Treatment for relapsed large B-cell lymphoma using NT-I7 after CAR T-cell therapy

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

This study is testing if a new treatment called NT-I7 can help people with relapsed large B-cell lymphoma feel better after receiving CAR T-cell therapy.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 57 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: NeoImmuneTech (Industry-sponsored)
• Drugs / interventions: CAR-T, CAR T, chemotherapy
• Locations: 4 sites (Duarte, California and 3 other locations)
• Trial ID: NCT05075603 on ClinicalTrials.gov

What this trial studies

This multicenter Phase 1b study evaluates the safety, tolerability, and preliminary anti-tumor activity of NT-I7 administered after standard CD19 CAR T-cell therapy in patients with relapsed or refractory large B-cell lymphoma (LBCL). The study includes a Dose Escalation phase with seven dose levels ranging from 60 µg/kg to 720 µg/kg, followed by a Dose Expansion phase where up to 15 subjects will receive the recommended dose. Participants must have measurable disease and be eligible for CAR T-cell therapy according to FDA guidelines.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with histologically confirmed relapsed or refractory LBCL who are eligible for CAR T-cell therapy.

Not a fit: Patients with non-relapsed or non-refractory large B-cell lymphoma or those not eligible for CAR T-cell therapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could improve outcomes for patients with difficult-to-treat relapsed or refractory large B-cell lymphoma.

How similar studies have performed: While this approach is novel, other studies have shown promise with CAR T-cell therapies, indicating potential for success.

Eligibility criteria

Subjects must meet all the following criteria for study entry:

1. Must be ≥18 years on the day of signing informed consent.
2. Be willing and able to provide written informed consent/assent for the study.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
4. Subjects should be eligible for CAR-T therapy respective to the current FDA-approved CAR-T label for Yescarta, Breyanzi, or Kymriah.
5. Subjects with histologically confirmed relapsed or refractory LBCL 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 SOC CD19 CAR T-cell Therapy.

   (a) Tumor tissue (fresh or archival) must have been tested to confirm the type of LBCL.
6. Subjects must have measurable disease by IWG response criteria for lymphoma \[Lugano classification (3)\]

   1. Baseline fluorodeoxyglucose (FDG)-PET/computed tomography (CT) scans must show positive lesions compatible with CT-defined anatomical tumor sites but will not be used in subsequent clinical decisions.
   2. A previously irradiated lesion can be considered a target lesion if the lesion is well defined, measurable, and has clearly progressed.
   3. Subjects that received bridging therapy pre-lymphodepletion will be allowed for enrollment regardless of re-staging results (PMR or CMR), even if the lesion is not measurable per the criteria mentioned above.
   4. PET/CT scans done as SOC up to 28 days pre-lymphodepletion therapy will be allowed.

   All subjects whose scans are \> 28 days from lymphodepletion therapy will need a re-staging FDG-PET/CT scan.
7. (This is a placeholder for inclusion criterion 7, which has been removed.)
8. 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 per institutional guidelines at the start of lymphodepleting chemotherapy as pre-conditioning for SOC CD19 CAR T-cell infusion.

The following laboratory parameters (9a-h) are recommendations. Labs outside of these ranges may be considered for inclusion after consultation with the medical monitor. Cytopenia resulting from disease or bridging therapy will not be considered exclusionary.

1. Hemoglobin ≥8.0 g/dL or ≥4.96 mmol/L
2. Absolute neutrophil count ≥1,000/µL
3. Platelets \>50,000/µL
4. Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) OR direct bilirubin ≤ULN for subjects with total bilirubin levels \>1.5 × ULN, except subject with documented Gilbert's syndrome (\>3 x ULN), who must have a baseline total bilirubin ≤ 3.0 mg/dL
5. AST(SGOT)/ALT(SGPT) ≤2.5 × ULN (AST and/or ALT ≤5 × ULN for subjects with liver metastasis)
6. Alkaline phosphatase ≤2.5 × ULN (≤5 × ULN for subjects with documented liver involvement or bone metastases)
7. Creatinine clearance (CrCl) ≥30 mL/min as calculated per institutional standard.
8. INR and aPTT ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants 10. Female subjects who are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks; female subjects of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or to use dual methods of contraception for the duration of study treatment and for 90 days after NT-I7 injection, whichever is longer. Female subjects of childbearing potential (including women who have had a tubal ligation) must have a negative serum or urine pregnancy test within 72 hours prior to NT-I7 injection. If the urine test is positive, or cannot be confirmed as negative, a serum pregnancy test will be required.

   11. ECG demonstrating Fridericia's corrected QT interval (QTcF) \< 500 ms. Patients with QTcF ≥ 500 ms will require clearance by a local cardiologist.

   Exclusion Criteria:

   Subjects meeting any of the following criteria are not eligible for enrollment in the study:
   1. In Dose Escalation phase: Grade ≥3 CRS or ICANS post-CD19 CAR T-cell infusion. Note: Grade 1 or 2 CRS or ICANs must be completely resolved \>3 days prior to NT-I7 injection
   2. In Dose Expansion phase: Grade ≥3 CRS or ICANS post-CD19 CAR T-cell infusion. Note: Grade 1 or 2 CRS or ICANS must be completely resolved \>3 days prior to NT-I7 injection
   3. 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.
   4. This exclusion criteria has been removed and remains as a placeholder.
   5. Subjects with documented current central nervous system (CNS) involvement by lymphoma are to be excluded from study participation.
   6. Any concurrent chemotherapy or biologic or hormonal therapy for cancer treatment.

      Note: Concurrent use of hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable. In addition, local treatment (eg, by local surgery or radiotherapy) of isolated lesions for palliative intent is acceptable beyond the DLT evaluation period with prior consultation and agreement with the medical monitor.
   7. 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. The following are exceptions to this criterion:

      1. Subjects with vitiligo or alopecia.
      2. Subjects with type 1 diabetes mellitus.
      3. Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
      4. Psoriasis not requiring systemic treatment.
      5. NOTE: Diverticulitis that is not associated with inflammatory bowel disease is not considered exclusionary (e.g., subjects who do not have active diarrhea due to chronic diverticulitis).
   8. Have active and clinically relevant bacterial, fungal, viral, or TB infection, including known Hepatitis A, B, or C or HIV (testing not required).
   9. Concurrent enrollment in another clinical study unless it is an observational (noninterventional) clinical study.
   10. Receipt of any conventional or investigational anticancer therapy, not otherwise specified above, within 30 days prior to NT-I7 injection.
   11. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v5.0 Grade ≤ 1 with the exception of alopecia and laboratory values listed per the inclusion criteria. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by any of the investigational products may be included (e.g., hearing loss, peripheral neuropathy) after consultation with the medical monitor.
   12. Receipt of live, attenuated vaccine within 30 days prior to NT-I7 injection. Note: Subjects, if enrolled, should not receive live vaccine during the study and through 30 days after NT-I7 injection, whichever is longer. The administration of killed vaccines is permitted at any time.
   13. Has had an allogenic tissue/solid organ transplant or bone marrow transplant.
   14. Subjects for whom intramuscular therapy is contraindicated.
   15. Has clinically significant cardiac disease, including, but not limited to, any of the following:

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   1. Uncontrolled atrial fibrillation
   2. Congestive Heart Failure NYHA Class ≥ 2
   3. Or any of the following within 6 months prior to Baseline, Day 0 CAR-T administration:

      * Unstable angina
      * Myocardial infarction
      * Coronary artery bypass grafting
      * Coronary angioplasty
      * Coronary stenting
      * Clinically significant cardiac arrhythmia and/or conduction abnormality
   4. History of other clinically significant cardiac disease that, in the opinion of the Investigator or designee, is a contraindication to study treatment is also excluded.

Where this trial is running

Duarte, California and 3 other locations

• City of Hope — Duarte, California, United States (Recruiting)
• Barbara Ann Karmanos Cancer Hospital dba Karmanos Cancer Center — Detroit, Michigan, United States (Recruiting)
• Washington University in St. Louis — Saint Louis, Missouri, United States (Recruiting)
• Duke Cancer Institute — Durham, North Carolina, United States (Recruiting)

Study contacts

• Study coordinator: Kristina Stermer, MMS

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