Acute Myeloid Leukemia
Conditions
Keywords
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
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.
Interventions
GENETICArm 1: NTLA-5001
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.
GENETICArm 2: NTLA-5001
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.
Sponsors
Intellia Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants That Experienced Dose-limiting Toxicities (DLTs) | Primary DLT assessment from NTLA-5001 infusion up to 28 days post-infusion | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of NTLA-5001 T-cell Receptor (TCR) Transgene Copy Number in the Peripheral Blood | From NTLA-5001 infusion up to 4 weeks post-infusion | Frequency of edited TCR transgene copy number in the peripheral blood of the participants was determined by droplet digital polymerase chain reaction (ddPCR). |
| Persistence of NTLA-5001 T Cell Receptor (TCR) Transgene Copy in Peripheral Blood | From NTLA-5001 infusion up to 4 weeks post-infusion | Persistence of edited TCR transgene copy in the peripheral blood of the participants determined by ddPCR. |
| Tumor Response in Participants With AML | From NTLA-5001 infusion up to 4 weeks post-infusion | 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). |
| Response Duration in Participants With AML | From NTLA-5001 infusion up to 4 weeks post-infusion | 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). |
| Disease Progression in Participants With AML | From NTLA-5001 infusion up to 4 weeks post-infusion | 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 |
Countries
United Kingdom, United States
Participant flow
Recruitment details
A total of 6 participants were enrolled at 3 sites in one country. A total of 2 participants received the product at Dose Level 1 in the Dose Escalation phase. The first participant was enrolled on 17 December 2021 and the last participant was enrolled on 21 July 2022. Dose escalation phase did not proceed beyond Dose Level 1. Dose Expansion phase was not initiated.
Pre-assignment details
Six participants were enrolled in the study (signed informed consent and underwent leukapheresis), but only two participants were dosed (administered Dose Level 1).
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: NTLA-5001 Participants With AML Blasts < 5% of Bone Marrow Arm 1: NTLA-5001: Autologous WT1-directed TCR T cells engineered ex vivo using CRISPR/Cas9 as intravenous infusion after pre-conditioning chemotherapy. | 1 |
| Arm 2: NTLA-5001 Participants With AML Blasts ≥ 5% of Bone Marrow Arm 2: NTLA-5001: Autologous WT1-directed TCR T cells engineered ex vivo using CRISPR/Cas9 as intravenous infusion after pre-conditioning chemotherapy. | 5 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| C1:DoseLevel1 Assignment | Pivoting to an allogeneic version of this program | 0 | 4 |
| C1:DoseLevel1 Dosed Participants (W1-16) | Death | 1 | 1 |
Baseline characteristics
| Characteristic | Arm 2: NTLA-5001 Participants With AML Blasts ≥ 5% of Bone Marrow | Total | Arm 1: NTLA-5001 Participants With AML Blasts < 5% of Bone Marrow |
|---|---|---|---|
| Age, Continuous | 57 years | 59 years | 68 years |
| Body Mass Index | 24.3 kg/m^2 STANDARD_DEVIATION 6.63 | 26.5 kg/m^2 STANDARD_DEVIATION 8.07 | 37.7 kg/m^2 STANDARD_DEVIATION 0 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 6 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 170.2 cm STANDARD_DEVIATION 9.18 | 173.5 cm STANDARD_DEVIATION 11.52 | 190.0 cm STANDARD_DEVIATION 0 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 6 Participants | 1 Participants |
| Region of Enrollment United States | 5 Participants | 6 Participants | 1 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 1 Participants |
| Weight | 71.3 kg STANDARD_DEVIATION 24.79 | 82.1 kg STANDARD_DEVIATION 34.5 | 136.0 kg STANDARD_DEVIATION 0 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 1 / 1 |
| other Total, other adverse events | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 1 / 1 |
Outcome results
Primary
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.
Time frame: Primary DLT assessment from NTLA-5001 infusion up to 28 days post-infusion
Population: The Safety Analysis Set (defined as all participants who received NTLA-5001) was used for this presentation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: NTLA-5001 Participants With AML Blasts < 5% of Bone Marrow | Participants That Experienced Dose-limiting Toxicities (DLTs) | 0 Participants |
| Arm 2: NTLA-5001 Participants With AML Blasts ≥ 5% of Bone Marrow | Participants That Experienced Dose-limiting Toxicities (DLTs) | 0 Participants |
Secondary
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
Time frame: From NTLA-5001 infusion up to 4 weeks post-infusion
Population: The Safety Analysis Set (defined as all participants who received NTLA-5001) was used for presentations of disease response data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: NTLA-5001 Participants With AML Blasts < 5% of Bone Marrow | Disease Progression in Participants With AML | NA Weeks |
| Arm 2: NTLA-5001 Participants With AML Blasts ≥ 5% of Bone Marrow | Disease Progression in Participants With AML | NA Weeks |
Secondary
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).
Time frame: From NTLA-5001 infusion up to 4 weeks post-infusion
Population: The Cell Kinetics Analysis Set (defined as all participants who received NTLA-5001 and have at least one evaluable cell kinetics sample) was used for this presentation.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm 1: NTLA-5001 Participants With AML Blasts < 5% of Bone Marrow | Frequency of NTLA-5001 T-cell Receptor (TCR) Transgene Copy Number in the Peripheral Blood | NA copy/ng gDNA |
| Arm 2: NTLA-5001 Participants With AML Blasts ≥ 5% of Bone Marrow | Frequency of NTLA-5001 T-cell Receptor (TCR) Transgene Copy Number in the Peripheral Blood | NA copy/ng gDNA |
Secondary
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.
Time frame: From NTLA-5001 infusion up to 4 weeks post-infusion
Population: The Cell Kinetics Analysis Set (defined as all participants who received NTLA-5001 and have at least one evaluable cell kinetics sample) was used for this presentation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: NTLA-5001 Participants With AML Blasts < 5% of Bone Marrow | Persistence of NTLA-5001 T Cell Receptor (TCR) Transgene Copy in Peripheral Blood | NA Days |
| Arm 2: NTLA-5001 Participants With AML Blasts ≥ 5% of Bone Marrow | Persistence of NTLA-5001 T Cell Receptor (TCR) Transgene Copy in Peripheral Blood | NA Days |
Secondary
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).
Time frame: From NTLA-5001 infusion up to 4 weeks post-infusion
Population: The Safety Analysis Set (defined as all participants who received NTLA-5001) was used for presentations of disease response data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: NTLA-5001 Participants With AML Blasts < 5% of Bone Marrow | Response Duration in Participants With AML | NA Weeks |
| Arm 2: NTLA-5001 Participants With AML Blasts ≥ 5% of Bone Marrow | Response Duration in Participants With AML | NA Weeks |
Secondary
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).
Time frame: From NTLA-5001 infusion up to 4 weeks post-infusion
Population: The Safety Analysis Set (defined as all participants who received NTLA-5001) was used for presentations of disease response data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: NTLA-5001 Participants With AML Blasts < 5% of Bone Marrow | Tumor Response in Participants With AML | 0 Participants |
| Arm 2: NTLA-5001 Participants With AML Blasts ≥ 5% of Bone Marrow | Tumor Response in Participants With AML | 0 Participants |