Stem Cell Transplant + Zometa for Pediatric Blood Cancers

Overseen By Jenny Weiland

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Wisconsin, Madison

Disqualifiers: Pregnant, HIV, Heart failure, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

22 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the safety of transplantation with a haploidentical donor peripheral blood stem cell graft depleted of TCRαβ+ cells and CD19+ cells in conjunction with the immunomodulating drug, Zoledronate, given in the post-transplant period to treat pediatric patients with relapsed or refractory hematologic malignancies or high risk solid tumors.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that patients must have fully recovered from the effects of prior treatments before joining the study, which might imply some medications need to be paused. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Zoledronic acid in combination with stem cell transplant for pediatric blood cancers?

Research shows that using Zoledronic acid after a specific type of stem cell transplant in children with high-risk acute leukemia can lower the chances of complications like graft-versus-host disease and improve survival rates. Patients who received three or more doses of Zoledronic acid had better outcomes, including higher survival rates and lower transplant-related mortality. ^{1 2 3 4 5}

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

The studies suggest that haploidentical stem cell transplantation (a type of stem cell transplant using a partially matched donor) is generally safe, with low toxicity and no transplant-related deaths reported in pediatric patients with solid tumors. However, specific safety data for the combination with Zometa (also known as Zoledronic acid) in pediatric blood cancers is not provided in these studies. ^{1 2 6 7 8}

How is the treatment TCRαβ+/CD19+ depleted Haploidentical HSCT with Zometa unique for pediatric blood cancers?

This treatment is unique because it combines a specialized stem cell transplant that removes specific immune cells (TCRαβ+ and CD19+ cells) with Zometa (a drug that strengthens bones), potentially reducing complications like graft-versus-host disease and improving outcomes for children with blood cancers. ^{1 2 9 10 11}

Research Team

Christian Capitini, MD

Principal Investigator

University of Wisconsin, Madison

Eligibility Criteria

This trial is for pediatric patients with high-risk or relapsed blood cancers and solid tumors who have a suitable haploidentical donor. It's not open to those pregnant, breastfeeding, with uncontrolled infections, prior organ transplants, or conditions that could affect study participation.

Inclusion Criteria

I have blood cancer and either can't find a matching donor or can't wait for one without my disease getting worse.

My AML is not responding to treatment and my bone marrow has less than 20% cancer cells.

Inclusion Criteria for Donors: Donor must be 18 years of age minimum, 65 years of age maximum Donor must be in good general health as determined by evaluating medical provider Must meet donor criteria for human cells, tissues, and cellular and tissue-based products per Code of Federal Regulations 21 CFR 1271, subpart C. Specifically: Donor screening in accordance with 1271.75 indicates that the donor: Is free from risk factors for, and clinical evidence of, infection due to relevant communicable disease agents and diseases; and Is free from communicable disease risks associated with xenotransplantation; and The results of donor testing for relevant communicable disease agents in accordance with 1271.80 and 1271.85 are negative or nonreactive, except as provided in 1271.80(d)(1). Haploidentical by HLA-typing Preference will be given to donors who demonstrate KIR incompatibility with recipient HLA class I ligands defined as the donor expressing a KIR gene for which the corresponding HLA class I ligand is not expressed by the recipient. Negative testing for relevant communicable diseases: Hepatitis B surface antigen (HBsAg) Hepatitis B core antibody (Anti-HBc) Hepatitis C antibody (Anti-HCV) HIV 1 & 2 antibody (Anti-HIV-1, 2 plus O) HTLV I/II antibody (Anti-HTLV I/II) RPR (Syphilis TP) CMV (Capture CMV) MPX for: HepB (HBV-PCR), HepC (HCV-PCR), HIV (HIV-PCR) NAT for West Nile Virus (WNV-PCR) T. Cruzi - EIA (Chagas)

Exclusion Criteria

I have a serious illness besides cancer that could make a stem cell transplant too risky.

I do not have heart failure or uncontrolled heart rhythm problems.

Exclusion Criteria for Donors: Lactating females

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Patients receive conditioning regimens with anti-thymocyte globulin, fludarabine, thiotepa, and either total body irradiation or melphalan depending on risk category

12 days

Peripheral Blood Stem Cell Transplantation

Patients undergo TCR-alpha/beta+ and CD19+ depleted KIR/KIR ligand-mismatched haploidentical donor peripheral blood stem cell transplantation

1 day

1 visit (in-patient)

Zoledronate Administration

Patients receive five doses of Zoledronate at 28-day intervals starting 28 days post-transplant

5 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Treatment Details

Interventions

• TCRαβ+/CD19+ depleted Haploidentical HSCT
• Zoledronate

Trial Overview The trial tests a transplant using stem cells from a half-matched donor that are filtered to remove certain immune cells (TCRαβ+/CD19+), combined with Zoledronate post-transplant. This Phase I study aims to assess the safety of this approach.

Participant Groups

Group I: TCRαβ+/CD19+ depleted Haploidentical HSCT+ Zoledronate Experimental Treatment 2 Interventions

Patients with high-risk leukemia (who are at least one year of age and who have not received TBI as conditioning for a previous HSCT) will receive myeloablative conditioning with ATG, Fludarabine, Thiotepa, and TBI. All other subjects will undergo a reduced-intensity conditioning regimen consisting of ATG, Fludarabine, Thiotepa, and Melphalan prior to transplant with a KIR/KIR ligand mismatched haploidentical donor peripheral blood stem cell graft depleted of TCR-αβ+ and CD19+ cells. Patients will receive 5 doses of zoledronate (at 28 day intervals) starting 28 days after stem cell transplant.

TCRαβ+/CD19+ depleted Haploidentical HSCT is already approved in United States, European Union for the following indications:

Approved in United States as Zometa for:

• Multiple myeloma
• Bone metastases from solid tumors
• Hypercalcemia of malignancy
• Paget’s disease of bone
• Osteoporosis

Approved in European Union as Zoledronic acid for:

• Prevention of skeletal events in patients with bone metastases from solid tumors
• Treatment of tumor-induced hypercalcemia
• Paget’s disease of bone
• Osteoporosis

Who Is Running the Clinical Trial?

University of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

Findings from Research

In a study of 168 patients with refractory/relapsed B-cell acute lymphoblastic leukemia, those who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) after CAR-T therapy had similar long-term survival rates compared to those who underwent haplo-HSCT after achieving minimal residual disease-negative complete remission from chemotherapy.

Patients who achieved a first complete remission (CR1) after chemotherapy had better overall survival and leukemia-free survival rates than those who had a second or more complete remission (≥CR2), highlighting the importance of achieving an earlier remission for better transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparable outcomes in patients with B-cell acute lymphoblastic leukemia receiving haploidentical hematopoietic stem cell transplantation: Pretransplant minimal residual disease-negative complete remission following chimeric antigen receptor T-cell therapy versus chemotherapy. Yang, TT., Meng, Y., Kong, DL., et al.[2022]

In a pilot study involving 6 pediatric patients with relapsed metastatic tumors, transplantation of haploidentical T and B cell depleted grafts with high NK cell counts showed feasibility and low toxicity, with primary engraftment achieved in all patients.

Despite significant tumor burden before transplantation, the approach resulted in rapid hematopoietic recovery and no transplant-related mortality, suggesting potential for further development in posttransplant immunomodulation strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical stem cell transplantation in patients with pediatric solid tumors: preliminary results of a pilot study and analysis of graft versus tumor effects. Lang, P., Pfeiffer, M., Müller, I., et al.[2022]

In a study of 27 children undergoing haploidentical hematopoietic stem cell transplantation, γδ T cells were found to be the main T-cell type shortly after the procedure, indicating their importance in early immune responses post-transplant.

The research highlighted that Vδ1 γδ T cells expanded in patients with cytomegalovirus reactivation and showed strong cytotoxic activity against leukemia cells, suggesting potential for targeted therapies using zoledronic acid to enhance these cells' effectiveness against cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes. Airoldi, I., Bertaina, A., Prigione, I., et al.[2022]

In a study involving 46 children with high-risk acute leukemia, the use of zoledronic acid after TcRαβ/CD19-cell depleted haplo-HSCT was found to be safe, with no severe adverse events reported and only mild side effects like hypocalcemia and flu-like symptoms.

Patients receiving three or more infusions of zoledronic acid experienced significantly lower rates of acute and chronic graft-versus-host disease (GvHD) and transplant-related mortality, suggesting that repeated doses may improve overall survival and disease-free survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia. Merli, P., Algeri, M., Galaverna, F., et al.[2021]

Infusing zoledronic acid (ZOL) in 43 pediatric patients receiving HLA-haploidentical stem cell transplants significantly enhanced the cytotoxic activity of γδ T cells against leukemia cells, particularly after multiple treatments.

Patients who received three or more ZOL infusions had a higher survival probability (86%) compared to those who received one or two treatments (54%), suggesting that ZOL may improve outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zoledronic acid boosts &#947;&#948; T-cell activity in children receiving &#945;&#946;+ T and CD19+ cell-depleted grafts from an HLA-haplo-identical donor. Bertaina, A., Zorzoli, A., Petretto, A., et al.[2022]

In a study involving five adults with relapsed B cell acute lymphoblastic leukemia (B-ALL), treatment with autologous T cells modified to express a CD19-specific CAR (19-28z) led to rapid tumor eradication and complete remissions without minimal residual disease (MRD), indicating strong efficacy of this therapy.

The treatment was generally well tolerated, although patients with higher tumor burdens experienced significant cytokine elevations, which required management with steroids, highlighting the need for monitoring and potential intervention during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Brentjens, RJ., Davila, ML., Riviere, I., et al.[2023]

In a study of 46 children and young adults with relapsed/refractory B-ALL who underwent hematopoietic stem cell transplantation (HSCT) after CAR T cell therapy, the median overall survival (OS) was 72.2 months, indicating that HSCT can be an effective consolidation treatment for these patients.

Factors such as having five or more prior lines of therapy and prior treatments with blinatumomab or inotuzumab were associated with decreased OS and event-free survival (EFS), suggesting that extensive prior therapy and high disease burden negatively impact outcomes after HSCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors Impacting Overall and Event-Free Survival following Post-Chimeric Antigen Receptor T Cell Consolidative Hematopoietic Stem Cell Transplantation. Molina, JC., Steinberg, SM., Yates, B., et al.[2023]

In a study of 52 patients with relapsed/refractory B-cell acute lymphoblastic leukemia, bridging CAR-T therapy to haploidentical-allogeneic hematopoietic stem cell transplantation (haplo-HSCT) resulted in high 1-year overall survival rates of 92.3% and event-free survival rates of 80.1%.

The study found that haplo-HSCT did not increase the risk of complications such as graft-versus-host disease or treatment-related mortality, suggesting it is a safe option to enhance remission sustainability after CAR-T therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unmanipulated haploidentical hematopoietic stem cell transplantation is an excellent option for children and young adult relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia after CAR-T-cell therapy. Hu, GH., Zhao, XY., Zuo, YX., et al.[2022]

A study reported a remarkable 3-year survival rate of over 90% for children with nonmalignant disorders who underwent haploidentical αβ+CD3+/CD19+-depleted allogeneic transplantation.

This transplantation method shows promise as a safe and effective treatment option for pediatric patients with these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haplo is the new black. Pulsipher, MA.[2021]

In a pilot study involving 16 pediatric and young adult patients with high-risk solid tumors, the use of reduced-intensity conditioning haploidentical bone marrow transplant (haploBMT) showed promising results, with an overall survival rate of 88% at 6 months and 56% at 12 months.

The approach demonstrated feasibility and acceptable toxicity, with most patients achieving full donor chimerism by day 30 and limited instances of graft-versus-host disease, suggesting it could be a viable treatment option for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients. Llosa, NJ., Cooke, KR., Chen, AR., et al.[2020]

A novel method of graft manipulation using negative depletion of αβ T and B cells in haploidentical stem cell transplantation for children with acute leukemia showed promising results, with a 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) at 71%.

The study involved 80 children and found that the outcomes were comparable to those of children receiving transplants from HLA-identical siblings or well-matched unrelated donors, suggesting that haplo-HSCT is a viable alternative for urgent allograft needs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. Locatelli, F., Merli, P., Pagliara, D., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Comparable outcomes in patients with B-cell acute lymphoblastic leukemia receiving haploidentical hematopoietic stem cell transplantation: Pretransplant minimal residual disease-negative complete remission following chimeric antigen receptor T-cell therapy versus chemotherapy. [2022]

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

Haploidentical stem cell transplantation in patients with pediatric solid tumors: preliminary results of a pilot study and analysis of graft versus tumor effects. [2022]

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

γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia. [2021]

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

Zoledronic acid boosts &#947;&#948; T-cell activity in children receiving &#945;&#946;+ T and CD19+ cell-depleted grafts from an HLA-haplo-identical donor. [2022]

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

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. [2023]

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

Factors Impacting Overall and Event-Free Survival following Post-Chimeric Antigen Receptor T Cell Consolidative Hematopoietic Stem Cell Transplantation. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Unmanipulated haploidentical hematopoietic stem cell transplantation is an excellent option for children and young adult relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia after CAR-T-cell therapy. [2022]

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

Haplo is the new black. [2021]

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

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients. [2020]

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

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. [2021]