 2: Cmax - Maximum Observed Blood Concentration of TAK-007 |  | Predose (Day 0) and at multiple timepoints postdose (up to 60 months) | 
| 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) | 
| 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) | 
| 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) | 
| Part 1 and Part 2: Concentration of Interleukin (IL)-15 and Other Soluble Immune Factors in Plasma Over Time | 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. | Up to 24 months | 
| Percentage of Participants with B-cell Aplasia Before and After TAK-007 Administration |  | Up to 24 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy, Chimeric antigen receptor, Natural killer cells, Cell therapy, Allogeneic