Phase I Study of Cell Therapies for the Treatment of Patients With Relapsed or Refractory AML or High-risk MDS

Phase I Study of Cell Therapies for the Treatment of Patients With Relapsed or Refractory AML or High-risk MDS

Master Protocol for the Phase 1 Study of Cell Therapies for the Treatment of Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome, Including Long-term Safety Follow-up

The purpose of this study is to evaluate the safety and preliminary activity of ARC-T cells and SPRX002 in participants with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS)

This is a Phase I open-label, safety, and dose-escalation study of ARC-T cells and SPRX002 in participants with relapsed or refractory AML or high-risk MDS. The study will have the following sequential phases: screening, enrollment, pretreatment with lymphodepletion (LD) chemotherapy, treatment with SPRX002 and ARCT cells, treatment extension with SPRX002, follow up, and long-term safety follow-up. Following a single infusion of SPRX002 and ARC T (Day 0) and followed by regular administration of SPRX002 at the assigned dose level, both safety and efficacy data will be assessed. Dose limiting toxicities (DLTs) will be assessed through Day 28 and safety data will be collected throughout the study. Long-term safety data will be collected for up to 15 years per health authority guidelines. Efficacy will be assessed monthly for the first 6 months, then quarterly up to 2 years, or upon subject relapse. ARC-T cells are a genetically modified autologous T-cell product. The T cell has been transduced using a third-generation lentiviral vector encoding a binding domain (referred to as AF101) chimeric antigen receptor (CAR), followed by CD8 spacer and transmembrane region that is fused to the intracellular signaling domains 4-1BB and CD3ζ. AF101 specifically binds to the "TAG" protein (referred to as Q26) of the soluble protein antigen-receptor x-linker (sparX; specifically, SPRX002).

Arm 1: Phase 1 Study of monovalent CD123-Specific Adapter (SPRX002) and Universal CAR-Modified T cell (ARC-T Cells) for the Treatment of Patients with Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

SPRX002 is a soluble protein with a "TAG" region to which ARC-T cells bind and a binding region targeting CD123

ARC-T Cells is a genetically modified autologous T-cell product. The T cell has a binding domain chimeric antigen receptor (CAR), which specifically binds to the "TAG" protein of the soluble protein antigen-receptor x-linker (sparX; specifically, SPRX002). When ARC-T cells bind to a "TAG" and the SPRX protein is bound to its target (in this case CD123), ARC-T cells are capable of activation, expansion, and killing (based on preclinical experiments).

Incidence of treatment-emergent adverse events (TEAEs), including dose-limiting toxicities (DLTs) and establish recommended Phase II dose (RP2D)

The RP2D will be determined based on the totality of data, including the maximum tolerated dose (MTD); if applicable, and other endpoints such as observed efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and other safety endpoints (adverse events (AEs), laboratory assessment, vital signs, and physical examinations)

Serial blood and bone marrow sampling to determine response to treatment by modified International Working Group (IWG) Response Criteria in AML and MDS, or other appropriate response criteria for the malignancy under study, such as overall response rate, composite complete remission rate, and rate of negative minimum residual disease (MRD)

Quantification of ARC-T cells and SPRX002 using vector copy number (VCN) on peripheral blood mononuclear cells

Inclusion Criteria: 18 years or older Acute myeloid leukemia (AML) Subjects: WHO-confirmed AML (WHO AML Criteria 2016), other than APL, with no standard treatment options available Relapsed or refractory disease after 1 or 2 lines of therapy Relapsed: Bone marrow blasts ≥ 5% following achievement of complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)/morphological leukemia-free state (MLFS) Refractory: Failure to achieve CR/CRi/MLFS with evidence of persistence leukemia by blood and/or bone marrow after any of the following: i. At least 2 cycles of 7+3 based therapy ii. At least 1 cycle of high or intermediate dose cytarabine containing induction regimen iii. at least 2 cycles of venetoclax (VEN)-based lower intensity therapy, e.g., with hypomethylating agents (HMA), or low-dose Cytarabine (LDAC) or cladribine+LDAC iv. at least 4 cycles of HMA-based therapy with venetoclax Myelodysplastic syndrome (MDS) Subjects: Diagnosis of MDS and ≥ 10% bone marrow blasts with indication of high-risk disease defined as those having resistant or refractory disease to at least one course of therapy including HMA given at conventional regimen, with or without venetoclax or other agents. Failure is defined as failure to attain a response, or relapse after prior response to HMA therapy per the modified IWG criteria. Patents relapsing after allogeneic hematopoietic stem cell transplant (HSCT) >6 months prior are eligible if they have recovered from all transplant-related toxicities and are off all immunosuppression for at least 6 weeks Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 Adequate organ function, including renal and hepatic function based on last clinical assessment performed within the screening period Creatinine clearance ≥50 ml/min (Cockcroft-Gault or 24-hour urine collection in cases in which Cockroft-Gault is unreliable or if preferred by physician) and not on dialysis Alanine aminotransferase <3 x upper limit of normal (ULN) Aspartate aminotransferase <3 x the upper limit of normal (ULN) Total bilirubin <2 x upper limit of normal (ULN) (except for patients with known or suspected history of Gilbert's Syndrome where up to 3x ULN is allowed) Left Ventricular Ejection Fraction (LVEF) ≥45% by echocardiography (ECHO) or multigated acquisition (MUGA) scan Pulse oxygenation ≥92% on room air Prothrombin time test (PTT), prothrombin time (PT)/international normalized ratio (INR) <1.5 x ULN, unless on a stable dose of anti-coagulant for thromboembolic event (patients with any history of thromboembolic stroke; or history or Grade 2 (G2) or greater hemorrhage within 60 days are excluded) Resolution of adverse events (AEs) from any prior systemic anticancer therapy, radiotherapy, or surgery to Grade 1 or baseline (except G2 alopecia and G2 sensory neuropathy) Prior allogeneic stem cell transplant is allowed, provided the subject has recovered from all AEs, there is no ongoing graft-versus-host-disease (GvHD) and subject is not on taking any immunosuppressive medications to prevent GvHD Male and females of childbearing potential must agree to use highly effective methods of birth control through 6 months after the dose of study treatment Patients must have an identified potential donor and transplant strategy/plan prior to initiation of the lymphodepletion regimen to ensure availability of hematopoeitic stem cells (HSCs) for potential urgent allogeneic HSC transplant (HSCT) if needed for persistent bone marrow aplasia without evidence of residual leukemia. Transplant decision making would be a discussion between subject and investigator due to potential for treatment-related mortality and is not required Willing to comply with and able to tolerate study procedures, including Long-Term Safety Follow-up lasting up to 15 years Subject's apheresis product from non-mobilized cells is received and accepted for cell processing by manufacturing site. NOTE: apheresis will be accepted only after all other eligibility criteria have been met Exclusion Criteria: Patients with acute promyelocytic leukemia (APL) Patients with active CNS involvement. Subjects may be cleared of CNS involvement if there has been no evidence of CNS involvement for at least 3 months prior to enrollment Hyperleukocytosis (≥25,000 blasts/μL) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy. (Note: Subjects may be receiving or may receive hydroxyurea to maintain or control hyperleukocytosis) Previous treatment with an investigational gene or chimeric antigen receptor therapy (Note: May be permitted after discussion with Medical Monitor) Previous treatment with a directed therapy (T-cell engager or ADC) against the target for the specific sparX protein in the specific arm for enrollment Use of any anti-AML/MDS directed chemotherapy or targeted therapy, except hydroxyurea therapy, within 14 days or 5 half-lives (whichever is shorter) prior to the date of leukapheresis and use of any anti-AML/MDS directed monoclonal antibody within 28 days prior to date of leukapheresis Known infection with Human Immunodeficiency Virus or Human T-Cell leukemia/lymphoma virus type 1 (HTLV-1) A known hypersensitivity or severe allergy to study drug components including dimethyl sulphoxide (DMSO) and human serum albumin Contraindication to cyclophosphamide or fludarabine Subject has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate treatment Severe uncontrolled intercurrent illness including: Cardiovascular disease Symptomatic congestive heart failure Unstable angina, arrythmia, or myocardial infarction (MI) within 6 months prior to screening Significant pulmonary dysfunction Uncontrolled thromboembolic events or recent severe hemorrhage Any history of pulmonary embolism (PE) ever or deep vein thrombosis (DVT) within 3 months of screening. Therapeutic dosing of anticoagulants (e.g., warfarin, low molecular weight heparin, Factor Xa inhibitors) is allowed for history of DVT if greater than 3 months from time of screening) Note: Central line thrombosis not requiring anticoagulation will not be excluded and will not require a 3-month screening window Autoimmune disease Seropositive for and with evidence of active hepatitis B or C infection at time of Screening Subjects with a history of hepatitis B but have received antiviral therapy and have non-detectable viral DNA for 6 months are eligible Subjects seropositive because of hepatitis B virus vaccine with no signs or active infection are eligible Subjects who had hepatitis C but have received antiviral therapy and show no detectable hepatitis C virus (HCV) viral RNA for 6 months are eligible Any sign of active CNS pathology within 6 months of screening including history of epilepsy, seizure requiring anti-seizure medications, paresis, aphasia, stroke, severe brain injury, dementia, cerebellar disease, Parkinson's disease, organic brain syndrome or psychosis. Subarachnoid hemorrhage or central nervous system (CNS) bleed within 3 months of screening Subject has active malignant tumors other than AML/MDS that requires active antineoplastic or radiation therapy at the time of screening. Maintenance therapy or hormonal therapy for well-controlled malignancy is allowed Females who are pregnant or breastfeeding Subjects with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in study (or full access to medical records) as written including follow up, the interpretation of data or place the subject at unacceptable risk are excluded