Adoptive T Cell Therapy With DC/AML Fusion Vaccine Plus Decitabine and Venetoclax in AML

Official title

A Phase 1, First in Human Study of Adoptive T Cell Therapy With T Cells Stimulated by Dendritic Cell (DC)/Tumor Fusions in Combination With Decitabine and Venetoclax in Patients With Acute Myeloid Leukemia (AML)

Overview

The goal of this research study is to test if the combination of a new T cell therapy (dendritic cell (DC) / acute myeloid leukemia (AML) primed T cells), vaccine (DC/AML fusion vaccine) and standard of care decitabine and venetoclax is feasible and safe and effective for treatment of acute myeloid leukemia (AML). The names of the study drugs involved in this study are: * DC/AML fusion vaccine (immune cell vaccine) * Granulocyte-macrophage colony-stimulating factor (GM-CSF) (a type of growth factor or hormone) * DC/AML Primed T cells (immune cells) * Decitabine (a type of chemotherapy drug) * Venetoclax (a type of antineoplastic agent)

Detailed description

The study is a dose escalation phase I clinical trial to evaluate the feasibility, safety, clinical and immune effects of adoptive T cell therapy with DC/AML Primed T cells in participants with acute myeloid leukemia (AML) treated with decitabine and venetoclax.

The U.S. Food and Drug Administration (FDA) has not approved DC/AML Vaxprimed T cells as a treatment for any disease. This is the first time that DC/AML Primed T cells will be given to humans.

The U.S. Food and Drug Administration (FDA) has not approved DC/AML fusion vaccine as a treatment for any disease. The U.S. Food and Drug Administration (FDA) has approved GM-CSF, decitabine and venetoclax as treatment options for acute myeloid leukemia (AML).

It is expected that about 30 people will take part in this research study

Interventions

• Biological DC/AML Fusion Vaccine
  Autologous fusion vaccine of dendritic cells and AML cells, via subcutaneous injection (under the skin) per standard of care.
• Biological T-Cell Therapy
  Autologous adoptive T cells, via intravenous (into the vein) infusion, per protocol.
• Drug Decitabine
  A pyrimidine nucleoside analogue, via intravenous infusion, per standard of care.
• Drug Venetoclax
  A BCL-2 inhibitor, taken orally per standard of care.
• Drug GM-CSF
  A Granulocyte-Macrophage Colony-Stimulating Factor, via subcutaneous injection, per standard of care.

Primary outcome measures

• Successful Manufacture and Administration Rate of Vaccine-Educated T Cells [Time frame: 28 weeks]
• Maximum Tolerated Dose (MTD) of Vaccine-Educated T Cells [Time frame: 56 Days]
• Toxicity Rate of Vaccine-Educated T Cells, Including CRS, Neurotoxicity, and Infections [Time frame: 5 years]

Secondary outcome measures (4)

• Relapse-Free Survival (RFS) at 1 Year Post Administration of Vaccine Educated T Cells [Time frame: 1 year]
• Relapse-Free Survival (RFS) at 2 Years Post Administration of Vaccine Educated T Cells [Time frame: 2 years]
• MRD Negative Conversion Rate [Time frame: MRD samples are collected up to 6 months after the last cell therapy dose.]
• Median Overall Survival (OS) [Time frame: 5 years]

Eligibility criteria

Inclusion Criteria Prior to Tumor Collection

• Patients must have AML at initial diagnosis for which decitabine/venetoclax is planned as standard of care therapy. This can include patients with IDH or FLT-3 mutations for whom the addition of targeted therapy agents directed at IDH or FLT-3 mutations to the decitabine/venetoclax regimen is preferred per the treating physician.
• Patients with AML in first relapse after cytotoxic and/or targeted therapy for which decitabine and venetoclax therapy is appropriate standard of care. This can include patients with IDH or FLT-3 mutations for whom the addition of targeted therapy agents directed at IDH or FLT-3 mutations to the decitabine/venetoclax regimen is preferred per the treating physician.
• ECOG performance status ≤ 2 (Appendix A)
• Participants must have normal organ and marrow function as defined below:

• total bilirubin≤ 2.0 mg/dL
• AST/ALT ≤ 3 × institutional upper limit of normal
• creatinine ≤ 2.0 mg/dl
• The effects of vaccine stimulated T cells on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria Prior to Tumor Collection

• Patients diagnosed with acute promyelocytic leukemia
• Patients treated at initial diagnosis who are appropriate for intensive induction therapy.
• Patients with active systemic autoimmune disease requiring ongoing systemic therapy are excluded. The following is an exception to this criterion: subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement. Patients with paraneoplastic auto-immune manifestations related to AML are allowed.
• Patients who have received a prior allogeneic transplant will be excluded.
• Because of compromised cellular immunity, patients who have active human immunodeficiency virus (HIV), untreated hepatitis C virus (HCV) or evidence of active hepatitis B virus (HBV).
• Patients must not have active significant cardiac disease characterized by symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia.
• Patients must not be pregnant. All premenopausal patients will undergo pregnancy testing. Men will agree to not father a child while on protocol treatment. Men and women will practice effective birth control while receiving protocol treatment.

Inclusion Criteria Prior to Leukapheresis

• Patients must have obtained a response of PR or better to decitabine and venetoclax as defined in Section 11.
• Resolution of all HMA/venetoclax related grade III-IV toxicity as per CTC criteria 4.0, other than grade 3 anemia.
• Laboratories:

• ANC ≥ 1,000/µL
• Platelets ≥ 50,000/uL
• Bilirubin ≤ 2.0 mg/dL
• Creatinine ≤ 2.0 mg/dL
• AST/ALT ≤ 3.0 x ULN

Exclusion Criteria Prior to Leukapheresis

• Patients must not have serious intercurrent illness such as infection requiring IV antibiotics, or significant cardiac disease characterized by significant arrhythmia, ischemic coronary disease or congestive heart failure
• Patients who, with their treating physician, choose to proceed with an allogeneic transplant at the time of remission will not be eligible for leukapheresis
• Patients with active systemic autoimmune disease requiring ongoing systemic therapy are excluded. The following is an exception to this criterion: subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement. Patients with paraneoplastic auto-immune manifestations related to AML are permitted.
• Current or prior use of immunosuppressive medication within 14 days prior to first T cell infusion. The following are exceptions to this criterion: intranasal, inhaled, topical or local steroid injections (eg. intra-articular injection); steroids as premedication for hypersensitivity reactions; systemic corticosteroid at physiologic doses not to exceed 10mg/day of prednisone or equivalent
• Known human immunodeficiency virus (HIV), untreated hepatitis C virus (HCV) or evidence of active hepatitis B virus (HBV).
• Female subjects who are pregnant, breast-feeding or female patients of reproductive potential who are not employing an effective method of birth control from starting treatment, including dosing interruptions through 90 days after last dose of treatment. Refrain from egg cell donation while receiving vaccination and for at least 90 days after the last dose of treatment.
• Male subjects who are not employing an effective method of birth control from starting vaccine, including dosing interruptions through 90 days after receipt of the last dose of treatment. Refrain from sperm cell donation while receiving vaccination and for at least 90 days after the last dose of treatment.

Inclusion Criteria Prior to Treatment with DC/AML Primed T cells and DC/AML fusion vaccine

• Patient completed 4 cycles of decitabine and venetoclax without evidence of disease recurrence or progression
• Resolution of all chemotherapy related grade III-IV toxicity as per CTC criteria 4.0, other than grade 3 anemia, at the time of initiation of cycle 5, 6, or 7 of decitabine/venetoclax therapy.
• Laboratories:

• ANC ≥ 1,000/µL
• Platelets ≥ 50,000/uL
• Bilirubin ≤ 2.0 mg/dL
• Creatinine ≤ 2.0 mg/dL
• AST/ALT ≤ 3.0 x ULN
• Generation of adequate yield of T cells to meet dosing requirement

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Beth Israel Deaconess Medical Center — Boston

Identifiers

NCT: NCT07374029 · 25-593

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗