Stem Cell Transplant for Blood Cancers

Overseen By Lindsay Danley

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Stanford University

Must not be taking: Immunosuppressants

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 4-6 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method for treating blood cancers like leukemia and myelodysplastic syndromes using stem cell transplants, with an emphasis on reducing side effects. Researchers use a method called reduced intensity conditioning (RIC) to prepare patients for the transplant, which is gentler on the body than traditional methods. The trial examines different donor matches and treatments to lower the risk of graft versus host disease (a condition where the donor's cells attack the patient's body) while aiding immune system recovery. People with blood cancers in remission or with minimal disease who cannot tolerate more aggressive treatments might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative approach.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. However, since the study involves stem cell transplantation and immunosuppressive agents, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators for specific guidance.

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

Research has shown that using Fludarabine and Melphalan together is generally safe, especially in lower doses. One study found this combination effective and safe for older patients with blood cancers, offering hope for those unable to tolerate stronger treatments.

For the Fludarabine and Thiotepa combination, studies also indicate positive safety results. Specifically, one study found that even when combined with another drug, this mix remains safe for patients, suggesting a manageable safety profile.

Patients in these studies often experienced some side effects, which is common with cancer treatments. However, the overall findings suggest these combinations are well-tolerated by most people. If the treatment has FDA approval for other uses, this can provide extra reassurance about its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the stem cell transplant for blood cancers because it uses purified regulatory T-cells (Treg) plus CD34+ hematopoietic stem and progenitor cells (HSPC). This approach is different because it aims to harness the body's immune system to reduce complications like graft-versus-host disease (GVHD), which is a common issue with standard transplants. Unlike traditional treatments that mainly focus on chemotherapy drugs, this method incorporates advanced cellular therapy to potentially improve outcomes and safety. Additionally, the use of tacrolimus and ruxolitinib for GVHD prophylaxis is a novel strategy that might offer better control over immune responses compared to conventional options.

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

Research has shown that using fludarabine in certain chemotherapy combinations before stem cell transplants can lead to high survival rates. In this trial, participants in various treatment arms will receive fludarabine as part of their preparative regimen. Melphalan, another chemotherapy drug used in some arms, has been linked to good outcomes, such as prolonged periods without cancer progression. Tacrolimus, used in all arms, helps prevent graft-versus-host disease (GVHD), where donor cells attack the patient's body, and has been associated with better short-term results after transplants. These treatments, when combined in the different arms, aim to make transplants safer and more effective for people with blood cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

Everett Meyer, MD,PhD

Principal Investigator

Stanford Universiy

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with various advanced blood cancers, including different types of leukemia and myelodysplastic syndromes. Participants must be in remission or have minimal disease, match specific donor criteria for stem cell transplant, and have good heart, lung, kidney function. Pregnant women and those with active infections or certain viruses are excluded.

Inclusion Criteria

My heart, lungs, kidneys, liver, and physical ability meet the study's requirements.

My leukemia is in a specific remission stage confirmed by tissue analysis.

I am willing to donate stem cells and meet the donation requirements.

Exclusion Criteria

Patients living outside the US

Patients with specific infections, CNS disease, pregnancy, or psychosocial circumstances

I am not eligible for specific intense cancer treatment plans or transplant methods.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive reduced intensity preparative chemotherapy conditioning followed by allogeneic hematopoietic cell transplantation (HCT) with T-cell depleted grafts and infusion of conventional and regulatory T-cells.

Approximately 4-6 weeks

Follow-up

Participants are monitored for safety, effectiveness, and incidence of GVHD and other outcomes post-transplantation.

12 months

Long-term follow-up

Participants are followed for long-term outcomes including overall survival, disease-free survival, and chronic GVHD incidence.

2 years

What Are the Treatments Tested in This Trial?

Interventions

• CliniMACS CD34 Reagent System
• Cyclophosphamide
• Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent
• Fludarabine
• Melphalan
• Plerixafor
• Purified regulatory T-cells (Treg) plus CD34+ HSPC
• Tacrolimus

Trial Overview

The study tests a reduced intensity conditioning regimen followed by a stem cell transplant from partially matched donors to treat blood cancers. It includes T-cell depletion using the CliniMACS system and medications like Fludarabine, Melphalan, Tacrolimus to prepare the body for transplantation.

How Is the Trial Designed?

Group I: Arm C2: 7/8 mismatched related/unrelated donor transplantation Experimental Treatment 7 Interventions

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant: * Fludarabine (160 mg/m2) * Thiotepa (5 mg/kg) * TBI (2-3 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.

Group II: Arm C1:7/8 mismatched related/unrelated donor transplantation (closed) Experimental Treatment 7 Interventions

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant: * Fludarabine (160 mg/m2) * Thiotepa (10 mg/kg) * TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).

Group III: Arm B: Haploidentical transplantation (closed) Experimental Treatment 8 Interventions

Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning: -. Fludarabine (160 mg/m2) * Melphalan (100 mg/m2 * TBI (4Gy) Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.

Group IV: Arm A3: Fully (8/8) matched related/unrelated donor transplantation Experimental Treatment 6 Interventions

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant: * Fludarabine (160 mg/m2) * Thiotepa (5 mg/kg) * TBI (2-3 Gy). All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Group V: Arm A2: Fully matched (8/8) related/unrelated donor transplantation Experimental Treatment 6 Interventions

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant: * Fludarabine (160 mg/m2) * Thiotepa (10 mg/kg) * TBI (4Gy) All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Group VI: Arm A1: Matched related/matched unrelated donor transplantation (closed) Experimental Treatment 6 Interventions

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:. * Fludarabine (160 mg/m2) * Melphalan (50 mg/m2) * TBI (4Gy) All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Orca Biosystems, Inc.

Industry Sponsor

Trials

8

Recruited

750+

Published Research Related to This Trial

In a study involving 15 multiple myeloma patients undergoing autologous stem cell transplantation (ASCT), two methods of depleting regulatory T (Treg) cells were tested, showing that both in vivo (IVTRD) and ex vivo (EVTRD) methods significantly reduced Treg levels post-transplant.

The ex vivo method (EVTRD) effectively removed 90% of Treg cells from the stem cell grafts, and both methods delayed Treg recovery, which could enhance the effectiveness of post-transplant immunotherapies and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory T-cell depletion in the setting of autologous stem cell transplantation for multiple myeloma: pilot study. Derman, BA., Zha, Y., Zimmerman, TM., et al.[2021]

In a study of 27 patients with metastatic colorectal cancer, both FOLFOX and FOLFIRI chemotherapy regimens significantly reduced the percentage and number of regulatory T-cells (Tregs) in patients who had high Treg levels before treatment.

This reduction in Tregs suggests that FOLFOX and FOLFIRI may enhance the body's antitumor immune response without affecting the overall number of lymphocytes or CD4+ T lymphocytes, indicating a potential mechanism for improved cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of chemotherapy for colorectal cancer on regulatory T-cells and tumor immunity. Maeda, K., Hazama, S., Tokuno, K., et al.[2022]

Chemotherapeutic agents cyclophosphamide (CPA) and gemcitabine (GEM) significantly suppress the induction of regulatory T-cells (Tregs) in vitro, which could enhance the effectiveness of cancer immunotherapy.

The concentrations of CPA that effectively suppress Treg induction are similar to those found in cancer patients receiving low-dose CPA, suggesting a potential therapeutic strategy to improve cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suppressive effects of cyclophosphamide and gemcitabine on regulatory T-cell induction in vitro. Kan, S., Hazama, S., Maeda, K., et al.[2022]

High-dose cyclophosphamide (Cy) combined with G-CSF significantly reduces T cell counts in patients with multiple myeloma, with only partial recovery observed by the time of stem cell collection.

Despite the decrease in overall T cell counts, the treatment does not eliminate regulatory T cells (Tregs), which can inhibit antitumor responses, suggesting a need for strategies to enhance T cell recovery while managing Treg levels post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional regulatory T cells are collected in stem cell autografts by mobilization with high-dose cyclophosphamide and granulocyte colony-stimulating factor. Condomines, M., Quittet, P., Lu, ZY., et al.[2019]

Cyclophosphamide, a well-established drug for over 40 years, has both antitumor and immunosuppressive properties, making it useful in cancer treatment and autoimmune diseases.

Low-dose cyclophosphamide selectively suppresses regulatory T cells, which can help counteract immunosuppression in cancer, suggesting that combining it with other immunomodulatory agents may enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. Ahlmann, M., Hempel, G.[2018]

The combination of cyclophosphamide, fluorouracil, and interleukin-2 (Cyt-FU-IL-2) was found to be safe and feasible for treating heavily pre-treated patients with solid tumors, with manageable side effects such as diarrhea and anemia.

In this study involving 14 patients, the treatment showed moderate activity, with 23% of patients achieving a partial response and a median overall survival of 7 months, indicating potential effectiveness despite prior treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide with or without fluorouracil followed by subcutaneous or intravenous interleukin-2 use in solid tumors: A feasibility off-label experience. Lo Re, G., Lo Re, F., Doretto, P., et al.[2020]

A CCR4 antagonist, when combined with cancer vaccines, effectively breaks the tolerance of regulatory T cells (Tregs) and induces CD8(+) T cells that can attack tumors, demonstrating its potential to enhance cancer vaccine efficacy.

In experiments with transgenic and normal mice, the CCR4 antagonist outperformed cyclophosphamide in generating anti-self CD8(+) T cells and inhibiting tumor growth, suggesting it could be a promising therapeutic strategy for treating hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens. Pere, H., Montier, Y., Bayry, J., et al.[2021]

Fludarabine phosphate significantly improved survival rates in mice undergoing marrow transplantation across major histocompatibility barriers, indicating its potential to enhance outcomes in such transplant scenarios.

However, fludarabine did not affect graft-versus-host disease or survival in cases involving minor histocompatibility barriers, suggesting its efficacy may be limited to specific transplant conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The prophylactic potential of fludarabine monophosphate in graft-versus-host disease after bone marrow transplantation in murine models. Or, R., Weiss, L., Amir, G., et al.[2013]

The combination of fludarabine and cyclophosphamide effectively reduces tumor burden in chronic lymphocytic leukemia, but it also leads to a significant reduction in CD4(+) and CD8(+) T cells, indicating potential immunosuppressive effects.

Despite the depletion of T cells, the surviving T cells exhibit a more mature phenotype and increased responsiveness to stimulation, suggesting that fludarabine/cyclophosphamide therapy may create a favorable environment for subsequent T cell activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia. Gassner, FJ., Weiss, L., Geisberger, R., et al.[2021]

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