Orca-T / Orca Biosystems - LARVOL DELTA

Precision-T (PhIII component): Precision-T: A Randomized Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies (clinicaltrials.gov) - P3 | N=174 | Active, not recruiting | Sponsor: Orca Biosystems, Inc. | Trial primary completion date: Apr 2025 ➔ Jul 2024 | Trial completion date: Apr 2027 ➔ Jul 2026

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • HLA-B • HLA-C • HLA-DRB1

Phase I Trial for Patients w/ Advanced Hematologic Malignancies Undergoing Allogeneic HCT (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Lori Muffly | Initiation date: Jan 2025 ➔ Jun 2025

Trial initiation date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

ORCA-T® DEMONSTRATES IMPROVED SURVIVAL FREE OF CHRONIC GVHD COMPARED TO CONVENTIONAL ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT: A RANDOMIZED PHASE 3 TRIAL IN ADVANCED HEMATOLOGIC MALIGNANCIES (EBMT 2025) - P3 | "We report results from the randomized, phase 3 component of Precision-T study comparing Orca-T to a conventional allograft with Tacrolimus/Methotrexate (Tac/MTX) (NCT05316701). The randomized phase 3 trial met its primary endpoint, demonstrating higher cGFS with Orca-T compared to Tac/MTX, owing to significantly reduced chronic GVHD and a positive trend in OS. Results suggest Orca-T may be considered as a new standard of care for patients with hematologic malignancies and HLA-matched donors following myeloablative conditioning. Clinical Trial Registry: NCT05316701https://clinicaltrials.gov/study/NCT05316701"

Clinical • Metastases • P3 data • Acute Graft versus Host Disease • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

OBSERVATIONAL COMPARISON OF OVERALL SURVIVAL BETWEEN PHASE 1B ORCA-T® AND REGISTRY-BASED POST-TRANSPLANT CYCLOPHOSPHAMIDE PATIENTS (EBMT 2025) - P1 | "Additionally, MAC regimens for the Ph1b' cohort were limited to busulfan/fludarabine/thiotepa, or total body irradiation (TBI)/cyclophosphamide, or TBI/etoposide between 2019-2024. Comparison of Orca-T phase 1b and PTCy patients from the CIBMTR registry demonstrated higher OS for Orca-T patients. The study was limited to OS and retrospective data, and further analysis is needed to explore factors like infection, relapse, and organ toxicity. A phase 3 randomized trial comparing Orca-T with single agent tacrolimus to conventional transplant with tacrolimus/methotrexate GvHD prophylaxis has recently completed accrual."

Clinical • P1 data • Post-transplantation • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

DIFFERENTIAL IMMUNE RECONSTITUTION PROFILES BETWEEN ORCA-T AND CD34 ALLOGRAFT RECIPIENTS PROVIDE INSIGHT FOR CONTROL OF VIRAL INFECTIONS (EBMT 2025) - P1, P3 | "Allo-CD34+ cells require several months to reconstitute donor-derived T cells. Orca-T provides immunologically active donor T cells upon infusion, and controls the pursuant GVHD risk with high precision regulatory T cells. Consistently, we observed that the Orca-T patients exhibited higher T cell chimerism levels and increased numbers of circulating donor T cells in the early post-infusion period."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Cytomegalovirus Infection • Epstein-Barr Virus Infections • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • CD34

Orca-T Stands Out From CD34 Grafts, Showing Lower Rates of EBV, CMV Reactivation in Hematologic Malignancies (OncLive) - "Lower rates of Epstein-Barr virus (EBV) and cytomegalovirus reactivation occurred when patients with select hematologic malignancies were treated with Orca-T vs a CD34 allograft, according to data from a retrospective comparative analysis presented at the 51st Annual EBMT Meeting. The rates of EBV reactivation were 2.3% and 25.4% in the Orca-T and CD34 arms, respectively (P < .001). With respect to CMV reactivation, the respective rates were 1.2% and 25.6% (P < .001). EBV and/or CMV reactivation occurred in 3.5% of patients who received Orca-T vs 45.9% of those who received CD34 grafts (P < .001)."

Retrospective data • Hematological Malignancies

Orca Bio Announces Positive Results from the Pivotal Phase 3 Study of Investigational Orca-T Compared to Allogeneic Stem Cell Transplant for the Treatment of Hematologic Malignancies (Businesswire) - P3 | N=174 | Precision-T (NCT05316701) | Sponsor: Orca Biosystems, Inc. | "Orca Bio...announced positive results from the pivotal Phase 3 Precision-T study of Orca-T, its lead investigational allogeneic T-cell immunotherapy, in patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), high-risk myelodysplastic syndrome (MDS) and mixed-phenotype acute leukemia (MPAL)....The primary endpoint of survival free of cGvHD was 78% (95% CI: 65%, 87%) in the Orca-T arm (n=93) and 38% (95% CI: 26%, 51%) in the alloHSCT arm (n=94) (HR 0.26; p<0.00001). An interim analysis of the secondary endpoint of overall survival was 94% (95% CI: 86%, 97%) in the Orca-T arm and 83% (95% CI: 73%, 90%) in the alloHSCT arm (HR 0.49; p=0.11823)....The complete results will be presented on April 2, 2025, at the 51st Annual Meeting of the EBMT in Florence, Italy....Orca Bio is preparing to submit these findings in a BLA to the U.S. FDA in 2025."

FDA filing • P3 data • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Myelodysplastic Syndrome

Kidney Function in allogenic hematopoietic cell transplant recipients treated with Orca-T GvHD prophylaxis compared to post transplant cyclophosphamide or methotrexate (NKF-SCM 2025) - "Patients had the following mean (SD) creatinine values obtained within 1 year post HCT: 76.3 (49.4) (Orca-T), 86.6 (46) (FK/MTX), and 73.7 (47.6) (PTCy). No patient met eGFR criteria for chronic kidney disease (CKD) at baseline despite some risk factors for CKD.Conclusion Based on this preliminary work we conclude that a comparable group of patients has received three different GvHD prophylaxis regimens at our center, and that this work can inform multivariate models comparing the eGFR change between the three groups."

Clinical • Post-transplantation • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Metabolic Disorders • Nephrology • Oncology • Transplantation

Observational Comparison of Overall Survival between Phase 1b Orca-T and Registry-Based Post-Transplant Cyclophosphamide Patients (TCT-ASTCT-CIBMTR 2025) - P1 | "Additional inclusion criteria for the Ph1b’ cohort were MAC regimens consisting of bu/flu/thiotepa, or total body irradiation/cy, or TBI/etoposide between 2019-2024. The study was limited to OS and retrospective data, and further analysis is needed to explore factors like infection, relapse, and organ toxicity. Phase 3 data are expected soon."

Clinical • P1 data • Post-transplantation • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Myelodysplastic Syndrome • Oncology • Transplantation

Preliminary Safety and Efficacy of Myeloablative Orca-Q with No GvHD Prophylaxis for Treatment of Advanced Hematologic Malignancies (TCT-ASTCT-CIBMTR 2025) - P1 | "Preventing GvHD often requires immunosuppressive drugs like methotrexate or post-transplant cyclophosphamide (PTCy), which can impair immune recovery and increase risks of organ damage, infections, and relapse...Patients received either busulfan/fludarabine/thiotepa (BFT; n=11) or total body irradiation-based (TBI; n=3) conditioning, and no post-therapy immunosuppression...One patient who received TBI/etoposide experienced grade 3 aGvHD and subsequently developed secondary graft loss, but no disease relapse...BFT conditioning has shown promising disease control with Orca-T (Salhotra et al...Disease control may be further augmented by BFT conditioning. The Orca-Q phase 1 study continues to enroll patients across the US."

Clinical • Metastases • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Oncology

Orca-T Is a Safe Addition to HSCT-RIC in Advanced Hematologic Malignancies (OncLive) - P1 | N=40 | NCT05088356 | "Orca-T plus hematopoietic bone marrow stem cell transplantation with reduced intensity conditioning (HSCT-RIC) was a safe and feasible alternative to conventional HSCT-RIC in patients with advanced hematologic malignancies, according to preliminary findings from a phase 1 study (NCT05088356) presented during the 2025 Transplantation & Cellular Therapy Meetings....The 12-month relapse-free survival (RFS) rate was 79% (95% CI, 65%-96%). The study included patients treated via a fully (8/8) HLA-matched related/unrelated donor (n = 27) and 7/8 HLA-mismatched related/unrelated donor (n = 3). In terms of safety, moderate chronic graft-vs-host disease (GVHD) was reported in 2 patients and grade 2 to 4 acute/late onset GVHD was observed in 4 patients. No patients experienced grade 3 or 4 acute/late onset GVHD or severe chronic GVHD."

P1 data • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Myelodysplastic Syndrome

Orca Bio’s Orca-T Meets Primary Endpoint in the Pivotal Precision-T Phase 3 Clinical Study for Hematologic Malignancies (Businesswire) - "Orca Bio...announced it will present positive results from the pivotal Phase 3 Precision-T study (NCT05316701) of its investigational allogeneic T-cell immunotherapy, Orca-T, in people with hematologic malignancies at the 51st Annual Meeting of the EBMT held March 30-April 2, 2025 in Florence, Italy."

P3 data • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Myelodysplastic Syndrome

Phase 1 Trial Results for Patients with Advanced Hematologic Malignancies Treated with Allogeneic T Cell Immunotherapy and Reduced Intensity Conditioning (TCT-ASTCT-CIBMTR 2025) - "These early results demonstrate that an Orca-T is a safe and feasible alternative to conventional HSCT-RIC, with robust and early donor myeloid and T-cell engraftment. The low incidence of acute and chronic GVHD and disease relapse suggest the promotion of an alloreactive tolerant environment that maintains an effective graft-versus-leukemia effect and merits larger multi-center studies to further validate these findings."

Clinical • Metastases • P1 data • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Oncology

FOXP3 and Helios Expressing CD4+ T Conventional Cells Correlate with T Cell Activation after Orca-T Allogeneic T Cell Immunotherapy (TCT-ASTCT-CIBMTR 2025) - "Overall, this study identifies an increase in T cell activation early after Orca-T immunotherapy, and we propose that the sequential addition of high-purity Tregs directs the immune reconstitution of CD4+ T cells towards a potentially immunomodulatory, FOXP3 and Helios-expressing phenotype. Further, we provide an in-depth examination of various immune activation states very early after cellular therapy for leukemia and we identify a novel T cell subset which may be predictive of long-term immune activation after T cell infusion."

IO biomarker • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • CD4 • CD8 • FOXP3 • IL2RA • ISG20

A Randomized Phase 3 Trial of Orca-T® in Patients with Advanced Hematologic Malignancies [WITHDRAWN] (TCT-ASTCT-CIBMTR 2025) - No abstract available

Clinical • Metastases • P3 data • Hematological Disorders • Hematological Malignancies • Oncology

Phase I Trial for Patients w/ Advanced Hematologic Malignancies Undergoing Allogeneic HCT (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Lori Muffly | Initiation date: Oct 2024 ➔ Jan 2025

Metastases • Trial initiation date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Safe and Effective Combination of Donor-Derived, Allogeneic CD19/CD22-CAR T Cells with Myeloablative Graft-Engineered Allo-HCT for High-Risk B-ALL (ASH 2024) - P1 | "Myeloablative conditioning with cyclophosphamide and total body irradiation precede infusion of investigational Orca-T, which consists of infusions of HSPCs and Tregs on Day 0 and an infusion of T conventional (Tcon) cells on Day 2. This paradigm shifting combination of allogeneic CAR T and allo-HCT resulted in 100% MRD- CR with full donor chimerism but without GVHD or severe CAR-mediated toxicity. These data, which demonstrate antigen-specific anti-tumor benefit of allogeneic CAR T cells in combination with GVHD prophylaxis mediated by Tregs and tacrolimus, have potential implications that could benefit patients with other hematologic diseases."

CAR T-Cell Therapy • IO biomarker • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • ABL1 • CD22 • TP53

Observational Comparison of Overall Survival between Phase 1b Orca-T and Registry-Based Post-Transplant Cyclophosphamide Patients (ASH 2024) - P1 | "Additional inclusion criteria for the Ph1b' cohort were treatment between 2019-2024 and use of Bu/Flu/TT, TBI/Cy, or TBI/etoposide MAC regimen, consistent with the phase 3 protocol. Further analysis is needed to identify the specific clinical factors such as infection, relapse and organ toxicity including cardiotoxicity that may account for the differences in OS. A phase 3 prospectively randomized trial comparing Orca-T to Tac/MTX pharmacological GvHD control recently completed enrollment."

Clinical • P1 data • Post-transplantation • Bone Marrow Transplantation • Cardiovascular • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Oncology • Transplantation

732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Finding the Ideal Donor and Graft: Going Beyond HLA (ASH 2024) - "The studies include optimizing donor selection using new molecular techniques, comparing outcomes between MMUD and MUD, investigating whether the probability of finding an 8/8 MUD affects prognosis, examining the impact of Orca-T infusion on post-transplant outcomes, and conducting an RCT comparing peripheral blood plus cord blood or bone marrow in Haplo-HSCT. Through this section, we hope clinicians can choose the most suitable donors and grafts from the currently available multiple donor options for each patient."

Bone Marrow Transplantation • Transplantation

Preliminary Safety and Efficacy of Myeloablative Orca-Q with No GvHD Prophylaxis for Treatment of Advanced Hematologic Malignancies (ASH 2024) - P1 | "Prevention of GvHD after alloHSCT routinely necessitates multi-agent immunosuppression consisting of either methotrexate or post-transplant cyclophosphamide (PTCy) combined with a calcineurin inhibitor and additional drugs...All patients received myeloablative conditioning, either busulfan/fludarabine/thiotepa (BFT; n=11) or total body irradiation-based (TBI; n=3)...One patient received TBI/etoposide and experienced grade 3 aGvHD that was treated to resolution...BFT conditioning has shown promising disease control with Orca-T (Salhotra et al...Disease control may be further augmented by BFT conditioning. The Orca-Q Phase 1 study continues to enroll patients across the US."

Clinical • Metastases • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Chronic Lymphocytic Leukemia • Chronic Myeloid Leukemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelofibrosis • Oncology • HLA-B • HLA-C • HLA-DRB1

Orca Bio Presents Three-Year Survival Data with Orca-T in Patients with Hematological Malignancies at the 66th ASH Annual Meeting (Businesswire) - P1b | N=255 | NCT04013685 | Sponsor: Orca Biosystems, Inc. | "This analysis from the multicenter Phase 1b clinical trial evaluated a subset of patients (n=77) who received Orca-T with TAC....Further analyses of these patient subsets found Orca-T may reduce non-relapse mortality (NRM) and increase relapse-free survival (RFS) compared to PTCy. At one year, NRM was 1.4% in the Orca-T group and 7.4% in the PTCy cohort. The rate of RFS at one year was 83% and 71% for patients receiving Orca-T and PTCy, respectively. Results also found that age had no significant impact on OS at one year. For patients receiving Orca-T, OS was 95% (88%-100%) in patients under the age of 50 and 97% (92%-100%) in patients over the age of 50. For patients in the PTCy cohort, OS was 86% (81%-92%) in patients under the age of 50 and 77% (70%-85%) in patients over the age of 50."

P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

Orca Bio to Present Clinical Data on Its High-Precision Cell Therapies at the 66th American Society of Hematology Annual Meeting (Businesswire) - "Three-year survival data with Orca Bio’s lead investigational allogeneic T-cell immunotherapy, Orca-T, will be presented from the multicenter Phase 1b clinical trial of patients with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and high-risk myelodysplastic syndrome (MDS). Additionally, initial feasibility, safety and efficacy data from an investigator-sponsored trial evaluating the combination of Orca-T with allogeneic CD19/CD22-CAR-T cells in patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) will be shared. In a third oral session, data from a multicenter Phase 1 clinical trial will be presented from patients treated with Orca Bio’s second-generation investigational allogeneic T-cell immunotherapy, Orca-Q, in patients with hematologic malignancies without the use of any post-treatment graft versus host disease (GvHD) prophylaxis."

Clinical data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Orca-T Following Chemotherapy and Total Marrow and Lymphoid Irradiation for the Treatment of Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia or Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=33 | Recruiting | Sponsor: City of Hope Medical Center | Initiation date: Sep 2024 ➔ May 2024

Trial initiation date • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Treatment of Acute Myeloid Leukemia With Orca-T (SOHO 2024) - P1, P3 | " Data from 37 patients with diagnosis of AML in CR/CRi who received myeloablative conditioning with busulfan, fludarabine, and thiotepa (BFT) followed by Orca-T as of 6/30/22 as part of a multicenter phase 1b single-arm trial (NCT04013685), are reported here. Results suggest that investigational Orca-T could represent a reduced toxicity alternative to conventional alloHSCT. Combination of Orca-T with BFT led to >80% RFS without NRM and 100% OS in this AML patient population. A multi-center randomized controlled phase 3 trial (NCT05316701) will report survival of moderate to severe chronic GvHD comparing Orca-T to standard of care."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Phase I Trial for Patients w/ Advanced Hematologic Malignancies Undergoing Allogeneic HCT (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Lori Muffly

Metastases • New P1 trial • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation