Stem Cell Transplant + Immunotherapy for Blood Cancers

Overseen By Brandon Triplett, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: Prior allogeneic HCT, uncontrolled infection, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

140 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Stem Cell Transplant + Immunotherapy for Blood Cancers?

Research shows that fludarabine and thiotepa, components of the treatment, are effective in preparing patients for stem cell transplants, achieving full donor chimerism (successful integration of donor cells) and maintaining remission in blood cancers. Additionally, fludarabine and cyclophosphamide have shown synergistic effects in treating chronic lymphocytic leukemia and non-Hodgkin lymphoma, suggesting potential benefits in similar blood cancer treatments. ^{1 2 3 4 5}

Is the combination of stem cell transplant and immunotherapy safe for blood cancer patients?

The combination of stem cell transplant and immunotherapy, using drugs like fludarabine, thiotepa, cyclophosphamide, and antithymocyte globulin, has been studied in various conditions. These treatments are generally well-tolerated, but they can cause side effects such as gastrointestinal issues and organ toxicity. Some studies report no severe organ toxicity, while others note considerable toxicity, including renal, hepatic, and cardiac issues. ^{1 3 6 7 8}

What makes the Stem Cell Transplant + Immunotherapy treatment for blood cancers unique?

This treatment combines stem cell transplantation with immunotherapy and a mix of drugs like cyclophosphamide, fludarabine, and melphalan, which are known for their ability to reduce tumor burden and modulate the immune system. The unique aspect is the combination of these drugs to create a suitable environment for T cell activation, potentially enhancing the body's immune response against cancer. ^{1 3 9 10 11}

What is the purpose of this trial?

Patients less than or equal to 21 years old with high-risk hematologic malignancies who would likely benefit from allogeneic hematopoietic cell transplantation (HCT). Patients with a suitable HLA matched sibling or unrelated donor identified will be eligible for participation ONLY if the donor is not available in the necessary time. The purpose of the study is to learn more about the effects (good and bad) of transplanting blood cells donated by a family member, and that have been modified in a laboratory to remove the type of T cells known to cause graft-vs.-host disease, to children and young adults with a high risk cancer that is in remission but is at high risk of relapse. This study will give donor cells that have been TCRαβ-depleted. The TCR (T-cell receptor) is a molecule that is found only on T cells. These T-cell receptors are made up of two proteins that are linked together. About 95% of all T-cells have a TCR that is composed of an alpha protein linked to a beta protein, and these will be removed. This leaves only the T cells that have a TCR made up of a gamma protein linked to a delta protein. This donor cell infusion will be followed by an additional infusion of donor memory cells (CD45RA-depleted) after donor cell engraftment. This study will be testing the safety and effects of the chemotherapy and the donor blood cell infusions on the transplant recipient's disease and overall survival.

Research Team

Brandon Triplett, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children and young adults up to 21 years old with high-risk blood cancers like leukemia or lymphoma, who are in remission but at risk of relapse. They must have a partially matched family donor available quickly, be HIV negative, not pregnant or breastfeeding, and their major organs must function well. It's not open to those with other active cancers or who've had certain transplants within the last year.

Inclusion Criteria

Patient must fulfill pre-transplant organ function criteria: Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%. Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2. Forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing. Karnofsky or Lansky (age-dependent) performance score ≥ 50 (See APPENDIX A). Bilirubin ≤ 3 times the upper limit of normal for age. Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age. Not pregnant. If female with child bearing potential, must be confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment. Not breast feeding. Does not have current uncontrolled bacterial, fungal, or viral infection.

Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).

My blood cancer is considered high risk, with specific genetic features or poor response to initial treatment.

Exclusion Criteria

N/A

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Participants receive a conditioning regimen of ATG, Cyclophosphamide, mesna, fludarabine, thiotepa, and melphalan

1 week

Transplantation

HPC,A Infusion (TCRα/β+ and CD19+ depleted) followed by CD45RA-depleted DLI at least two weeks after engraftment

3 weeks

Blinatumomab Administration

Blinatumomab is given at least one week post-DLI to patients with CD19+ malignancies

Up to 90 days post-transplant

Follow-up

Participants are monitored for safety and effectiveness after treatment, including incidence of GVHD and overall survival

1 year

Treatment Details

Interventions

• ATG (rabbit)
• Blinatumomab
• CD45RA-depleted DLI
• CliniMACS
• Cyclophosphamide
• Fludarabine
• G-csf
• Melphalan
• Mesna
• TCRα/β+
• Thiotepa

Trial Overview The study tests a transplant using blood cells from a family member that have been modified in the lab to reduce graft-vs-host disease risk. These cells lack TCRαβ proteins known for causing this complication. After engraftment, patients receive an additional infusion of memory T-cells from the donor. The effects on patient survival and cancer recurrence are being studied alongside chemotherapy drugs used.

Participant Groups

Group I: Transplant participants Experimental Treatment 12 Interventions

Participants receive a conditioning regimen of ATG (rabbit),Cyclophosphamide 60 mg/kg intravenous once daily, mesna, fludarabine, thiotepa, melphalan, followed by HPC,A Infusion(TCRα/β+ and CD19+ depleted),HPC, A infusion (if needed to achieve goal CD34+ cell dose.CD45RA-depleted DLI will be given at least two weeks after engraftment. Blinatumomab will be given at least one week post-DLI, and only to patients with CD19+ malignancies. G-csf 5mcg/kg subcutaneous or intravenous daily until ANC \>2000 for 2 consecutive days. Cells for infusion are prepared using the CliniMACS system.

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?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Findings from Research

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]

The new conditioning regimen using thiotepa and fludarabine (TT-FLUDA) was well tolerated in six patients undergoing allogeneic bone marrow transplantation, with successful engraftment and stable donor chimerism in most cases.

Despite the patients being poor candidates for standard treatments, the TT-FLUDA regimen showed no major toxicity, although one patient died from acute graft-versus-host disease (GVHD), indicating a need for careful monitoring of GVHD prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa and fludarabine (TT-FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. Alessandrino, EP., Bernasconi, P., Colombo, AA., et al.[2019]

The combination therapy of fludarabine, cyclophosphamide, and rituximab (FC-R) resulted in high objective response rates (83%) and complete response rates (42%) among 76 evaluable patients, demonstrating its efficacy in treating chronic lymphocytic leukemia (CLL) and follicular lymphoma.

Patients with CLL showed particularly impressive results, with 100% objective response and 67% complete response rates when treated as first-line therapy, indicating that FC-R is a potent option for both initial and salvage therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Tam, CS., Wolf, M., Prince, HM., et al.[2015]

The increased-intensity FBCA conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 22 patients with severe aplastic anemia resulted in prompt and sustained hematopoietic reconstitution, with median neutrophil and platelet engraftment times of 15 and 16 days, respectively.

The study reported a low incidence of graft-versus-host disease (GVHD) at 9.1% for acute and 15.8% for chronic cases, with a 13.6% transplantation-related mortality rate, indicating that the regimen is effective with manageable safety outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Fludarabine-based increased-intensity conditioning regimen for allogeneic hematopoietic stem cell transplantation in acquired severe aplastic anemia]. Sun, C., Lin, X., Huang, Y., et al.[2014]

In a study of 31 patients with hematologic malignancies who were poor candidates for total body irradiation (TBI), the fludarabine-melphalan regimen resulted in successful engraftment for all patients, indicating its efficacy in stem cell transplantation.

However, the treatment was associated with significant regimen-related toxicities, including renal, hepatic, and mucosal issues, leading to seven regimen-related deaths, highlighting the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. Van Besien, K., Devine, S., Wickrema, A., 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]

The reduced-intensity conditioning regimen of fludarabine and melphalan was found to be feasible and effective in achieving 100% donor chimerism in 22 patients with metastatic breast cancer and renal cell carcinoma after allogeneic stem cell transplantation.

The treatment resulted in a 45% response rate in terms of tumor regression, with some patients experiencing complete or partial responses, suggesting that the graft-versus-host disease may contribute to the graft-versus-tumor effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. Ueno, NT., Cheng, YC., Rondón, G., 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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning regimen with thiotepa and fludarabine followed by allogeneic blood stem cell transplantation in haematological malignancies. [2013]

3. Germany pubmed.ncbi.nlm.nih.gov

Thiotepa and fludarabine (TT-FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. [2019]

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

Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. [2015]

5. China pubmed.ncbi.nlm.nih.gov

[Fludarabine-based increased-intensity conditioning regimen for allogeneic hematopoietic stem cell transplantation in acquired severe aplastic anemia]. [2014]

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

Phase I study of the safety and pharmacokinetics of plerixafor in children undergoing a second allogeneic hematopoietic stem cell transplantation for relapsed or refractory leukemia. [2021]

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

Regimen-related toxicity after fludarabine-melphalan conditioning: a prospective study of 31 patients with hematologic malignancies. [2013]

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

Treosulfan, cyclophosphamide and antithymocyte globulin for allogeneic hematopoietic cell transplantation in acquired severe aplastic anemia. [2016]

9. Germany pubmed.ncbi.nlm.nih.gov

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

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

Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

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