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Methotrexate

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Tacrolimus

For patients randomized to the Orca-T arm, Orca-T will be administered after myeloablative conditioning regimen. Single-agent GVHD prophylaxis with tacrolimus will be administered following Tcon infusion (generally Day +3).

For patients randomized to the standard-of-care control arm, an unmanipulated allograft derived from the peripheral blood of a matched donor will be administered after a myeloablative conditioning regimen. Dual-agent prophylaxis consisting of tacrolimus plus methotrexate will be administered starting on Day -3.

an allogeneic stem cell and T-cell immunotherapy biologic

Orca-T

Standard-of-Care

This study will evaluate the safety, tolerability, and efficacy of Orca-T, an allogeneic stem cell and T-cell immunotherapy biologic manufactured for each patient (transplant recipient) from the mobilized peripheral blood of a specific, unique donor. It is composed of purified hematopoietic stem and progenitor cells (HSPCs), purified regulatory T cells (Tregs), and conventional T cells (Tcons) in participants undergoing myeloablative allogeneic hematopoietic cell transplant transplantation for hematologic malignancies.

This posting represents the Phase III component of Precision-T. The Precision-T Ph1b component is described under NCT04013685.

The Phase III is a randomized, open-label, multicenter study comparing outcomes between patients receiving Orca-T followed by single-agent tacrolimus or standard-of-care (SOC) control followed by dual agent, tacrolimus-based Graft-versus-Host-Disease (GVHD) prophylaxis regimen

Precision-T: A Randomized Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies

A Randomized Phase III Trial of Patients With Advanced Hematologic Malignancies Undergoing Allogeneic Hematopoietic Cell Transplantation With Either Orca-T, a T-cell-Depleted Graft With Additional Infusion of Conventional T Cells and Regulatory T Cells, or Standard-of-Care Allogeneic Graft

An event for this time-to-event outcome is defined as death by any cause or moderate to severe cGVHD as defined by NIH consensus criteria, whichever is earlier.

An event for this time-to-event outcome is defined as time from randomization to the first onset of of moderate or severe cGVHD within 730 days after randomization. Death within 730 days after randomization without prior moderate or severe cGVHD is considered a competing event.

GRFS is defined as the time from randomization to death from any cause, relapse, the first onset of grade 3 or 4 aGVHD (graded per MAGIC criteria), or the first onset of moderate or severe cGVHD (graded per NIH consensus criteria), whichever is earliest.

OS is defined as the time from randomization to death from any cause .

Orca Biosystems, Inc.

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Myeloproliferative Disorders

Chronic Disease

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Dendritic Cell Tumor

Blastic Plasmacytoid Dendritic Cell

Chronic Myeloproliferative Disorders

This is a non-randomized, single-arm study. All enrolled subjects will receive an allogeneic HCT with the Orca-T product.

This study will evaluate the safety, tolerability, and efficacy of Orca-T, an allogeneic stem cell and T-cell immunotherapy biologic manufactured for each patient (transplant recipient) from the mobilized peripheral blood of a specific, unique donor. It is composed of purified hematopoietic stem and progenitor cells (HSPCs), purified regulatory T cells (Tregs), and conventional T cells (Tcons) in participants undergoing myeloablative allogeneic hematopoietic cell transplant transplantation for hematologic malignancies.

Precision-T: A Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies

A Phase Ib Trial of Patients With Advanced Hematologic Malignancies Undergoing Allogeneic Hematopoietic Cell Transplantation With Either Orca-T, a T-cell-Depleted Graft With Additional Infusion of Conventional T Cells and Regulatory T Cells, or Standard-of-Care Allogeneic Graft

1 year graft-versus-host-disease-free and relapse-free survival (GRFS)

incidence and severity of acute and chronic graft vs host disease (GvHD)

incidence of engraftment of platelets and neutrophils

Graft vs Host Disease

Homologous Wasting Disease

Anti-Infective Agents

Micronutrients

Hematinics

Vitamins

Antibodies

Fludarabine

Fludarabine phosphate

Rituximab

Cyclosporine

Cyclosporins

Immunoglobulins

Thiotepa

Antilymphocyte Serum

Treosulfan

Immunologic Factors

Antineoplastic Agents, Immunological

Antimetabolites

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunosuppressive Agents

Clotrimazole

Miconazole

Antifungal Agents

Calcineurin Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Folinic Acid

Folate

Vitamin B9

Patients MRD will be randomized to receive Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 \& ATG-Fresenius S® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2

Patients receiving stem cell transplantation from a matched related donors (MRD) will be randomized to receive only Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²) + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 (total dose of 150 mg/m²) after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals (total dose of 8 mg/kg)+ Cyclosporine A iv at a starting dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL (In the absence of GvHD CSA will be tapered after day + 180 and stopped at 9-12 months) + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6

Patients MUD will be randomized to receive Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11 + ATG-Fresenius S ® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 \& Rituximab in a single infusion of 200 mg/m2 on day -1

Patients MUD will be randomized to receive only Treosulfan iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 + Fludarabine iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan + Thiotepa iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals + Cyclosporine A iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL + Methotrexate iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11 + ATG-Fresenius S ® iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2

iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)

polyclonal antibody

iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)

iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan

iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals

iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL

Cyclosporine A

iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6

iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6 and at a dose of 10 mg/m2 on day +11

Maria Ester Bernardo, MD

Franco Locatelli

Franco Locatelli, Prof

• The primary aim of the present trial is to assess in a randomized fashion the benefit on standard graft-versus-host disease (GVHD) prophylaxis of the addition of ATG-Fresenius S ® in transplants from matched related donors (MRD) and of anti-CD20 rituximab in transplants from matched unrelated donors (MUD). Both safety and efficacy of the treatment will be assessed, in particular in respect to the clinical status of the patient, i.e. prevention of graft failure and chronic GvHD and of Ebstein Barr virus (EBV) viremia for MUD patients.

The conditioning proposed combines myeloablative drugs with a favorable safety profile such as treosulfan, thiotepa (Tepadina®) and fludarabine with the intent to reduce the traditional immediate and late toxicity of busulfan and cyclophosphamide.

For patients transplanted from a MRD

The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to:

* primary and secondary graft failure,
* aGVHD II-IV,
* cGVHD,
* death, whichever occurs first.

For patients transplanted from a MUD

The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to:

* aGVHD II-IV,
* EBV viremia, whichever occurs first.

T&B Depletion Non Malignant

A Phase II Multicentre, Randomized, Controlled Open-label Study on the Use of Anti-thymocyte Globulin and Rituximab for Immunomodulation of Graft-versus-host Disease in Allogeneic Matched Transplants for Non Malignancies

For patients transplanted from a MRD

The cumulative incidence of a combined end-point defined as the time from randomization to:

* primary and secondary graft failure,
* aGVHD II-IV,
* cGVHD,
* death, whichever occurs first.

For patients transplanted from a MUD

The cumulative incidence of a combined end-point defined as the time from randomization to:

* aGVHD II-IV,
* EBV viremia, whichever occurs first.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Precision-T: A Randomized Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies	NCT05316701	Acute Myeloid L... Acute Lymphoid ... Mixed Phenotype... Undifferentiate... Myelodysplastic... Acute Leukemia Therapy-Related...	Orca-T Standard-of-Car...	18 Years - 65 Years	Orca Biosystems, Inc.
Precision-T: A Randomized Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies	NCT05316701	Acute Myeloid L... Acute Lymphoid ... Mixed Phenotype... Undifferentiate... Myelodysplastic... Acute Leukemia Therapy-Related...	Orca-T Standard-of-Car...	18 Years - 65 Years	Orca Biosystems, Inc.
Precision-T: A Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies	NCT04013685	Acute Myeloid L... Acute Lymphoid ... Myelodysplastic... Acute Leukemia Blastic Plasmac... Chronic Myeloid...	Orca-T	18 Years - 75 Years	Orca Biosystems, Inc.
T&B Depletion Non Malignant	NCT01810926	Graft Versus Ho...	polyclonal anti... Rituximab Treosulfan Fludarabine Thiotepa Cyclosporine A Methotrexate Methotrexate	28 Days - 64 Years	Bambino Gesù Hospital and Research Institute
Precision-T: A Randomized Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies	NCT05316701	Acute Myeloid L... Acute Lymphoid ... Mixed Phenotype... Undifferentiate... Myelodysplastic... Acute Leukemia Therapy-Related...	Orca-T Standard-of-Car...	18 Years - 65 Years	Orca Biosystems, Inc.

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