Dose Finding Study to Evaluate the Safety of BSB-2002 in Relapsed or Refractory Acute Myeloid Leukemia (AML) Patients With NPM1 Mutation

This is a Phase I, multicenter, open-label, non-randomized study to characterize the safety and clinical activity of BSB-2002, a genetically modified autologous T cell product incorporating an HLA-A*02:01-restricted mutant NPM1-directed T cell receptor (TCR), administered to patients with relapsed or refractory acute myeloid leukemia (AML). Enrolled patients must be HLA-A*02:01+ and positive for the NPM1 mutation which produces the alternative amino acid sequence CLAVEEVSL (Type A, D, G or H).

The study is an adaptive dose escalation design with up to 3 cohorts to evaluate single doses of BSB-2002, employing the 3+3 design.

Inclusion criteria

• Male or female patients, ages 18 years or older,
• AML diagnosed per ELN criteria1 which has been treated with at least two lines of therapy,

• which is relapsed (after previously complete remission, CR, CRh or CRi), or
• refractory (failed to achieve complete remission) to the last treatment*, *Primary refractory patients should have received at least two cycles of induction treatment
• Patients who are MRD positive by NGS for NPM1 after being MRD negative following the last treatment
• HLA-A*02:01,
• Positive for NPM1 mutation type A, D, G or H (see Appendix 3)2
• Adequate venous access for apheresis or agree to use of a central line for apheresis collection,
• Willing and able to provide informed consent and adhere to all study requirements.

Exclusion criteria

• Leukemic blast count of >20,000/μl. If the blast count can be maintained below the threshold with hydroxyurea, the patient would be eligible.
• Patients with extramedullary only AML.
• Patients that are candidates for hematopoietic stem cell transplant.
• Patients that are eligible to receive an approved targeted therapy.
• Treatment with other investigational agents within 5 half-lives of the planned dosing of BSB-2002 (day 1).
• Subject has had hematopoietic stem cell transplant (HSCT) and has any of the following:

• Is within 3 months of transplant;
• Has clinically significant graft-versus-host disease requiring systemic treatment;
• Has ≥ Grade 2 persistent non-hematological toxicity related to the transplant.
• Other malignancy that requires treatment.
• Uncontrolled bacterial, viral, or fungal infections at time of enrollment.
• Active Hepatitis B or C infection.
• Seropositive for Human Immunodeficiency Virus-1 or -2.
• CNS involvement refractory to intrathecal chemotherapy and/or standard cranial- spinal radiation.
• Subject has congestive heart failure NYHA class 3 or 4, or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless an echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%.
• Renal insufficiency, with estimated creatinine clearance of < 40 ml/min/1.73m2 by the Cockcroft-Gault equation with adjustment if the weight is ≥ 125% of ideal body weight OR inadequate renal function defined by serum creatinine > 1.6 mg/dL
• Total bilirubin > 2x upper limit of normal (unless attributed to Gilbert's Syndrome).
• AST or ALT > 3x upper limit of normal.
• Pregnant or lactating women.
• Eastern Cooperative Oncology Group (ECOG) performance status >2.
• Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine or systemic steroids at any dose)
• Women of childbearing potential (WOCBP) and men who are fertile and are unwilling to use an effective birth control method or abstinence for 12 months. Effective forms of birth control are listed in the Contraception section.
• Any condition, in the judgement of the Investigator, that would interfere with study participation, pose a significant risk to the patient, or interfere with study data interpretation.