Orca-T Following Chemotherapy and Total Marrow and Lymphoid Irradiation for the Treatment of Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia or Myelodysplastic Syndrome

NCT06195891 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: 23343NCI-2023-08816P30CA033572
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial tests the side effects and best dose of total marrow lymphoid irradiation along with chemotherapy, with fludarabine and melphalan, with or without thiotepa, in combination with Orca-T cells for patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome (MDS). Total marrow and lymphoid irradiation is a targeted form of total body irradiation that uses intensity-modulated radiation therapy to target marrow, lymph node chains, and the spleen. It is designed to reduce radiation-associated side effects and maximize the radiation therapeutic effect. Giving chemotherapy with medications such as thiotepa, fludarabine, and melphalan before a treatment with stem cells helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Orca-T cells take cells from a donor and remove some of the T cells and replace them with partially engineered T cells in order to induce better tolerance in patients. Giving total marrow and lymphoid irradiation and chemotherapy followed by Orca -T cells may be an effective treatment for patients with AML, ALL or MDS.

Conditions

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (1)

• Incidence of adverse events

  Will be scored on both the Bearman Scale and National Cancer institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 scale.

  From start of conditioning to day +100

Secondary Outcomes (6)

• Relapse/progression rate

  From start of therapy to relapse/progression, up to 2 years

• Non-relapse mortality

  From start of therapy until non-disease related death, disease relapse/progression, whichever comes first, up to 2 years

• Incidence of infection

  From day 0 to day +100

• Incidence of adverse events

  From day -9 to day +100

• Acute graft versus host disease (GVHD) of grades 2-4 and 3-4

  From date of stem cell infusion to document/biopsy proven acute GVHD onset date (within the first 100 days post-transplant)

Study Arms (1)

Treatment (TMLI, fludarabine, melphalan, Orca-T)

EXPERIMENTAL

PREPARATIVE REGIMEN: Patients undergo TMLI BID on days -8 to -5, followed by fludarabine IV on days -4 to -2 and melphalan IV on day -2. Patients receiving the lowest dose of TMLI also receive thiotepa IV on days -4 and -3. HCT: Patients receive Orca-T CD34+HSPC and Treg products IV on day 0, followed by the Orca-T tcon product IV on day 2. GVHD PROPHYLAXIS: Patients undergoing haplo-HCT receive tacrolimus starting on day 14 and continuing until day 90 with a taper per treating physician's discretion. Patients also undergo ECHO or MUGA scans, DECT/MRI scans, bone marrow biopsies/aspirates, and blood sample collection throughout the study.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Dual-Energy Computed Tomography; Procedure: Echocardiography; Drug: Fludarabine; Procedure: Magnetic Resonance Imaging; Drug: Melphalan; Procedure: Multigated Acquisition Scan; Biological: Partially Engineered T-regulatory Cell Donor Graft TRGFT-201; Drug: Tacrolimus; Drug: Thiotepa; Radiation: Total Marrow and Lymphoid Irradiation

Interventions

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Melphalan DRUG

Given IV

Also known as: Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Dual-Energy Computed Tomography PROCEDURE

Undergo DECT/MRI scan

Also known as: DECT

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Echocardiography PROCEDURE

Undergo echocardiography

Also known as: EC

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Fludarabine DRUG

Given IV

Also known as: Fluradosa

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Magnetic Resonance Imaging PROCEDURE

Undergo DECT/MRI scan

Also known as: Magnetic Resonance, Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA scan

Also known as: Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Partially Engineered T-regulatory Cell Donor Graft TRGFT-201 BIOLOGICAL

Given IV

Also known as: Orca-T, Partially Engineered and Enriched Treg Donor Graft TRGFT-201, T-cell-Depleted Graft With Additional Infusion of Conventional T Cells and Regulatory T Cells, TregGraft, TRGFT 201, TRGFT-201, TRGFT201

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Tacrolimus DRUG

Given tacrolimus

Also known as: FK 506, FK-506, Fujimycin, Hecoria, Prograf, Protopic, Tacforius

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Thiotepa DRUG

Given IV

Also known as: 1,1',1''-Phosphinothioylidynetrisaziridine, Girostan, N,N', N''-Triethylenethiophosphoramide, Oncotiotepa, STEPA, Tepadina, TESPA, Tespamin, Tespamine, Thio-Tepa, Thiofosfamide, Thiofozil, Thiophosphamide, Thiophosphoamide, Thiophosphoramide, Thiotef, Tifosyl, TIO TEF, Tio-tef, Triethylene Thiophosphoramide, Triethylenethiophosphoramide, Tris(1-aziridinyl)phosphine sulfide, TSPA, WR 45312

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Total Marrow and Lymphoid Irradiation RADIATION

Undergo TMLI

Also known as: TMLI

Treatment (TMLI, fludarabine, melphalan, Orca-T)

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented informed consent of the participant
• Agreement to allow the use of archival tissue from diagnostic bone marrow biopsies
• If unavailable, exceptions may be granted with study primary investigator (PI) approval
• Age: 60-75 years
• Karnofsky performance status ≥ 70
• Eligible patients will have a histopathological confirmed diagnosis of hematologic malignancy in one of the following categories:
• Acute myelogenous leukemia:
• Patients with de novo or secondary disease in CR1 or more with European LeukemiaNet (ELN) intermediate or adverse risk category, or
• Patients with active disease
• Morphologically; or
• Minimal residual disease (MRD) + (flow cytometry of ≥ 0.1%, next generation sequencing \[NGS\] or cytogenetics)
• Acute lymphoblastic leukemia (ALL):
• Patients with de novo or secondary disease according to National Comprehensive Cancer Network (NCCN) guidelines for ALL hypoploidy (\< 44 chromosomes); t(v;11q23): MLL rearranged; t(9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (≥ 30,000 for B lineage or ≥ 50,000 for T lineage); iAMP21loss of 13q, and abnormal 17p; or
• Patients with active disease:
• Morphologically; or

You may not qualify if:

• PATIENTS: Prior allogeneic stem cell transplant
• PATIENTS: More than 3 prior lines of intensive chemotherapy, where the regimen intent was to induce remission
• PATIENTS: Receiving any other investigational agents or concurrent biological, intensive chemotherapy or radiation therapy for the previous 2 weeks from conditioning NOTE: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted. These include: Hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs). FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
• PATIENTS: History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• PATIENTS: Having any uncontrolled illness including ongoing or active bacterial, viral or fungal infection requiring antibiotics
• PATIENTS: Patients with other active malignancies are ineligible for this study, other than non-melanoma skin cancer, in situ cervical cancer and prostate cancer. Patients with prior history of localized prostate cancer treated with curative intent regardless of time from the treatment to study entry, and patients with prostate cancer receiving active surveillance not requiring therapy are eligible
• PATIENTS: The recipient has a medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the principal investigator would place the recipient at unacceptable risk
• PATIENTS: Females only: Pregnant or breastfeeding
• PATIENTS: Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• PATIENTS: Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

RECRUITING

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Specimen Handling; Biopsy; fludarabine; Magnetic Resonance Spectroscopy; Melphalan; Tacrolimus; Thiotepa; Lymphatic Irradiation

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Spectrum Analysis; Chemistry Techniques, Analytical; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Macrolides; Lactones; Phosphoramides; Organophosphorus Compounds; Triethylenephosphoramide; Aziridines; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Radiotherapy; Therapeutics

Study Officials

• Amandeep Salhotra

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2023
• First Posted: January 8, 2024
• Study Start: May 24, 2024
• Primary Completion (Estimated): March 22, 2030
• Study Completion (Estimated): March 22, 2030
• Last Updated: April 29, 2026

Record last verified: 2026-04

Locations

US (1)