Cellular Therapy + Ruxolitinib for Graft-versus-Host Disease

Overseen By Partow Kebriaei, MD

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: M.D. Anderson Cancer Center

Must be taking: Ruxolitinib

Disqualifiers: Chronic GVHD, Uncontrolled infections, 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: 8

Duration: 4 weeks

24 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 acute graft-versus-host disease (GVHD) that does not respond to steroids. Researchers combine a drug called ruxolitinib (also known as Jakafi or Jakavi), which may block cancer cell growth, with special cells from umbilical cord blood that can help treat the disease. The study examines whether adding these cells to ruxolitinib can better control GVHD. Participants with GVHD affecting the gut or liver, who have not improved with steroid treatments, might be suitable candidates. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it seems that you must not have been on ruxolitinib for more than 96 hours before starting the trial.

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

Research shows that ruxolitinib is usually well-tolerated by patients. Studies have found it promising for treating graft-versus-host disease, with many patients responding positively. It can also be used long-term with few serious side effects.

Regarding cord blood tissue-derived mesenchymal stromal cells (cb-MSCs), research suggests they might help prevent and treat graft-versus-host disease. Although detailed safety data for cb-MSCs in humans remains limited, similar studies have shown potential benefits without major safety concerns.

Since this trial is in an early phase, the main goal is to assess safety and identify any possible side effects. Early-phase trials often have limited safety data, and the treatment is being tested to gather more information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for graft-versus-host disease because they combine ruxolitinib with mesenchymal stromal cells (MSCs), offering a potential new way to tackle this condition. While standard treatments often involve corticosteroids to dampen the immune response, these new approaches aim to enhance treatment effectiveness by adding MSCs, which have immunomodulatory properties. The trial is exploring both lower and higher doses of MSCs, alongside ruxolitinib, to determine the most effective combination. This dual approach could not only improve outcomes but also reduce reliance on steroids, which can have significant side effects.

What evidence suggests that this trial's treatments could be effective for graft-versus-host disease?

Research has shown that ruxolitinib, which participants in this trial may receive, effectively treats acute graft-versus-host disease (aGVHD). In one study, two-thirds of patients stopped using steroids, and most survived three years after starting ruxolitinib. Another study found that patients treated with ruxolitinib responded better after 28 days compared to those who received other treatments.

In this trial, some participants will receive ruxolitinib alone, while others will receive it combined with cord blood tissue-derived mesenchymal stromal cells (cb-MSCs). Research indicates that cb-MSCs can help manage aGVHD by calming the immune system. In one report, patients with severe aGVHD who received cb-MSCs showed positive responses and improved outcomes. Together, these treatments offer hope for those with aGVHD that doesn't respond to steroids. ^{1 3 4 5 6}

Who Is on the Research Team?

Partow Kebriaei, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients aged 12-80 with acute graft versus host disease that's not improving with steroids, specifically affecting the lower GI tract or liver. They must have a certain level of kidney function and be able to consent. Women who can get pregnant and men must use birth control. People with skin-only GVHD, uncontrolled infections, significant oxygen needs, allergies to certain animal products, or using other treatments are excluded.

Inclusion Criteria

I can care for myself but may need occasional help.

I can give my consent, or my legal representative can, for this trial.

I am between 12 and 80 years old.

Exclusion Criteria

I do not have any infections, or if I do, they are under control with no worsening signs.

I have a skin condition caused by a recent transplant.

I have been diagnosed with new onset chronic graft-versus-host disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive ruxolitinib orally twice daily. In Arm 2 and Arm 3, patients also receive cb-MSCs intravenously twice weekly over 4 consecutive weeks.

4 weeks

8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of GVHD status and incidence of infections.

6 months

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Cord Blood Tissue-Derived Mesenchymal Stromal Cells
• Ruxolitinib

Trial Overview The study tests adding cord blood tissue-derived mesenchymal stromal cells (cb-MSCs) to ruxolitinib in treating steroid-refractory acute graft versus host disease after stem cell transplant. It explores whether cb-MSCs combined with ruxolitinib can better manage the condition compared to standard treatments.

How Is the Trial Designed?

Group I: Arm 3 (ruxolitinib, higher dose ds-MSCs) Experimental Treatment 2 Interventions

Patients receive ruxolitinib PO BID as in Arm 1. Patients also receive higher dose of cb-MSCs IV for up to 60 minutes twice weekly (at least 3 days apart) over 4 consecutive weeks for 8 total doses.

Group II: Arm 2 (ruxolitinib, lower dose ds-MSCs) Experimental Treatment 2 Interventions

Patients receive ruxolitinib PO BID as in Arm 1. Patients also receive lower dose of cb-MSCs IV for up to 60 minutes twice weekly (at least 3 days apart) over 4 consecutive weeks for 8 total doses.

Group III: Arm 1 (ruxolitinib) Active Control 1 Intervention

Patients receive ruxolitinib PO BID for at least 3 days and may consider tapering after 6 months of therapy if response occurs and therapeutic corticosteroid doses have been discontinued.

Ruxolitinib is already approved in United States, European Union for the following indications:

Approved in United States as Jakafi for:

• Intermediate or high-risk myelofibrosis
• Polycythemia vera
• Steroid-refractory acute graft-versus-host disease
• Chronic graft-versus-host disease
• Vitiligo

Approved in European Union as Jakavi for:

• Intermediate or high-risk myelofibrosis
• Polycythemia vera
• Steroid-refractory acute graft-versus-host disease
• Chronic graft-versus-host disease
• Non-segmental vitiligo

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 8 patients with acute or chronic graft versus host disease (GVHD) who were unresponsive to standard treatments, ruxolitinib demonstrated a high overall response rate of 85%, with 50% achieving complete response.

Ruxolitinib was well-tolerated, indicating it could be a promising rescue therapy for patients suffering from refractory GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis. Sarmiento Maldonado, M., Ramírez Villanueva, P., Bertín Cortes-Monroy, P., et al.[2022]

Ruxolitinib (Jakafi) has received approval for the treatment of chronic graft-vs-host disease, indicating its efficacy in managing this condition.

The approval of ruxolitinib highlights its role as a kinase inhibitor, which works by targeting specific pathways involved in the immune response, potentially improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Indication for Ruxolitinib. Aschenbrenner, DS.[2023]

Cytokine-induced killer (CIK) cell therapy showed improved T cell recovery and a higher complete remission rate (53%) compared to donor lymphocyte infusion (DLI) which had a 29% remission rate, despite CIK patients having a worse prognosis at the time of treatment.

CIK therapy also demonstrated a lower 6-month cumulative incidence of relapse (22%) compared to DLI (55%), indicating better efficacy and safety for patients at high risk of relapse after hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clearance of Hematologic Malignancies by Allogeneic Cytokine-Induced Killer Cell or Donor Lymphocyte Infusions. Merker, M., Salzmann-Manrique, E., Katzki, V., et al.[2020]

In an expanded access program involving 609 patients (60 with acute GVHD and 549 with chronic GVHD), ruxolitinib demonstrated a tolerable safety profile, with serious adverse events (SAEs) reported in 68.3% of acute and 33.9% of chronic GVHD patients.

The most common SAEs included infections, with sepsis and respiratory failure being prevalent in acute GVHD, indicating that while ruxolitinib is generally well-tolerated, careful monitoring for infections is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety analysis of patients who received ruxolitinib for steroid-refractory acute or chronic graft-versus-host disease in an expanded access program. Schroeder, MA., Hari, PN., Blithe, A., et al.[2022]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, was approved by the FDA for treating steroid-refractory acute graft-versus-host disease (GVHD) based on promising results from the Phase II REACH1 trial.

The drug shows potential not only for treating SR acute GVHD but also for preventing GVHD and possibly serving as a first-line therapy, highlighting its versatility in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of graft-versus-host disease. Ali, H., Salhotra, A., Modi, B., et al.[2021]

Bone marrow transplantation from haploidentical donors has seen significant advancements over the past 20 years, leading to high engraftment rates and low incidences of graft-versus-host disease, making it a viable option even for elderly patients.

Survival rates for haploidentical donor transplants are comparable to those from unrelated donors, indicating that this approach is effective and safe, with ongoing improvements expected from strategies aimed at enhancing immune recovery and preventing leukemia relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Evolution of T Cell Depleted Haploidentical Transplantation. Aversa, F., Pierini, A., Ruggeri, L., et al.[2020]

In a clinical trial involving 25 elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), the combination of non-ablative chemotherapy followed by HLA-mismatched allogeneic T-cell infusion (allo-TLI) resulted in high overall response rates of 94% for AML and 75% for MDS patients.

The treatment demonstrated a favorable safety profile, with a low 60-day treatment-related mortality of 8%, and significantly improved overall survival rates compared to historical controls, suggesting it could be a viable first-line treatment for these patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-Ablative Chemotherapy Followed by HLA-Mismatched Allogeneic CD3+ T-Cells Infusion Causes An Augment of T-Cells With Mild CRS: A Multi-Centers Single-Arm Prospective Study on Elderly Acute Myeloid Leukemia and int-2/High Risk Myelodysplastic Syndrome Patients. Huang, Y., Hong, M., Qu, Z., et al.[2022]

Ruxolitinib prophylaxis showed a 41.2% incidence of acute graft-versus-host disease (aGVHD) in patients after modified donor lymphocyte infusion, indicating it can help reduce the severity of aGVHD in high-risk leukemia patients post-transplant.

Among the 17 patients studied, 58.8% achieved a complete response, suggesting that ruxolitinib may effectively maintain the graft-versus-leukemia (GVL) effect while managing aGVHD, despite a median follow-up of only 8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib on acute graft-versus-host disease prophylaxis after modified donor lymphocyte infusion. Tang, Y., Yang, D., Xie, R., et al.[2023]

Escalating hematopoietic progenitor cells can facilitate successful engraftment of haploidentical transplants in leukemia patients, overcoming genetic barriers and preventing graft-versus-host disease, as shown in both murine models and clinical data.

Donor NK cells play a crucial role in reducing relapse rates in acute myeloid leukemia (AML) patients receiving haploidentical transplants, while immune reconstitution is slower in adults compared to children, highlighting the need for tailored approaches in transplant strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplantation tolerance induced by "mega dose" CD34+ cell transplants. Reisner, Y., Martelli, MF.[2019]

HLA mismatched hemopoietic stem cell transplants can be successfully performed, as all seven patients in the study achieved engraftment and complete remission after receiving the transplants.

The conditioning regimen of busulfan and cyclophosphamide, with the addition of antithymocyte globulin, was effective, and G-CSF mobilized peripheral blood stem cells proved to be a viable source for these transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Human leukocyte antigen mismatched hemopietic stem cell transplants for the treatment of leukemia]. Huang, X., Chen, Y., Han, W., et al.[2018]

In a phase I trial involving 6 patients with myeloid malignancies who relapsed after haploidentical hematopoietic cell transplantation, the infusion of cytokine-induced memory-like (CIML) NK cells resulted in a rapid and sustained expansion of NK cells, increasing by 10 to 50 times over several months.

The treatment was well tolerated, with common side effects including fever and pancytopenia, indicating a favorable safety profile for CIML NK cell therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse. Shapiro, RM., Birch, GC., Hu, G., et al.[2022]

Haploidentical stem cell transplantation (haplo-SCT) shows superior or comparable outcomes to HLA-matched sibling donor transplantation (MSDT) in treating hematological malignancies, as demonstrated in a study involving 135 patients with acute myeloid leukemia.

The study revealed that haplo-SCT enhances the immune response against leukemia, leading to prolonged survival and reduced leukemia burden, primarily due to increased cytotoxic activity of T cells and natural killer cells compared to MSDT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation. Guo, H., Chang, YJ., Hong, Y., et al.[2022]

HLA haploidentical peripheral blood stem cell transplantation showed promising results in treating 30 patients with refractory leukemia, with 27 patients achieving complete remission after the procedure.

While the therapy can lead to disease-free survival in some patients, there were significant risks, including severe acute graft versus host disease in six patients, highlighting the need for careful monitoring and management post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The outcomes of the thirty patients with refractory leukemia treated with related HLA haploidentical stem cells transplantation]. Wu, BY., Guo, KY., Song, CY., et al.[2014]

In a study of 138 patients who underwent haploidentical hematopoietic transplantation, NK-cell alloreactivity was found to significantly improve graft-versus-host disease (GvHD) and relapse-free survival in T-cell-depleted transplants, suggesting a beneficial role in this specific context.

However, NK-cell alloreactivity did not show a significant impact on GvHD or relapse-free survival in unmanipulated transplants, indicating that the effects of NK-cell alloreactivity may depend on the type of transplant performed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural killer cell alloreactivity in HLA-haploidentical hematopoietic transplantation: a study on behalf of the CTIWP of the EBMT. Ruggeri, L., Vago, L., Eikema, DJ., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11357908/

Human umbilical cord-derived mesenchymal stromal cells ... In this study, we report the outcomes of 86 patients with grade III-IV (82.6% grade IV) steroid refractory aGVHD who were treated with human ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1465324921007441

Umbilical cord-derived mesenchymal stem cells promote ... In summary, the present results indicate that hUCMSCs are more effective than other MSCs in preventing GVHD and elucidate a potential mechanism underlying the ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7027118/

Mesenchymal stromal cells for the prophylaxis and treatment ... Mesenchymal stromal cells for treatment of acute steroid-refractory graft versus host disease: clinical responses and long-term outcome. Stem Cells. 2016;34 ...

4. nature.com nature.com/articles/s41423-023-01022-z

Current perspectives on mesenchymal stromal cell therapy ... The overall response of those with aGvHD was 54.9% at Day 28 in the phase II trial and 62% in the randomized trial, with a durable OR of 40% at ...

5. bmcmedicine.biomedcentral.com bmcmedicine.biomedcentral.com/articles/10.1186/s12916-024-03782-5

a multicentre, randomized, double-blind, phase 2 trial | BMC ... In vitro, mesenchymal stem cells (MSCs) have shown efficacy in the treatment of GVHD via their immunomodulatory effects, including the ...

6. nature.com nature.com/articles/s41591-024-02990-z

Two-year safety of iPS cell-derived stromal cells in GvHD We now report results at the 2-year follow-up: 9 of 15 (60%) participants survived, which compares favorably with previously reported outcomes ...