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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment for children and young adults with certain high-risk blood cancers, such as specific types of leukemia and lymphoma, who are in remission but at risk of relapse. It involves a stem cell transplant and immunotherapy, using donor cells specially prepared to reduce harmful side effects, followed by additional donor memory cells. The goal is to determine if this approach is safe and improves survival. Suitable candidates for this trial are individuals aged 21 or younger with high-risk blood cancer who lack a quickly available fully matched donor. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Previous studies have shown varying levels of safety and tolerability for the treatments tested in this trial.

ATG (rabbit) helps prevent graft-versus-host disease by reducing harmful T-lymphocytes, though it can increase the risk of infections like cytomegalovirus (CMV) and Epstein-Barr virus (EBV).

Blinatumomab, used for certain types of leukemia, has shown that about 78% of patients had no detectable cancer after treatment. However, serious side effects, such as infections and low white blood cell counts, have been reported.

CD45RA-depleted DLI (donor lymphocyte infusion) has been studied for safety and is generally well-tolerated, aiding successful donor cell transplantation without severe issues.

Cyclophosphamide, a common cancer treatment, can cause side effects like low blood counts and nausea. It suppresses the immune system to reduce the chance of cancer returning.

Fludarabine, used before stem cell transplants to stop cancer growth, is generally well-tolerated but can rarely cause a serious brain condition called leukoencephalopathy.

Melphalan, often used before stem cell transplants for bone marrow cancer, has an acceptable safety profile, though side effects can include low blood counts and nausea.

TCRα/β+ cell depletion aims to reduce harmful T cells, preventing complications after stem cell transplants, and is generally considered safe.

Thiotepa treats blood cancers before transplants and is feasible with tolerable toxicity, even in heavily treated patients.

This trial is in Phase 2, indicating some safety data from earlier studies, but more information is needed to fully confirm safety in the specific group being studied. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment because it combines stem cell transplants with immunotherapy to target blood cancers more effectively. Unlike traditional treatments that primarily rely on chemotherapy or radiotherapy, this approach uses TCRα/β+ depleted cells to minimize harm to healthy cells while boosting the immune system to fight cancer. The added use of Blinatumomab for patients with CD19+ malignancies aims to enhance targeting of cancer cells. This innovative combination could potentially improve outcomes and reduce side effects compared to existing therapies.

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

Research has shown that several components of the treatment in this trial have potential in treating blood cancers and improving transplant outcomes. Participants will receive a conditioning regimen that includes Cyclophosphamide, which effectively prevents graft-versus-host disease after stem cell transplants. Fludarabine, when combined with Melphalan, stops cancer cells from growing and is often used to prepare patients for transplants. ATG (rabbit) lowers the risk of graft-versus-host disease and improves survival rates post-transplant. Blinatumomab, administered to patients with CD19+ malignancies, effectively targets specific cancer cells and improves outcomes in certain blood cancers. Lastly, using TCRαβ-depleted donor cells aims to reduce complications and improve survival rates by minimizing harmful immune reactions. Combining these therapies offers a comprehensive approach to making transplants more effective and safer for young patients with high-risk blood cancers. ^{1 3 6 7 8}

Who Is on the Research Team?

Brandon Triplett, MD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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 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]

Citations

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Effectiveness and Safety of Rabbit Anti-Thymocyte Globulin ... rATG demonstrated significant reductions in the incidence of both aGVHD and cGVHD and increased the overall survival across donor types and stem ...

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Outcomes of split-dose lymphocyte-adjusted rabbit ATG in ... Methods: This retrospective, single-center review evaluated patients who received an allogeneic stem cell transplant from any donor type with ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10997457/

Impact of Rabbit Anti-Thymocyte Globulin (ATG) Exposure ... A low post-HCT rATG exposure was associated with 3-4-fold lower risk of NRM compared to the 2 higher exposure groups.

4. sciencedirect.com sciencedirect.com/science/article/pii/S000649712311593X

Effectiveness and Safety of Rabbit Anti-Thymocyte Globulin ... rATG demonstrated significant reductions in the incidence of both aGVHD and cGVHD and increased the overall survival across donor types and stem cell sources.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10112795/

Systematic review and meta-analysis of anti-thymocyte ... The ATG-T dose ≥7mg/kg versus the lower dose showed a number needed to treat 7.4 for acute GvHD III-IV, with a number to harm of 7.7 for relapse at one year in ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5286931/

Anti-thymocyte globulin as graft-versus-host disease ... This article reviews recent studies assessing the impact of anti-thymocyte globulin on transplantation outcomes in patients given peripheral blood stem cells.

7. eviq.org.au eviq.org.au/clinical-resources/side-effect-and-toxicity-management/haematological/1027-antithymocyte-globulin-for-gvhd-prophylaxis-i

1027-Antithymocyte globulin for GVHD prophylaxis in ... Antithymocyte globulins (ATG) are polyclonal purified horse or rabbit antibodies against human lymphocytes that deplete the number of T-lymphocytes in the ...

8. masseycancercenter.org masseycancercenter.org/news/antibodies-from-rabbits-reduce-risks-associated-with-unrelated-donor-stem-cell-transplantation/

Antibodies from rabbits reduce risks associated with ... This study is one of the first to use ATG in stem cell transplantation. ATG works by reducing the number of circulating T-lymphocytes, a key ...