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

40 Participants Needed

Trial Summary

What is the purpose of this trial?

Reduced intensity conditioning (RIC) has emerged and been increasingly adopted as a modality to allow preparative conditioning pre transplant to be tolerated by older adults or those patients that are otherwise unfit for myeloablative conditioning. In this study, we aim to use RIC followed by matched related/unrelated donor, 7/8 matched related/unrelated donor, or haploidentical donor peripheral blood stem cell transplantation. Standard strategies to control the alloreactivity following HCT utilize immunosuppressive or cytotoxic medications. In this study, we explore donor graft engineering to enrich for immmunoregulatory populations to facilitate post transplantation immune reconstitution while minimizing graft versus host disease (GVHD) with post-transplant immunosuppressive agents.

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.

What data supports the effectiveness of this treatment for blood cancers?

Research shows that high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) are effective in mobilizing stem cells for transplantation, which is crucial for treating blood cancers. Additionally, these treatments help maintain regulatory T-cells, which are important for immune balance and may improve outcomes in stem cell transplants. ^{1 2 3 4 5}

Is stem cell transplant for blood cancers generally safe in humans?

High-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) are used in stem cell transplants and can cause a significant decrease in T cell counts, which are important for immune function. However, regulatory T cells (Tregs), which help control immune responses, recover better than other T cells after treatment, suggesting a complex impact on the immune system. ^{1 2 3 5 6}

What makes this stem cell transplant treatment for blood cancers unique?

This treatment is unique because it combines stem cell transplantation with a specific mix of drugs and purified regulatory T-cells (Treg) to potentially enhance immune recovery and control immune responses, which is different from standard treatments that may not include this combination of immune-modulating components. ^{1 2 7 8 9}

Research Team

Everett Meyer, MD,PhD

Principal Investigator

Stanford Universiy

Eligibility Criteria

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.

I am between 18 and 75 years old and meet specific health and blood test criteria.

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

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]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Impact of chemotherapy for colorectal cancer on regulatory T-cells and tumor immunity. [2022]

2. United States 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. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Regulatory T-cell depletion in the setting of autologous stem cell transplantation for multiple myeloma: pilot study. [2021]

4. England 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. [2020]

5. Greece pubmed.ncbi.nlm.nih.gov

Suppressive effects of cyclophosphamide and gemcitabine on regulatory T-cell induction in vitro. [2022]

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

A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia. [2021]

9. England pubmed.ncbi.nlm.nih.gov

The prophylactic potential of fludarabine monophosphate in graft-versus-host disease after bone marrow transplantation in murine models. [2013]