Orca-T and Radiation Therapy for Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Investigational agents

Disqualifiers: Prior stem cell transplant, uncontrolled illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

33 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for individuals with certain blood cancers, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). It combines targeted radiation and chemotherapy with a special type of donor cell therapy (Orca-T cells, also known as Partially Engineered T-regulatory Cell Donor Graft TRGFT-201) to determine if it reduces cancer and promotes the growth of healthy blood cells. Participants may qualify if they have been diagnosed with one of these conditions and have experienced difficulties with other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, it mentions that low dose or maintenance chemotherapy is allowed within 7 days of enrollment, and certain medications like FLT-3 inhibitors can be taken up to 3 days before the conditioning regimen.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Orca-T cells, a type of specially engineered donor cell, have promising safety results. They are generally well-tolerated and lead to fewer cases of moderate-to-severe chronic graft-versus-host disease (cGvHD), a condition where donor cells attack the patient’s body, a common risk with traditional stem cell transplants.

Studies indicate that total marrow and lymphoid irradiation (TMLI) is generally safe and can be used even in older patients or those with other health issues. It aims to target radiation more precisely, reducing damage to healthy tissues.

The safety of chemotherapy drugs like fludarabine, melphalan, and thiotepa varies. Fludarabine is usually well-tolerated, but high doses can cause serious nerve problems. Melphalan is commonly used in cancer treatment but can lead to heart rhythm changes. Thiotepa has shown good safety in some studies, though side effects can still occur.

Overall, previous research has demonstrated a balance of effectiveness and manageable side effects for these treatments. However, since this trial is in an early phase, it primarily focuses on assessing safety and determining the best doses. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike traditional leukemia treatments, which often rely on high-dose chemotherapy and radiation, the new approach using Orca-T is all about precision and adaptability. Researchers are excited because Orca-T involves a unique combination of targeted radiation therapy and specialized immune cells. This method leverages TMLI (total marrow and lymphoid irradiation) to specifically target cancerous cells, while Orca-T introduces modified immune cells that could help prevent graft-versus-host disease, a common complication in transplants. This dual-action strategy not only aims to be more effective against the leukemia cells but also hopes to reduce some of the harsh side effects associated with standard treatments.

What evidence suggests that this trial's treatments could be effective for leukemia?

In this trial, participants will receive a combination of treatments, including Orca-T cells and Total Marrow and Lymphoid Irradiation (TMLI). Studies have shown that Orca-T cells, designed to improve tolerance, yield promising results in blood cancer treatments. In one study, patients who received Orca-T had a 94% survival rate after one year, compared to 83% with traditional stem cell transplants. TMLI, a targeted form of radiation therapy, has demonstrated good survival outcomes in patients undergoing stem cell transplants for blood cancers. These treatments work together in this trial to target and destroy cancer cells effectively while preparing the body for new, healthy cells. Current research supports the potential effectiveness of this combination for treating conditions like acute myeloid leukemia and other related disorders. ^{6 7 8 9 10}

Who Is on the Research Team?

Amandeep Salhotra

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome (MDS). Participants must be eligible for stem cell transplant and have adequate organ function. Specific details on inclusion and exclusion criteria are not provided.

Inclusion Criteria

Agreement to allow the use of archival tissue from diagnostic bone marrow biopsies

My lung function tests are at least half of what is expected for someone my age and size.

I stopped all intense cancer treatments 2 weeks ago.

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent

I do not have any active cancers except for certain skin, cervical, or prostate cancers.

I have had a stem cell transplant from a donor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparative Regimen

Patients undergo total marrow and lymphoid irradiation (TMLI) twice a day on days -8 to -5, followed by fludarabine intravenously (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.

8 days

Hematopoietic Cell Transplantation (HCT)

Patients receive Orca-T CD34+ hematopoietic stem and progenitor cells (HSPC) and T-regulatory cell (Treg) products IV on day 0, followed by the Orca-T conventional t-cell (tcon) product IV on day 2.

2 days

GVHD Prophylaxis

Patients undergoing haploidentical (haplo)-HCT receive tacrolimus starting on day 14 and continuing until day 90 with a taper per treating physician's discretion.

76 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including incidence of acute and chronic GVHD, infections, and other adverse events.

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Fludarabine
• Melphalan
• Partially Engineered T-regulatory Cell Donor Graft TRGFT-201
• Thiotepa
• Total Marrow and Lymphoid Irradiation

Trial Overview The trial tests a combination of targeted radiation therapy called total marrow lymphoid irradiation, chemotherapy drugs like fludarabine, melphalan, possibly thiotepa, and Orca-T cells—a type of engineered donor T-cell graft—to treat AML, ALL or MDS.

How Is the Trial Designed?

Group I: Treatment (TMLI, fludarabine, melphalan, Orca-T) Experimental Treatment 13 Interventions

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.

Fludarabine is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Fludara for:

• Chronic lymphocytic leukemia
• Mantle-cell lymphoma
• Non-Hodgkin's lymphoma

Approved in United States as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Stem Cell Transplant Conditioning

Approved in Canada as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Combining low-dose fludarabine with arabinosylcytosine (ara-C) enhances the effectiveness of treatment for adult acute myelogenous leukemia, as fludarabine helps increase the accumulation of ara-C's active form.

The rationale for this combination therapy is that both drugs work together to inhibit DNA replication and repair, potentially leading to improved response rates in patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine for treatment of adult acute myelogenous leukemia. Gandhi, V.[2019]

In a study of 30 adults with refractory or relapsed acute lymphocytic leukemia (ALL), the combination of fludarabine and intermediate-dose cytosine arabinoside (ara-C) resulted in a 30% complete remission rate, with a median remission duration of 22 weeks.

The treatment was generally safe, though myelosuppression-related side effects were common, affecting 93% of patients, indicating a need for future studies to explore ways to mitigate these complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and cytosine arabinoside in the treatment of refractory or relapsed acute lymphocytic leukemia. Suki, S., Kantarjian, H., Gandhi, V., et al.[2019]

In a study of 89 hematopoietic cell transplantation recipients, higher levels of the active metabolite of cyclophosphamide (PM AUC0-8 hr) were linked to worse nonrelapse mortality and overall survival, indicating that careful monitoring of this metabolite is crucial for patient outcomes.

Patients with low levels of the active metabolite of fludarabine (F-ara-ADay-4) and low PM AUC0-8 hr had significantly lower nonrelapse mortality, suggesting that optimizing drug exposure could improve safety and efficacy in reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. Takahashi, T., Scheibner, A., Cao, Q., et al.[2021]

Fludarabine phosphate (F-ara-AMP) is highly effective in treating chronic lymphocytic leukemia, but high doses can lead to severe neurotoxicity, as shown in mice with leukemia L1210.

Co-administering NBMPR-P, a nucleoside transport inhibitor, significantly reduces the neurotoxic effects of F-ara-AMP and improves treatment outcomes, resulting in a higher cure rate in the experimental model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protection against fludarabine neurotoxicity in leukemic mice by the nucleoside transport inhibitor nitrobenzylthioinosine. Adjei, AA., Dagnino, L., Wong, MM., et al.[2019]

Fludarabine significantly enhances the delay of tumor regrowth when combined with radiation therapy in murine models, with the most effective results observed when administered 24 hours before radiation.

The enhancement effect of fludarabine is dose-dependent and varies based on the timing of administration, suggesting its potential as a clinical radiation enhancer for treating solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potentiation of radiation-induced regrowth delay in murine tumors by fludarabine. Grégoire, V., Hunter, N., Milas, L., et al.[2013]

In patients with B-cell chronic lymphocytic leukemia who were resistant to standard treatments, fludarabin phosphate (fludara) achieved an 18% complete remission and a 27% partial remission, with 45% of patients showing stabilization of their condition.

Long-term remission was observed in patients with low and moderate grade non-Hodgkin's lymphoma resistant to standard treatments, attributed to the combination therapy of fludara and cytosinarabinoside (FAVAMP).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The use of fludarabine phosphate (Fludara) to treat chronic B-cell lymphocytic leukemia and non-Hodgkin's lymphoma resistant to standard chemotherapy]. Gershanovich, ML., Zaritskiĭ, AIu., Medvedeva, NV., et al.[2013]

Fludarabine phosphate is effective in treating lymphoid malignancies, such as chronic lymphocytic leukemia and non-Hodgkin's lymphoma, but showed limited efficacy in solid tumors based on phase II trials.

The recommended dosing schedule for fludarabine is 18-25 mg/m2/d for five days, repeated every 28 days, with myelosuppression and neurotoxicity identified as significant dose-limiting toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine phosphate. A new anticancer drug with significant activity in patients with chronic lymphocytic leukemia and in patients with lymphoma. Rodriguez, G.[2019]

Fludarabine monophosphate (FAMP) is being tested as a treatment for various cancers, but it has been associated with a case of diffuse interstitial pneumonitis in a patient with chronic lymphocytic leukemia.

The pulmonary toxicity observed in this case resolved with high-dose steroids, indicating that while FAMP can be effective, it may also pose risks that require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary toxicity associated with fludarabine monophosphate. Hurst, PG., Habib, MP., Garewal, H., et al.[2019]

In a study involving three children with refractory severe aplastic anemia (SAA), a radiotherapy-free conditioning regimen using fludarabine and other agents was effective in preparing them for hemopoietic cell transplantation (HCT) without the development of graft-versus-host disease (GVHD).

All patients achieved normal blood counts and complete donor chimerism after the transplant, demonstrating that fludarabine-based conditioning can be a safe and effective option for children undergoing HCT from alternative donors, even after previous transplant failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Urban, C., Benesch, M., Sykora, KW., et al.[2013]

Fludarabine phosphate (2-F-ara-AMP) shows significant cytotoxic effects against various leukemia cell lines, particularly when combined with cytarabine, which produced synergistic effects in several cell lines, suggesting a strong potential for combination therapy.

The study indicates that combining fludarabine phosphate with methotrexate or vincristine is not effective and may be inappropriate, highlighting the importance of selecting the right combinations for chemotherapy in treating leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro cytotoxic effects of fludarabine (2-F-ara-A) in combination with commonly used antileukemic agents by isobologram analysis. Kano, Y., Akutsu, M., Tsunoda, S., et al.[2019]

Citations

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Press release Patients in the Orca-T group achieved an estimated overall survival (OS) of 94% compared to 83% in the alloHSCT arm at one year. "Today, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06195891

NCT06195891 | Orca-T Following Chemotherapy and Total ... This phase I trial tests the side effects and best dose of total marrow lymphoid irradiation along with chemotherapy, with fludarabine and melphalan, ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/partially-engineered-t-regulatory-cell-donor-graft-trgft-201?pn=1

Clinical Trials Using Partially Engineered T-regulatory Cell ... Review the clinical trials studying partially engineered t-regulatory cell donor graft trgft-201 on this list and use the filters to refine the results by ...

4. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04013685/

Clinical Trial: NCT04013685 This study will evaluate the safety, tolerability, and efficacy of an engineered donor graft ("TregGraft"/"Orca-T", a T-cell-Depleted Graft ...

5. onclive.com onclive.com/view/orca-t-offers-favorable-post-transplant-outcomes-in-advanced-hematologic-malignancies

Orca-T Offers Favorable Post-Transplant Outcomes in ... The 1-year GRFS rate in patients who received the Orca-T graft was 70% compared with 21% in the patients who got the unmanipulated graft. The ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/15051774/

Efficacy and safety of oral fludarabine phosphate in ... This study demonstrates that oral fludarabine phosphate is clinically effective and generally well tolerated by patients with previously untreated B-cell ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2007/020038s031lbl.pdf

Fludara - accessdata.fda.gov When used at high doses in dose-ranging studies in patients with acute leukemia, FLUDARA FOR INJECTION was associated with severe neurologic effects, including.

8. products.sanofi.us products.sanofi.us/oforta/oforta.html

OFORTA™ (fludarabine phosphate) Tablets Severe neurologic effects, including blindness, coma, and death were observed in dose-ranging studies in patients with acute leukemia when fludarabine phosphate ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT01762202

Study Details | NCT01762202 | Assessment of Efficacy and ... Given that: rituximab, fludarabine and cyclophosphamide (FCR) front-line treatment was associated with a high OR rate, superior PFS and OS as compared to ...

10. ashpublications.org ashpublications.org/blood/article/112/4/975/25335/Long-term-results-of-the-fludarabine

Long-term results of the fludarabine, cyclophosphamide, and ... The overall response rate was 95%, with complete remission in 72%, nodular partial remission in 10%, partial remission due to cytopenia in 7%, ...