Antigen-specific T Cell Therapy for AML or MDS Patients With Relapsed Disease After Allo-HCT

Sponsor

NexImmune Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04284228

Collaborator

(none)

Enrollment

Locations

Arms

36.3

Anticipated Duration (Months)

4.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This Research study is being done to characterize the safety, tolerability, and preliminary antitumor activity of the NEXI-001 T cell product (a new experimental therapy), which contains populations of CD8+ T cells targeting multiple leukemia associated antigen peptides in patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) who have relapsed disease after an allogeneic hematopoietic cell transplant (HCT).

The study will enroll AML or MDS patients who have either Minimal Residual Disease (MRD) or relapsed disease after a human leukocyte antigen (HLA)-matched allogeneic HCT. Patients who have had an HLA-mismatched or haploidentical allogeneic HCT will not be eligible to participate in this study. Eligible patients for this study must also have ≥ 50% T-cell chimerism from the original donor at the time study entry.

The enrolled patients will undergo bridging therapy for the purposes of disease control while the NEXI-001 T cell product is being manufactured. Choice of bridging therapy administered will be per the Investigator's discretion, but is limited to acceptable agents as specified in the protocol. Bridging therapy will be administered prior to lymphodepleting (LD) therapy, with the last dose of the bridging therapy administered ≥ 14 days prior to initiation of LD therapy. Within 72 hours after completing LD therapy, patients will receive a single IV infusion of the NEXI-001 T cell product.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS)	Biological: Infusion of NEXI-001 T Cells	Phase 1/Phase 2

Detailed Description

The NEXI-001 is an adoptive cellular therapy product which contains populations of antigen-specific CD8+ T cells. The antigen-specific CD8+ T cells in the NEXI-001 T cell product are derived from Peripheral Blood Mononuclear Cells (PBMC) obtained from the original stem cell donor. During the manufacturing process, these cells are primed and expanded ex vivo using nano-size artificial Antigen Presenting Cells (aAPC) loaded with five leukemia associated antigen peptides in combination with a proprietary T cell enrichment and expansion process.

The NEXI-001 T cell product is restricted to patients that are HLA-A2.01 allele positive for this study.

There are two parts to this study, a Safety Evaluation Phase and a Dose Expansion Phase. The Safety Evaluation Phase will determine the safety and tolerability of a single dose of NEXI-001 T cell product, and will consist of Dose Escalation at two dose levels - each with cohorts of three patients.

When all three patients at Dose Level 1 have dosed and cleared the DLT period, three additional patients will be enrolled at Dose Level 2. When three patients have cleared the DLT period at the highest dose level, that dose will be advanced to the Dose Expansion Phase. The Dose Expansion Phase will enroll up to 16 additional patients to further define the safety and evaluate the initial anti-tumor efficacy of the NEXI- 001 T cell product at the dose established from the Safety Evaluation Phase.

All patients will enter a Post-Treatment Follow-Up period after infusion of the NEXI- 001 T cell product. During this phase, all patients will be monitored for AEs and followed for anti-leukemia response until the end of study visit is complete (up to one year).

Additional assessments for safety, disease status, and other secondary and exploratory endpoints will also be monitored during the follow-up period.

All patients will be followed for overall survival (OS) from time of disease progression until the last visit of the last patient. During this time, patients will be followed via telephone or other electronic contact at 12 week intervals for monitoring of OS.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

22 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

There are two parts to this study. The initial Safety Evaluation Phase will determine the safety and tolerability of a single dose of NEXI-001 T cells. The second part of the study, the Dose Expansion Phase, to further define the safety and evaluate the initial efficacy of the NEXI-001 T cells at the dose established from the Safety Evaluation Phase.There are two parts to this study. The initial Safety Evaluation Phase will determine the safety and tolerability of a single dose of NEXI-001 T cells. The second part of the study, the Dose Expansion Phase, to further define the safety and evaluate the initial efficacy of the NEXI-001 T cells at the dose established from the Safety Evaluation Phase.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1 / 2 Study to Evaluate the Safety, Tolerability and Initial Anti-Tumor Activity of Adoptively Transferred T Lymphocytes Targeting WT1, PRAME and Cyclin A1 AML or MDS Patients With Relapsed Disease After Matched Allogeneic HCT

Actual Study Start Date :

Feb 20, 2020

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Safety Evaluation Phase Treatment with NEXI-001 T cells, derived from PBMCs of original HLA- matched HCT donor.	Biological: Infusion of NEXI-001 T Cells Procedure: A single IV infusion of NEXI-001 T Cells at Day 1 after Lymphodepletion(LD) Therapy. At dose Level 1: 1.0 x 108 total viable T cells At dose Level 2: 2.0 x 108 total viable T cells Procedure: Lymphodepletion: IV administration of fludarabine 30 mg/2 and cyclophosphamide 300 mg/m2 for 3 days. lymphodepletion (LD) Therapy: Subjects will received bridging therapy agents during lymphodepletion for 3 consecutive days prior to receiving the NEXI-001 product Drug: Fludarabine Fludarabine infusion Other Name: Fludarabine monophosphate Drug: Cyclophosphamide Cyclophosphamide infusion Other Name: Cytoxan
Experimental: Dose Expansion Phase Dose Expansion Phase to further define the safety, tolerability and initial anti-tumor efficacy of the NEXI-001 T cell product at the dose established from the Safety Evaluation Phase.	Biological: Infusion of NEXI-001 T Cells Procedure: A single IV infusion of NEXI-001 T Cells at Day 1 after Lymphodepletion(LD) Therapy. At dose Level 1: 1.0 x 108 total viable T cells At dose Level 2: 2.0 x 108 total viable T cells Procedure: Lymphodepletion: IV administration of fludarabine 30 mg/2 and cyclophosphamide 300 mg/m2 for 3 days. lymphodepletion (LD) Therapy: Subjects will received bridging therapy agents during lymphodepletion for 3 consecutive days prior to receiving the NEXI-001 product Drug: Fludarabine Fludarabine infusion Other Name: Fludarabine monophosphate Drug: Cyclophosphamide Cyclophosphamide infusion Other Name: Cytoxan

Arm

Intervention/Treatment

Experimental: Safety Evaluation Phase

Treatment with NEXI-001 T cells, derived from PBMCs of original HLA- matched HCT donor.

Biological: Infusion of NEXI-001 T Cells

Procedure: A single IV infusion of NEXI-001 T Cells at Day 1 after Lymphodepletion(LD) Therapy. At dose Level 1: 1.0 x 108 total viable T cells At dose Level 2: 2.0 x 108 total viable T cells Procedure: Lymphodepletion: IV administration of fludarabine 30 mg/2 and cyclophosphamide 300 mg/m2 for 3 days. lymphodepletion (LD) Therapy: Subjects will received bridging therapy agents during lymphodepletion for 3 consecutive days prior to receiving the NEXI-001 product Drug: Fludarabine Fludarabine infusion Other Name: Fludarabine monophosphate Drug: Cyclophosphamide Cyclophosphamide infusion Other Name: Cytoxan

Experimental: Dose Expansion Phase

Dose Expansion Phase to further define the safety, tolerability and initial anti-tumor efficacy of the NEXI-001 T cell product at the dose established from the Safety Evaluation Phase.

Biological: Infusion of NEXI-001 T Cells

Outcome Measures

Primary Outcome Measures

Adverse Events of Special Interest (AESIs) events [At year 1]
Dose Limiting Toxicities (DLTs)
Adverse Events of Special Interest (AESIs) events [At year 1]
For Incidence of TEAEs and serious TEAEs (Treatment-emergent adverse events (TEAEs) are defined as those AEs that started on or after LD therapy or that worsened after LD therapy
Adverse Events of Special Interest (AESIs) events (AEs) [At year1]
Infusion Related Reactions (IRR)
Survival [At 12 months]
Median Progressive free Survival (PFS)
Survival [At 12 months]
Overall Response Rate (ORR)
Survival [At 12 months]
Overall Survival (OS)
Adverse events (AEs) Reporting [At year 1]
Incidence of TEAEs leading to study withdrawal
Adverse Events of Special Interest (AESIs) events (AEs) Reporting [At year 1]
Cytokine Release Syndrome (CRS)
Adverse Events of Special Interest (AESIs)events (AEs) Reporting [At year 1]
Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

General

Ability to provide informed consent and documentation of informed consent prior to initiation of any study-related tests or procedures that are not part of standard-of-care for the patient's disease. Patients must also be willing and able to comply with study procedures, including the acquisition of specified research specimens
Age ≥ 18 years old
Expression of HLA-A*0201 as determined by high resolution sequence-based typing method (e.g. TruSight HLA v2 Sequence Panel)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Patients must have a confirmed diagnosis of AML (according to World Health Organization (WHO) classification) or MDS with evidence of MRD or morphological relapse after HLA-matched allogeneic HCT

MRD includes:

Detection of blasts <5% in bone marrow
Detection of a clonal abnormal blast population via multi-color flow cytometry
Detection of known or new myeloid gene mutations
Donor match at 10 of 10 loci for HLA-A, -B, -C, -DRB1 and DQB1, with each typed at high resolution by DNA-based methods.

Patients who have had prior HLA-mismatched or haploidentical allogeneic HCT will not be eligible

T-cell chimerism ≥ 50% to donor (by PCR analysis)
Acceptable laboratory parameters as follows:
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN)
Total bilirubin ≤ 1.5 × ULN, except patients with Gilbert's syndrome, who may enroll if the conjugated bilirubin is within normal limits
Creatinine < 1.5 mg/dL or a calculated or measured creatinine clearance (CL) ≥ 50 mL/min per standard calculation
Recovery to Grade 1 or baseline of non-hematologic toxicities from prior treatments, excluding alopecia
Female patients of childbearing potential must test negative for pregnancy at enrollment and during the study. Sexually active women of child-bearing potential, unless surgically sterile, must be willing to use a highly effective method of birth control defined as those which result in a low failure rate (i.e., less than 1% per year) such as implants, injectables, combined oral contraceptives, intra-uterine devices (IUDs) or vasectomized partner
Male patients with partners of childbearing potential must be either vasectomized or agree to use a condom in addition to having their partners use another method of contraception resulting in a highly effective method of birth control defined as those which result in a low failure rate (i.e., less than 1% per year) such as implants, injectables, combined oral contraceptives, or IUDs. Patients should not have sexual intercourse with females who are either pregnant or lactating without double-barrier contraception Is not pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the prescreening or screening visit through one year from administration of NEXI-001 cells

Exclusion Criteria:

Active acute or chronic graft versus host disease (GvHD)
Eligible patients will not be on any steroids ≥10 mg per day prednisone or equivalent or other immunosuppressants such as tacrolimus, cyclosporine, etc.
Intermittent topical, inhaled or intranasal corticosteroids are allowed
Have active or uncontrolled infections with positive cultures and/or requiring treatment with IV anti-infective agents
History of clinically significant cardiovascular disease including but not limited to:
Myocardial infarction or unstable angina within the 6 months prior to the initiation of study
Stroke or transient ischemic attack within 6 months prior to initiation of study
Clinically significant cardiac arrhythmia
Uncontrolled hypertension: systolic blood pressure (SBP) > 180 mmHg, diastolic blood pressure (DBP) > 100 mmHg
Congestive heart failure (New York Heart Association [NYHA] class III-IV)
Pericarditis or clinically significant pericardial effusion
Myocarditis
Clinically significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation
History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus erythematosus, etc.) resulting in end organ injury or requiring systemic immunosuppression / systemic disease modifying agents within the last 2 years prior to enrollment. Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and subjects with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for the study
Human immunodeficiency virus (HIV) seropositive; HIV testing within 2 years of enrollment
Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV). Patients who are hepatitis B surface antigen (HBsAg) negative and HBV viral DNA negative are eligible
Patients who had HBV but have received an antiviral treatment and show non-detectable viral DNA for 6 months are eligible
Patients who are seropositive because of HBV vaccine are eligible
Seropositive for and with active viral infection with hepatitis C virus (HCV)

Patients who had HCV but have received an antiviral treatment and show no detectable HCV viral DNA for 6 months are eligible

Second primary invasive malignancy that has not been in remission for greater than 2 years. Exceptions that do not require a 2-year remission include: resected non-melanoma skin cancer; carcinoma in situ (cervix, bladder, breast, etc.) or squamous intraepithelial lesion on Pap smear; localized prostate cancer (Gleason score < 6); or resected melanoma in situ
History of trauma or major surgery within 4 weeks prior to the study enrollment
Any serious underlying medical or psychiatric condition that would impair the ability of the patient to receive or tolerate the planned treatment and follow up
Known hypersensitivity to any component of NEXI-001 T cells, cyclophosphamide, fludarabine or tocilizumab
Vaccination with any live virus vaccine is not permitted prior to the initiation of study treatment. Inactivated annual influenza vaccination is allowed.
Dementia or altered mental status that would preclude understanding and rendering of informed consent
History of seizures, aphasia, psychosis or other chronic clinically significant neurologic disorders

Patients with remote history of seizures that are well controlled on anti-seizure medications and without any seizure episode for 6 months are eligible

Any issue that in the opinion of the investigator, would contraindicate the patient's participation in the study or confound the results of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
2	Advent Health Medical Group Blood & Marrow Transplant	Orlando	Florida	United States	32804
3	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
4	David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center	New York	New York	United States	10021
5	The James Cancer Hospital and Solove Research Institute OSUCC	Columbus	Ohio	United States	43210