Study Investigating NTLA-5001 in Subjects With Acute Myeloid Leukemia

Study Overview
=================
Brief Summary
-----------------
This study will be conducted to evaluate the safety, tolerability, cellular kinetics (CK), activity, and pharmacodynamics (PD) of NTLA-5001 in participants with Acute Myeloid Leukemia (AML).

Detailed Description
-----------------
This 2-part first in human (FIH) study is comprised of two open-label arms. It is a multi-center, Phase 1/2a study evaluating the safety and activity of NTLA-5001 in subjects with persistent or recurrent Acute Myeloid Leukemia after first-line or later therapy.

Official Title
-----------------
Phase 1/2a, Single Dose Study Investigating NTLA-5001 in Subjects With Acute Myeloid Leukemia

Conditions
-----------------
Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Genetic: Arm 1: NTLA-5001
* Genetic: Arm 2: NTLA-5001


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (abbreviated): Has AML as defined by World Health Organization Has detectable disease following first-line therapy Is ≥ 18 years of age. Carries the human leukocyte antigen-A0201 (HLA-A*02:01) allele. Has ECOG performance status of 0 to 1. Has adequate absolute total lymphocyte count Has adequate cardiac, renal, and liver organ function Exclusion Criteria (abbreviated): Has received AML-directed therapy or immunomodulatory therapy within a specified window prior to study entry. Has received allogeneic hematopoietic cell transplant within 84 days, with ongoing GVHD, with recent DLI, or on active immunosuppression. Has CNS involvement by tumor. Has severe autoimmunity requiring immunomodulatory therapy. Has active disseminated intravascular coagulation (DIC), bleeding or coagulopathy. Has leukocytosis ≥ 20,000 blasts/μL despite hydroxyurea or has rapidly progressive disease Has human immunodeficiency virus (HIV) infection, or any uncontrolled infection. Female subjects are pregnant or breastfeeding; or are of childbearing potential and are unwilling to use protocol specified method of contraception. Male subjects who have female partners of childbearing potential and are unwilling to use protocol specified method of contraception.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: NTLA-5001<br>Up to three escalation cohorts in phase 1 followed by one expansion cohort in phase 2. Subjects have AML and bone marrow blast count <5%, administered by IV infusion following lymphodepleting chemotherapy. | Genetic: Arm 1: NTLA-5001<br>* Autologous WT1-directed TCR T cells engineered ex vivo using CRISPR/Cas9 as intravenous infusion after pre-conditioning chemotherapy. Cyclophosphamide and Fludarabine will be administered on Day -5, -4, and -3 as intravenous infusion.<br>|
| Experimental: Arm 2: NTLA-5001<br>Up to three escalation cohorts in phase 1 followed by one expansion cohort in phase 2. Subjects have AML and bone marrow blast count ≥5%, administered by IV infusion following lymphodepleting chemotherapy. | Genetic: Arm 2: NTLA-5001<br>* Autologous WT1-directed TCR T cells engineered ex vivo using CRISPR/Cas9 as intravenous infusion after pre-conditioning chemotherapy. Cyclophosphamide and Fludarabine will be administered on Day -5, -4, and -3 as intravenous infusion.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants That Experienced Dose-limiting Toxicities (DLTs) | DLTs were defined as events with onset within 28 days of infusion. AEs were collected from time of informed consent through the Week 112 visit. AEs were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.0. Severity of AEs was assessed by the investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 toxicity grading criteria. The measure reported below for the primary outcome consists of DLT data only. Adverse events are reported in the Adverse Event section of this presentation. | Primary DLT assessment from NTLA-5001 infusion up to 28 days post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of NTLA-5001 T-cell Receptor (TCR) Transgene Copy Number in the Peripheral Blood | Frequency of edited TCR transgene copy number in the peripheral blood of the participants was determined by droplet digital polymerase chain reaction (ddPCR). | From NTLA-5001 infusion up to 4 weeks post-infusion | 
| Persistence of NTLA-5001 T Cell Receptor (TCR) Transgene Copy in Peripheral Blood | Persistence of edited TCR transgene copy in the peripheral blood of the participants determined by ddPCR. | From NTLA-5001 infusion up to 4 weeks post-infusion | 
| Tumor Response in Participants With AML | Rate of objective response, where response is complete response without measurable residual disease (CRMRD-) (Arm 1). Rate of objective response, where response is CRMRD-, complete response, complete remission with incomplete hematologic recovery, morphologic leukemia-free state, and partial remission (Arm 2). | From NTLA-5001 infusion up to 4 weeks post-infusion | 
| Response Duration in Participants With AML | Bone marrow results were planned to be used to determine the duration of response / remission (DOR) for subjects with objective response, from first response until MRD was measured above the lower level of detection for the central laboratory assay, or death from any cause, whichever occurred first (Arm 1). Bone marrow results were planned to be used to determine DOR for subjects with composite CR, from first response to progression or death due to any cause, whichever occurred first (Arm 2). | From NTLA-5001 infusion up to 4 weeks post-infusion | 
| Disease Progression in Participants With AML | Bone marrow results were used to determine the time to clinical progression. Progressive disease was defined as an increase from baseline of at least 25% of bone marrow blasts or an absolute increase of at least 5,000 cells/μL in the number of circulating leukemia cells | From NTLA-5001 infusion up to 4 weeks post-infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NTLA-5001, cell kinetics, Pharmacodynamics, clustered regularly interspaced short palindromic repeats, CRISPR, AML, Acute Myeloid Leukemia, TCR T Cell Therapy, Autologous, Leukemia, Neoplasms, Immune System Diseases, Immunoproliferative Disorders