A Study to Evaluate the Safety, Tolerability and Preliminary Anti-tumor Activity of NT-I7 (Efineptakin Alfa) Post-Tisagenlecleucel (Kymriah®) in Relapsed/Refractory Large B-cell Lymphoma Subjects
Study Details
Study Description
Brief Summary
This is 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-Tisagenlecleucel (Kymriah®) in subjects with relapsed/refractory large B-cell Lymphoma.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
This is a multicenter Phase 1b study evaluating the safety, tolerability and preliminary anti-tumor activity of NT-I7 administration following SOC Kymriah 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.
Dose Escalation phase The Dose Escalation phase is designed to assess the safety and tolerability, including determination of the MTD and/or the RP2D, of NT-I7 when administered after Kymriah infusion for r/r LBCL. Seven dose levels (DLs) are planned: the starting DL (DL1) will be 60 mcg/kg, and the highest DL to be tested (DL7) will be 720 mcg/kg, as outlined in the Treatment Schema. Other intermediate DLs between 60 mcg/kg and 720 mcg/kg may be explored based on emerging data.
The Dose Escalation phase will begin with an accelerated phase with 1 subject per cohort at the first 2 DLs (DL1 = 60 mcg/kg and DL2 = 120 mcg/kg), followed by a standard 3+3 design on the remaining 5 DLs (see Treatment Schema), each with a cohort of 3 independent subjects each time and with a maximum total of 6 subjects per cohort. If at least 2 Grade ≥ 2 AEs or any 1 Dose Limiting Toxicity (DLT) are observed in the single subject enrolled in either DL1 or DL2, the accelerated phase will convert to a conventional 3+3 design at the DL where the AEs or DLT are observed and remain so for all the DLs above. In addition to converting to the 3+3 design, the next DL will not exceed 50% of the previous DL. Similarly, if a 2nd DLT occurs in a DL, the next DL in the escalation scheme will not exceed 33% of the previous DL.
In all DLs that followed the 3+3 design, subjects will be dosed in a 3-week staggered fashion: the 1st subject in a DL will be monitored for 3 weeks; after 3 weeks, if the safety is acceptable, the 2nd subject will be enrolled and treated at that same DL; similarly, the 3rd subject will be enrolled and treated only if the safety appears to be acceptable for both the 1st and 2nd subjects after the 2nd subject has been monitored for 3 weeks. If additional subjects are required for a DL, they will be enrolled and treated in similar 3-week staggered fashion.
Dose Expansion phase Once RP2D has been determined from the Dose Escalation phase, up to 15 subjects will be enrolled in the Dose Expansion phase and treated at the RP2D to further evaluate the safety and preliminary anti-tumor activity of NT-I7 administration following SOC Kymriah CAR T-cell therapy for eligible subjects with r/r LBCL.
Treatment Plan:
• NT-I7 (aka rhIL-7-hyFc, efineptakin alfa): NT-I7 will be administered as an intramuscular (IM) injection at the appropriate DL for each cohort. Each subject will receive only one NT-I7 injection administered on Day 21 +/-2 days (post-Kymriah infusion). Subjects will be hospitalized for NT-I7 injection and monitored for at least 24 hours after NT-I7 injection. If subjects develop Grade 2 or higher AEs, subjects will remain hospitalized until resolution of AEs to grade 1 or better. Subjects can be kept in the hospital longer at the discretion of the treating physicians. Additionally, subjects will be asked to stay within 1-hour radius of the location where they received treatment and will be closely monitored by appropriately trained medical staff 2-3 times (or more often, as clinically indicated) during the first 1 week and at least weekly for at least 3 more weeks.
• Tisagenlecleucel (Kymriah®): Kymriah will be administered per manufacturer's recommendations and in accordance with FDA prescribing guidelines and best institutional practices for SOC use.
• Duration of Treatment, Study and Follow-up: The enrollment date is at the start of lymphodepleting chemotherapy in preparation for infusion of the Kymriah product. The duration on study will be approximately 3 months following infusion of Kymriah. Subjects will then be followed up per standard of care and per the REMS program for Kymriah.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Single Arm Drug: NT-I7 (efineptakin alfa) |
Drug: Tisagenlecleucel
NT-I7 is administered via intramuscular injection 21 days after Kymriah® infusion
Other Names:
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Outcome Measures
Primary Outcome Measures
- To evaluate the safety and tolerability of NT-I7 when administered after Kymriah infusion [Up to 21 days]
Incidence of adverse events graded according to NCI CTCAE v5.0
- To evaluate the safety and tolerability of NT-I7 when administered after Kymriah infusion [Up to 21 days]
nature of adverse events graded according to NCI CTCAE v5.0
- To evaluate the safety and tolerability of NT-I7 when administered after Kymriah infusion [Up to 21 days]
Severity of adverse events graded according to NCI CTCAE v5.0
- To determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of NT-I7 when administered after Kymriah infusion [Up to 21 days]
Incidence of DLTs
- To determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 To determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of NT-I7 when administered after Kymriah infusion [Up to 21 days]
Nature of DTLs
- To determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 To determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of NT-I7 when administered after Kymriah infusion [Up to 21 days]
Potential correlation of dose levels with safety and efficacy parameters
Secondary Outcome Measures
- To explore the preliminary anti-tumor activity of NT-I7 when administered after Kymriah infusion for r/r LBCL [Up to 3 months]
Overall Response Rate (ORR)
- To explore the preliminary anti-tumor activity of NT-I7 when administered after Kymriah infusion for r/r LBCL [Up to 3 months]
Duration of Response
- To explore the preliminary anti-tumor activity of NT-I7 when administered after Kymriah infusion for r/r LBCL [Up to 3 months]
Progression -Free Survival (PFS)
- To explore the preliminary anti-tumor activity of NT-I7 when administered after Kymriah infusion for r/r LBCL [Up to 3 months]
Overall Survival (OS)
- To continue evaluating the effect of NT-I7 when administered after Kymriah infusion on safety profile [Up to 3 months]
Rates of grade 3 and higher Cytokine Release Syndrome (CRS)
- To continue evaluating the effect of NT-I7 when administered after Kymriah infusion on safety profile [Up to 3 months]
Rates of grade 3 and higher Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
Other Outcome Measures
- To make a preliminary assessment of PK parameters of Kymriah when administered NT-I7 post- Tisagenlecleucel therapy [Up to 3 months]
Parameters of expansion
- To make a preliminary assessment of PK parameters of Kymriah when administered NT-I7 post- Tisagenlecleucel therapy [Up to 3 months]
Parameters of maximum concentration (Cmax)
- To make a preliminary assessment of PK parameters of Kymriah when administered NT-I7 post- Tisagenlecleucel therapy [Up to 3 months]
Parameters of time to maximum concentration (Tmax)
- To make a preliminary assessment of PK parameters of Kymriah when administered NT-I7 post- Tisagenlecleucel therapy [Up to 3 months]
Parameters of persistence
- To make a preliminary assessment of PK parameters of Kymriah when administered NT-I7 post- Tisagenlecleucel therapy [Up to 3 months]
Parameters of terminal half-life (T1/2)
- To make a preliminary assessment of PK parameters of Kymriah when administered NT-I7 post- Tisagenlecleucel therapy [Up to 3 months]
Parameters of last measured concentration (Clast)
- To make a preliminary assessment of PK parameters of Kymriah when administered NT-I7 post- Tisagenlecleucel therapy [Up to 3 months]
Parameters of time of last measured concentration (Tlast)
- To make a preliminary assessment of PK parameters of Kymriah when administered NT-I7 post- Tisagenlecleucel therapy [Up to 3 months]
Area under the curve for CAR T-cell expansion for days 0-21 (prior to NT-I7 administration)
- To make a preliminary assessment of PK parameters of Kymriah when administered NT-I7 post- Tisagenlecleucel therapy [Up to 3 months]
Area under the curve for days 22-90 (after NT-I7 administration)
- To make a preliminary assessment of PK parameters of Kymriah when administered NT-I7 post- Tisagenlecleucel therapy [Up to 3 months]
Area under the curve for days 22-90 ( 3 months post Kymriah infusion)
Eligibility Criteria
Criteria
Inclusion Criteria:
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Must be ≥18 years on the day of signing informed consent.
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Be willing and able to provide written informed consent/assent for the study.
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Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
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Have received at least 2 prior lines of therapy and must be eligible for Kymriah therapy as SOC
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Subjects with 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 , and DLBCL arising from follicular lymphoma, must be eligible for Kymriah therapy as SOC.
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Subjects must have measurable disease by IWG response criteria for lymphoma [Lugano classification (1)]
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All subjects must consent to biopsies
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Subjects must have a life expectancy of greater than or equal to 12 weeks per assessment from the enrolling physician.
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Adequate organ and marrow function at the start of lymphodepleting chemotherapy as pre-conditioning for Kymriah infusion
Exclusion Criteria:
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In Dose Escalation phase: Grade ≥2 CRS or ICANS post-Kymriah infusion.
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In Dose Expansion phase: Grade ≥3 CRS or ICANS post-Kymriah infusion.
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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.
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Had previously received CD19-directed therapy
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Subjects with documented current central nervous system (CNS) involvement by lymphoma are to be excluded from study participation.
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Any concurrent chemotherapy or biologic or hormonal therapy for cancer treatment.
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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.
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Have active and clinically relevant bacterial, fungal, viral, or TB infection, including known Hepatitis A, B, or C or HIV (testing not required).
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Concurrent enrollment in another clinical study unless it is an observational (non interventional) clinical study.
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Receipt of any conventional or investigational anticancer therapy, not otherwise specified above, within 30 days prior to NT-I7 injection.
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Unresolved toxicities from prior anticancer therapy
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Receipt of live, attenuated vaccine within 30 days prior to NT-I7 injection.
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Has had an allogenic tissue/solid organ transplant or bone marrow transplant.
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Subjects for whom intramuscular therapy is contraindicated.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope | Duarte | California | United States | 91010 |
| 2 | Washington University in St. Louis | Saint Louis | Missouri | United States | 63110 |
| 3 | Duke Cancer Institute | Durham | North Carolina | United States | 27710 |
Sponsors and Collaborators
- NeoImmuneTech
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NIT-112