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

Trial Summary

What is the purpose of this trial?

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 several courses and to determine what side effects are seen in patients with Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS), Myeloproliferative Neoplasms (MPN), Chronic Myelomonocytic Leukemia (CMML), or Myelofibrosis (MF).

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.

What safety information is available for Ipilimumab and its combination with other treatments?

Ipilimumab, used in cancer treatment, can cause immune-related side effects like diarrhea, skin rash, and liver inflammation. When combined with other drugs, these side effects can be more frequent and severe, but they are often reversible with medication. Close monitoring by experienced healthcare providers is important to manage these side effects effectively. ^{1 2 3 4 5}

How is the treatment Ipilimumab + DLI for Leukemia different from other treatments?

Ipilimumab + DLI (donor lymphocyte infusion) is unique because it combines an immune checkpoint inhibitor (Ipilimumab) with a cellular therapy (DLI), potentially enhancing the immune system's ability to target leukemia cells, unlike standard treatments that primarily use tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia. ^{6 7 8 9 10}

Research Team

John Koreth, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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]

References

1. United States 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. [2023]

2. United States 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. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Ipilimumab and immune-mediated adverse events: a case report of anti-CTLA4 induced ileitis. [2018]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Second-generation TKIs: which and when? [2020]

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

Long-term tolerability and efficacy after initial PegIFN-α addition to dasatinib in CML-CP: Five-year follow-up of the NordCML007 study. [2022]

8. England 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. [2022]

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

Determinants of frontline tyrosine kinase inhibitor choice for patients with chronic-phase chronic myeloid leukemia: A study from the Registro Italiano LMC and Campus CML. [2023]

10. England pubmed.ncbi.nlm.nih.gov

An indirect comparison between bosutinib, nilotinib and dasatinib in first-line chronic phase chronic myeloid leukemia. [2022]