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

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the treatment Orca-T and Radiation Therapy for Leukemia?

Research shows that fludarabine, a component of the treatment, can enhance the effects of radiation therapy by delaying tumor regrowth in animal studies. Additionally, fludarabine has been effective in treating chronic lymphocytic leukemia and shows potential when combined with other agents for treating different types of leukemia. ^{1 2 3 4 5}

What safety data exists for the treatment involving Orca-T and Radiation Therapy for Leukemia?

Fludarabine, a component of the treatment, has been associated with severe neurotoxicity at high doses and pulmonary toxicity in some cases, but these effects can be managed with additional medications. Fludarabine-based conditioning is considered powerfully immunosuppressive and has been used safely in children with severe aplastic anemia undergoing stem cell transplantation. ^{1 2 4 6 7}

What makes the Orca-T and Radiation Therapy treatment for leukemia unique?

The Orca-T and Radiation Therapy treatment for leukemia is unique because it combines fludarabine, melphalan, and thiotepa, which are drugs that work together to inhibit DNA synthesis and damage cancer cells, potentially enhancing the effectiveness of radiation therapy. This combination may offer a novel approach for patients who have not responded well to other treatments. ^{2 3 8 9 10}

Research Team

Amandeep Salhotra

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Potentiation of radiation-induced regrowth delay in murine tumors by fludarabine. [2013]

2. Germany pubmed.ncbi.nlm.nih.gov

Protection against fludarabine neurotoxicity in leukemic mice by the nucleoside transport inhibitor nitrobenzylthioinosine. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

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

4. England 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. [2019]

5. Russia (Federation) 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]. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Pulmonary toxicity associated with fludarabine monophosphate. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. [2013]

8. United States 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. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Fludarabine and cytosine arabinoside in the treatment of refractory or relapsed acute lymphocytic leukemia. [2019]

10. United States 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. [2021]