Ipilimumab + DLI for Leukemia

Recruiting at 1 trial location

Overseen By John Koreth, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Antitumor chemotherapy, Immunotherapy

Disqualifiers: Autoimmune disease, Organ transplant, HIV, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

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

Compensation: Varies

Number of Visits: 1

Duration: 12 weeks

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of ipilimumab in patients with certain blood cancers, such as Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS). The researchers aim to determine the highest safe dose while monitoring for side effects. Participants will receive ipilimumab along with donor lymphocyte infusion (DLI), which involves returning specific immune cells to the patient. This trial may suit individuals who have relapsed at least two months after a stem cell transplant and still have their original stem cell donor available. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as systemic corticosteroids and other treatments for GVHD, at least 4 weeks before participating. If you are on anti-tumor chemotherapy, investigational agents, or immunotherapy, you must also stop these before joining the trial.

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

Research has shown that ipilimumab is often used to treat cancer, but it can cause immune-related side effects, such as diarrhea, skin rash, and liver inflammation. This study examines the safety of using ipilimumab with a specific cell therapy called CD25hi Treg-depleted DLI.

As a Phase 1 trial, the primary goal is to determine the safe dosage and identify any side effects in individuals with certain blood cancers, like Acute Myeloid Leukemia (AML). The treatment is still in the early stages of safety testing in humans. Detailed information about side effects from this specific study is not yet available, but the focus remains on ensuring the treatment's safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for leukemia?

Unlike the standard leukemia treatments, which typically involve chemotherapy and radiation, the combination of Ipilimumab with DLI offers a unique approach by utilizing the immune system to fight cancer. Ipilimumab is a checkpoint inhibitor that helps activate the immune system's T-cells to recognize and attack cancer cells, a mechanism different from traditional methods that directly target cancer cells. Additionally, the use of CD25hi Treg-depleted DLI is designed to enhance this immune response further by reducing regulatory T-cells that can suppress the immune attack on cancer. Researchers are excited about this treatment because it represents a novel immunotherapy approach that could offer improved effectiveness with potentially fewer side effects compared to conventional therapies.

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

In this trial, participants will receive a combination of ipilimumab and a special type of cell therapy called Treg-depleted DLI. Research on this combination shows promise for treating blood cancers like leukemia. Previous studies have demonstrated that this combination can enhance the immune system's ability to attack cancer cells, a response known as the "graft-versus-leukemia" effect. This treatment has generally been tolerable for patients, though risks exist, such as graft-versus-host disease, where immune cells might attack the body. The main focus has been on ensuring safety and determining the right dose, but early results are encouraging for those whose cancer has returned after treatments like stem cell transplants. ^{1 2 3 6 7}

Who Is on the Research Team?

John Koreth, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults over 18 with certain relapsed myeloid diseases after a matched stem cell transplant can join. They must have adequate organ function, no severe GVHD or recent treatments for it, and agree to use contraception. Excluded are those with autoimmune diseases, uncontrolled illnesses, prior anti-CTLA-4/PD-1 therapy, active infections like HIV/hepatitis B/C, or pregnant/nursing women.

Inclusion Criteria

LVEF >40%

I agree to use birth control during and after the study as required.

I haven't taken high doses of steroids for conditions other than GVHD in the last 4 weeks.

Exclusion Criteria

I haven't had cancer treatment or still have side effects from treatments done more than 4 weeks ago, except for hydroxyurea.

I do not have any serious illnesses that would stop me from following the study's requirements.

I am not HIV-positive or not on antiretroviral therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CD25/Treg-depleted DLI plus Ipilimumab intravenously every 12 weeks

12 weeks

1 visit every 12 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 weeks

What Are the Treatments Tested in This Trial?

Interventions

• CD25hi Treg depleted DLI
• Ipilimumab

Trial Overview The trial is testing the highest safe dose of Ipilimumab and CD25hi Treg depleted DLI in patients with AML, MDS, MPN (including CMML), or Myelofibrosis post-transplant. It aims to find out what side effects occur at different doses.

How Is the Trial Designed?

Group I: CD25/Treg-depleted DLI + Ipilimumab Experimental Treatment 2 Interventions

* Ipilimumab is administered intravenously every 12 weeks * Patients will receive a defined dose of CD25hi Treg depleted DLI intravenously

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

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 373 patients from 11 phase I clinical trials, ipilimumab-related grade 3/4 adverse events were more common in patients who responded to treatment, indicating a potential link between therapeutic response and toxicity.

The likelihood of experiencing severe adverse events increased with the number of additional agents used alongside ipilimumab, while longer treatment duration was associated with more low-grade toxicities but not high-grade ones.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic and predictive factors associated with ipilimumab-related adverse events: a retrospective analysis of 11 NCI-sponsored phase I clinical trials. Chauhan, A., Kabir, T., Wu, J., et al.[2023]

Combined immune checkpoint blockade (ICB) using nivolumab and ipilimumab shows significant efficacy in treating advanced melanoma, but it also leads to a higher frequency and severity of adverse drug reactions (ADRs) compared to single-agent therapies, based on pooled safety data from 1551 patients.

Most immune-related ADRs are reversible with glucocorticoids, but due to the increased risk and rapid onset of these toxicities, clinicians must be well-trained to monitor and manage these side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Hassel, JC., Heinzerling, L., Aberle, J., et al.[2022]

Bosutinib shows equivalent efficacy to nilotinib and dasatinib in treating newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML), based on an unanchored matching-adjusted indirect treatment comparison using patient-level data from the BFORE trial and aggregated data from other studies.

While there were no statistically significant differences in major molecular response (MMR) or disease progression between bosutinib and the other two drugs, bosutinib demonstrated a trend towards better outcomes in achieving deeper molecular responses (MR4 and MR4.5) compared to nilotinib and dasatinib after 24 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An indirect comparison between bosutinib, nilotinib and dasatinib in first-line chronic phase chronic myeloid leukemia. Muresan, B., Mamolo, C., Cappelleri, JC., et al.[2022]

In a study of 117 patients with chronic myeloid leukemia, dasatinib showed higher adherence to treatment (91%) compared to nilotinib (82%) over two years.

Both dasatinib and nilotinib demonstrated similar efficacy in terms of progression-free survival (PFS) at 92%, indicating that while dasatinib may be better adhered to, both drugs are equally effective in preventing disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adherence, persistence and efficacy of dasatinib and nilotinib in the treatment of patients resistant or intolerant to imatinib with chronic myeloid leukemia in chronic phase: an Italian multicenter study over two years in real life. Santoleri, F., Ranucci, E., La Barba, G., et al.[2022]

Ipilimumab, an antibody that enhances T-cell activation, is effective for treating metastatic melanoma but can cause immune-mediated side effects, including rare cases of ileitis without colitis, as seen in a 54-year-old patient.

The study highlights the need for further research into genetic and epigenetic factors to personalize treatment and minimize adverse effects associated with ipilimumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and immune-mediated adverse events: a case report of anti-CTLA4 induced ileitis. Venditti, O., De Lisi, D., Caricato, M., et al.[2018]

Immune checkpoint antibodies targeting the PD-1/PD-L1 pathway have shown significant antitumor activity and have been approved for use as single-agent therapies in metastatic malignant melanoma and nonsmall-cell lung cancer.

Understanding the toxicities associated with PD-1/PD-L1 blockade and having effective management strategies is crucial for maximizing both the safety and efficacy of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Naidoo, J., Page, DB., Li, BT., et al.[2023]

In a meta-analysis of 11,465 patients from 18 clinical trials, PD-1/PD-L1 inhibitors were found to significantly increase the risk of developing dermatologic adverse effects like rash and pruritus compared to chemotherapy, with relative risks of 1.84 and 3.74, respectively.

PD-1/PD-L1 inhibitors showed a lower risk of mucosal inflammation and alopecia compared to chemotherapy, indicating a distinct safety profile that differs from traditional cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of dermatologic and mucosal adverse events associated with PD-1/PD-L1 inhibitors in cancer patients: A meta-analysis of randomized controlled trials. Yang, W., Li, S., Yang, Q.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03912064

NCT03912064 | A Phase 1 Trial of CD25/Treg-depleted ... This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124075918

Induction of Graft-Versus-Leukemia Effect with Treg ... Treg-depleted DLI plus IPI is a novel combinatorial therapy for myeloid disease relapse following HCT that is tolerable despite risk for GVHD and IPI-related ...

3. dana-farber.org dana-farber.org/clinical-trials/19-142

A phase 1 trial of CD25/Treg-depleted DLI plus Ipilimumab ... In this research study, our main goal for the ipilimumab portion of the study is to determine the highest dose of ipilimumab that can be given safely in ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03912064?term=AREA%5BConditionSearch%5D(%22Myelofibrosis%22)%20AND%20AREA%5BInterventionSearch%5D(%22Antineoplastic%20Agents,%20Immunological%22)&rank=9

A Phase 1 Trial of CD25/Treg-depleted DLI Plus ... In this research study, our main goal for the ipilimumab portion of the study is to determine the highest dose of ipilimumab that can be given safely in ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5046655/

A phase I study of CD25/regulatory T-cell-depleted donor ... DLI has been successful in relapsed chronic myeloid leukemia with greater than 70% sustained response rates. Its efficacy in other diseases is limited by two ...

6. withpower.com withpower.com/trial/phase-1-leukemia-6-2019-f45e4

Ipilimumab + DLI for Leukemia · Info for Participants Ipilimumab, used in cancer treatment, can cause immune-related side effects like diarrhea, skin rash, and liver inflammation. When combined with other drugs, ...

7. researchgate.net researchgate.net/publication/386468760_Induction_of_Graft-Versus-Leukemia_Effect_with_Treg-Depleted_DLI_Plus_Ipilimumab_for_Myeloid_Disease_Relapse_after_HLA-Matched_Transplant

Induction of Graft-Versus-Leukemia Effect with Treg- ... Together, these observations motivated the combination of Treg-depleted DLI with IPI as a novel therapy to treat post-HCT relapse of MDS and AML ...