Relapsed/Refractory Large B-cell Lymphoma With NT-I7 Post-CD19 CAR T-cell Therapy

Study Overview
=================
Brief Summary
-----------------
This is a multicenter Phase 1b study evaluating the safety, tolerability, and preliminary anti-tumor activity of NT-I7 administration following standard of care CD19 CAR T-cell therapy for eligible subjects with r/r LBCL.

Detailed Description
-----------------
This is a multicenter Phase 1b study evaluating the safety, tolerability, and preliminary anti-tumor activity of NT-I7 administration following standard of care CD19 CAR T-cell therapy for eligible subjects with r/r LBCL. The study consists of a Dose Escalation phase followed by a Dose Expansion phase. In the Dose Escalation phase, subjects will be enrolled in 1 of 7 dose levels, starting with 60 µg/kg and up to 720 µg/kg. A dose schedule for an individual dose level will not be taken into expansion until the Dose Escalation phase has been completed or a maximum tolerated dose (MTD) has been determined, whichever occurs first. In the Dose Expansion phase, up to 15 subjects will be enrolled and treated with the recommended dose identified in the Dose Escalation phase. Up to 17- 42 subjects in the Dose Escalation phase, and up to 15 subjects in the Dose Expansion phase will be enrolled at approximately 6 study centers. Treatment Plan: NT-I7 (aka rhIL-7-hyFc, efineptakin alpha), Tisagenlecleucel (Kymriah®), Axicabtagene ciloleucel (Yescarta®), Lisocabtagene Maraleucel (Breyanzi®) *CAR-T Therapy will be administered per manufacturer's recommendations and in accordance with FDA prescribing guidelines and best institutional practices for standard of care use.

Official Title
-----------------
A Phase 1b Study Evaluating the Safety, Tolerability and Preliminary Anti-tumor Activity of NT-I7 (Efineptakin Alfa) a Long-acting Human IL-7, Post-Kymriah® (Tisagenlecleucel), Post-Yescarta® (Axicabtagene Ciloleucel), or Post-Breyanzi® (Lisocabtagene Maraleucel) in Subjects With Relapsed/Refractory Large B-cell Lymphoma

Conditions
-----------------
Refractory Diffuse Large B-cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, Recurrent Diffuse Large B-Cell Lymphoma, Refractory High Grade B-Cell Lymphoma, Refractory Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: Efineptakin alfa
* Drug: Tisagenlecleucel
* Drug: Axicabtagene ciloleucel
* Drug: Lisocabtagene Maraleucel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must be ≥18 years on the day of signing informed consent. Be willing and able to provide written informed consent/assent for the study. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 Have received at least 2 prior lines of therapy and must be eligible for standard of care CD19 CAR T-cell therapy Subjects with histologically confirmed relapsed or refractory LBCL after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), high grade B-cell lymphoma, DLBCL arising from follicular lymphoma, and primary mediastinal large B-cell lymphoma, must be eligible for standard of care CD19 CAR T-cell Therapy. Subjects must have measurable disease by IWG response criteria for lymphoma [Lugano classification (1)] Subjects must have a life expectancy of greater than or equal to 12 weeks per assessment from the enrolling physician. 9. Adequate organ and marrow function at the start of lymphodepleting chemotherapy as pre-conditioning for standard of care CD19 CAR T-cell infusion Exclusion Criteria: In Dose Escalation phase: Grade ≥3 CRS or ICANS post-CD19 CAR T-cell infusion. In Dose Expansion phase: Grade ≥3 CRS or ICANS post-CD19 CAR T-cell infusion. Pregnant, lactating or breastfeeding or expecting to conceive or father children within the study duration from screening through 120 days after the last dose of study treatment. Had previously received CD19-directed therapy Subjects with documented current central nervous system (CNS) involvement by lymphoma are to be excluded from study participation. Any concurrent chemotherapy or biologic or hormonal therapy for cancer treatment. Subjects who have autoimmune disease history for the past 2 years, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Have active and clinically relevant bacterial, fungal, viral, or Tuberculosis infection, including known Hepatitis A, B, or C or HIV (testing not required). Concurrent enrollment in another clinical study unless it is an observational (non interventional) clinical study. Receipt of any conventional or investigational anticancer therapy, not otherwise specified above, within 30 days prior to NT-I7 injection. Unresolved toxicities from prior anticancer therapy Receipt of live, attenuated vaccine within 30 days prior to NT-I7 injection. Has had an allogenic tissue/solid organ transplant or bone marrow transplant. Subjects for whom intramuscular therapy is contraindicated.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NT-I7 after CAR-T (Kymriah, Yescarta, or Breyanzi) infusion<br>CAR-T infusion administered per standard of care at Day 0 followed by NT-I7 on Day 21. | Drug: Efineptakin alfa<br>* NT-I7 is administered via a single intramuscular injection after CAR-T infusion on Day 21.<br>* Other names: rhIL-7-hyFc;Drug: Tisagenlecleucel<br>* Administered as standard of care as described in the package insert on Day 0.<br>* Other names: Kymriah;Drug: Axicabtagene ciloleucel<br>* Administered as standard of care as described in the package insert on Day 0.<br>* Other names: Yescarta;Drug: Lisocabtagene Maraleucel<br>* Administered as standard of care as described in the package insert on Day 0.<br>* Other names: Breyanzi;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For Dose Escalation Phase: Incidence of adverse events (AE) | According to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | 21 Days | 
| Incidence of Dose Limiting Toxicities (DLT) | DLT is defined as any AE occurring within the first 21 days after NT-I7 injection that is considered to be at least possibly, probably, or definitely related to the study treatment (NT-I7) per the investigator, and that meets at least one of the non-hematologic or hematologic criteria listed below. | 21 Days | 
| To determine the Maximum Tolerated Dose (MTD) | The MTD will be defined as the dose of NT-I7 that yields a DLT rate ≤ 33%. | 21 Days | 
| To determine the Recommended Phase 2 Dose (RP2D) | Determination of the RP2D: The RP2D will be based on an accumulation of all available data. All available data including clinical Pharmacokinetic, Pharmacodynamic, anti-tumor activity (including best overall response rate) and safety, and nonclinical pharmacology data will be pooled. Integrated dose-response and exposure-response analyses will be conducted to determine the RP2D | 21 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of Duration of Response (DOR) | Duration of Response (DoR) for the responders defined as the time from the first occurrence of a documented objective response (Partial Response [PR] or Complete Response [CR]) to the time of the first documented disease progression or death from any cause, whichever occurs first, per the Lugano classification as determined by the investigator. | up to 3 months | 
| Measurement of Progression-Free Survival (PFS) | Progression Free Survival (PFS) defined as the time from the first study treatment (Day 1) to the first occurrence of progression or death from any cause, whichever occurs first, per the Lugano classification as determined by the investigator. | up to 3 months | 
| Measurement of Overall Survival (OS) | Overall survival (OS) defined as the time from first study treatment (Day 1) to death from any cause. | up to 3 months | 
| Rates of grade 3 and higher cytokine release syndrome (CRS) | Grading of CRS will be based on American Society for Transplantation and Cellular Therapy (ASTCT) guidelines. | Up to 3 months | 
| Rates of grade 3 and higher immune effector cell associated neurotoxicity syndrome (ICANS) | Grading of ICANS will be based on American Society for Transplantation and Cellular Therapy (ASTCT) guidelines. | Up to 3 months | 
| The effect of NT-I7 on CAR-T cells expansion by Quantitative DNA Polymerase Chain Reaction (PCR) |  | Up to 3 months | 
| The effect of NT-I7 on CAR-T cells expansion by fluorescence-activated cell sorting (FACS) |  | Up to 3 months |