DR-18 for Leukemia

Overseen By Elizabeth Krakow

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Fred Hutchinson Cancer Center

Must not be taking: Anti-C5, Anticomplement

Disqualifiers: Thrombotic microangiopathy, Renal insufficiency, Cardiac events, others

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

Compensation: Varies

Number of Visits: 12

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called DR-18 (Decoy-resistant interleukin-18) for individuals with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that has returned or persisted after a stem cell transplant. In its early stages, the trial aims to find the safest and most effective dose while monitoring for side effects. DR-18 may assist the immune system in fighting cancer by blocking proteins that inhibit the immune response. Ideal candidates have persistent or relapsed AML or MDS after a transplant and have not experienced severe graft-versus-host disease, a condition where transplanted cells attack the body. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot have had cellular immunotherapy or new targeted therapy in the 4 weeks before enrolling. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that DR-18 is likely to be safe for humans?

Research shows that a new treatment called decoy-resistant interleukin-18 (DR-18) may help treat leukemia. Earlier studies found that DR-18 can boost the immune system's ability to fight cancer by increasing the activity of natural killer (NK) cells, counteracting the immune suppression caused by a protein that binds to IL-18.

The trial primarily focuses on safety, and some early research suggests that DR-18 might be well-tolerated. It could help manage relapse after a transplant without causing severe graft-versus-host disease (GvHD), where donated cells attack the body. However, since this is the first trial in humans, information on how people react to DR-18 remains limited. As with any new treatment, monitoring for side effects is crucial.

In this phase of the trial, researchers are beginning to assess the safety of DR-18 in humans. As the trial progresses, more details will emerge about its safety and potential side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard leukemia treatments that often involve chemotherapy and radiation, DR-18 uses a novel approach by incorporating decoy-resistant interleukin-18. This unique mechanism targets the immune system more precisely, potentially boosting the body's natural defense against cancer cells without the severe side effects of traditional therapies. Researchers are excited because DR-18 could offer a more targeted and less toxic option for patients, possibly leading to better outcomes and improved quality of life.

What evidence suggests that DR-18 might be an effective treatment for leukemia?

Research shows that DR-18, which participants in this trial will receive, may help treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). DR-18 blocks a natural substance called IL-18 binding protein (IL-18BP), enabling the immune system to better attack cancer cells. Studies in mice have shown that DR-18 can slow tumor growth. Its effectiveness is linked to its ability to work with T cells, crucial components of the immune system. Early results suggest that DR-18 might help patients whose cancer has returned or persists after a stem cell transplant. ^{4 6 7 8 9}

Who Is on the Research Team?

Elizabeth Krakow

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that has returned or persisted after a stem cell transplant. Participants must have had the transplant as their prior treatment.

Inclusion Criteria

My last stem cell transplant was from a fully matched donor.

Evidence of primary engraftment post-HCT: ANC ≥ 0.5 x 10^9/L for ≥ 3 consecutive days and platelets ≥ 30 x 10^9/L

Not pregnant/breastfeeding

Exclusion Criteria

I do not have uncontrolled heart rhythm problems.

I have not undergone hemodialysis in the last 4 weeks.

I have had moderate to severe heart failure symptoms in the last month.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive DR-18 subcutaneously once weekly on approximately days 0, 7, 14, and 21

4 weeks

4 visits (in-person)

Maintenance

Patients without severe GVHD may receive DR-18 subcutaneously once weekly on approximately days 35, 42, 49, and 56

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Weekly for 4 weeks, monthly through 6 months, and at 12 months

What Are the Treatments Tested in This Trial?

Interventions

• Decoy-resistant interleukin-18

Trial Overview The trial is testing DR-18, a new form of interleukin-18, to see if it's safe and effective in treating AML/MDS after relapse or persistence post-transplant. It also involves bone marrow aspiration and biospecimen collection for study purposes.

How Is the Trial Designed?

Group I: Treatment (DR-18) Experimental Treatment 3 Interventions

INDUCTION: Patients receive DR-18 SC once weekly on approximately days 0, 7, 14, and 21. MAINTENANCE: Two weeks after induction treatment, patients without grade 3-4 acute GVHD, grade 2 acute GVHD requiring ongoing systemic immunosuppression, or moderate/severe chronic GVHD may receive DR-18 SC once weekly on approximately days 35, 42, 49 and 56. Additionally, patients undergo blood and bone marrow sample collection throughout the study.

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

Simcha Therapeutics

Collaborator

Trials

2

Recruited

40+

Published Research Related to This Trial

Administration of anti-IL-2 receptor monoclonal antibodies or chimeric IL-2 toxins can effectively target activated lymphocytes for immunosuppression, showing promise in treating IL-2R+ leukemia and lymphoma.

Preliminary evidence from open studies suggests that chimeric IL-2 toxins are well tolerated and may improve conditions in patients with IL-2R+ leukemia/lymphoma, as well as in those with refractory rheumatoid arthritis or new-onset diabetes mellitus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-2 receptor-directed therapies: antibody-or cytokine-based targeting molecules. Strom, TB., Kelley, VR., Murphy, JR., et al.[2021]

In a phase I trial involving 22 patients with myelodysplastic syndromes, recombinant human interleukin-6 (rhIL-6) showed potential to improve platelet counts in 36% of patients, with some achieving significant increases, although the maximum tolerated dose was determined to be 3.75 micrograms/kg/d due to dose-limiting toxicities like fatigue and fever.

IL-6 appears to function as a maturational agent for megakaryocytes rather than a colony-stimulating factor, indicating that while it can promote platelet production, its significant side effects limit its use as a standalone treatment, prompting further research into combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. Gordon, MS., Nemunaitis, J., Hoffman, R., et al.[2022]

In a clinical trial involving patients with hematological malignancies, treatment with recombinant human interleukin-11 (rhIL-11) significantly increased serum levels of sTNFRI and CRP, indicating its immunomodulatory effects during chemotherapy.

Patients receiving rhIL-11 experienced fewer infections and fever episodes compared to those on placebo, suggesting that rhIL-11 may help modulate immune responses and reduce inflammation in a chemotherapy setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of the systemic inflammatory response by recombinant human interleukin-11: a prospective randomized placebo controlled clinical study in patients with hematological malignancy. Ellis, M., Hedstrom, U., Frampton, C., et al.[2015]

In a phase 2 study involving 64 patients with untreated stage IV melanoma, recombinant human IL-18 (rhIL-18) was found to be well tolerated, with only a few grade 3 adverse events reported, indicating a favorable safety profile.

Despite its safety, rhIL-18 showed limited clinical efficacy as a single agent, with only one patient achieving a partial response and a median progression-free survival of about 7.5 weeks across all dose groups, leading to the study's termination after stage 1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma. Tarhini, AA., Millward, M., Mainwaring, P., et al.[2021]

In a phase 1 trial involving 12 patients with acute myeloid leukaemia (AML), the anti-IL-6 receptor monoclonal antibody tocilizumab was found to be safe when combined with standard chemotherapy, with no dose-limiting toxicities reported.

The trial showed promising efficacy, as 9 out of 10 evaluable patients responded to treatment, suggesting that an 8 mg/kg dose of tocilizumab could be a viable option for further studies in AML therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab in combination with a standard induction chemotherapy in acute myeloid leukaemia patients (TOCILAM study): a single-centre, single-arm, phase 1 trial. Peterlin, P., Garnier, A., Le Bourgeois, A., et al.[2023]

In a study of 14 patients with advanced acute myelogenous leukemia (AML), high-dose interleukin-2 (IL-2) treatment led to complete remission in 8 patients, demonstrating its potential as an effective therapy for those with low residual bone marrow blasts.

The treatment was well-tolerated with no toxic deaths reported, and five patients maintained long-term remission for up to 68 months, suggesting that IL-2 could be a valuable option for patients with resistant or relapsed AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-2 may induce prolonged remissions in advanced acute myelogenous leukemia. Meloni, G., Foa, R., Vignetti, M., et al.[2021]

The human leukemia cell line J6-1 consistently expresses IL-18 mRNA, which may play a role in promoting the proliferation of these cancer cells, as indicated by a 43.3% inhibition of cell growth when IL-18 was targeted with antisense oligodeoxynucleotide (ASODN).

IL-18 expression in J6-1 cells was found to be higher than in other leukemia cell lines, suggesting that it could be a key factor in leukemogenesis, although it did not show significant mutation in its coding region.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Expression of interleukin-18 in human leukemia cell line J6-1 and its significance]. Wang, Y., Li, G., Rao, Q.[2006]

In a pilot study of 12 patients with acute myeloid leukaemia (AML), recombinant interleukin 2 (rIL2) treatment showed promising results, particularly in patients with limited disease, where 3 out of 5 achieved complete remission after treatment.

While rIL2 alone did not show objective responses in patients with advanced disease, it was effective in combination with chemotherapy for some, and side effects were manageable, suggesting that rIL2 could be a feasible treatment option for certain AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of acute myeloid leukaemia patients with recombinant interleukin 2: a pilot study. Foa, R., Meloni, G., Tosti, S., et al.[2019]

In a phase II study involving 49 patients with refractory or relapsed acute leukemia, high-dose recombinant Interleukin-2 (rIL-2) demonstrated significant immune activation but resulted in severe hematologic toxicity, with 84% of patients experiencing grade IV thrombopenia.

Only 7% of patients with acute myeloid leukemia achieved complete remission, and no responses were observed in patients with acute lymphoblastic leukemia, suggesting that while rIL-2 has some anti-leukemic activity, its severe side effects limit its therapeutic value in advanced leukemia cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of interleukin-2 in 49 patients with relapsed or refractory acute leukemia. Maraninchi, D., Vey, N., Viens, P., et al.[2019]

The study found a significant association between the IL-18 rs187238(G/C) polymorphism and chronic myelogenous leukemia (CML) in Turkish patients, with the C allele being more prevalent in CML cases compared to healthy controls.

While the CC genotype was linked to an increased risk of chronic lymphocytic leukemia (CLL), the overall findings are preliminary due to the small sample size, indicating a need for larger studies to confirm these associations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The -137G/C Polymorphism in Interleukin-18 Gene Promoter Contributes to Chronic Lymphocytic and Chronic Myelogenous Leukemia Risk in Turkish Patients. Yalçın, S., Mutlu, P., Çetin, T., et al.[2018]

In a murine model of acute myeloid leukemia (AML), systemic administration of recombinant IL-33 significantly inhibited leukemia growth and extended survival, primarily through the activation of CD8+ T cells.

Combining IL-33 treatment with PD-1 blockade further enhanced survival rates, with half of the treated mice experiencing complete regression of leukemia, highlighting IL-33's potential as a therapeutic agent in leukemia immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exogenous IL-33 overcomes T cell tolerance in murine acute myeloid leukemia. Qin, L., Dominguez, D., Chen, S., et al.[2023]

The study presents a newly engineered form of interleukin-18 that is resistant to decoy mechanisms, which enhances its effectiveness in targeting tumors.

This engineered interleukin-18 shows strong antitumor activity, suggesting it has significant potential for use in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer-killing, decoy-resistant interleukin-18. Nakamura, K., Bald, T., Smyth, MJ.[2020]

IL-18 mRNA and protein were found in various human hematopoietic neoplasms, with seven out of eight cell lines expressing IL-18 receptors, indicating a potential role for IL-18 in these cancers.

Blocking the IL-18 signaling pathway did not significantly inhibit the growth of leukemic cell lines, suggesting that IL-18 may not play a direct role in the proliferation of leukemia cells through an autocrine mechanism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of IL-18 and its receptor in human leukemia cells. Zhang, B., Ma, XT., Zheng, GG., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7381364/

IL-18BP is a secreted immune checkpoint and barrier to IL- ... These results indicate that the anti-tumor efficacy of DR-18 is driven by its independence from IL-18BP. DR-18 requires adaptive T cell immunity ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06492707

Study Details | NCT06492707 | DR-18 for the Treatment of ... This phase I trial tests the safety, side effects and best dose of decoy-resistant interleukin-18 (DR-18) and how well it works in treating patients with ...

3. jitc.bmj.com jitc.bmj.com/content/12/12/e009716

Durable antitumor response via an oncolytic virus ... Recombinant IL-18 has displayed limited clinical efficacy in part due to the expression of the decoy receptor, IL-18 binding protein (IL-18BP).

4. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper205690.html

Paper: Preclinical Efficacy of Decoy-Resistant IL-18 in ... Here we evaluated murine DR-18 in a diverse set of mouse hematological tumor models, including in combination with conventional chemotoxic and ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1044532325000697

Review Unlocking IL-18: A hidden key in cancer immunity To overcome the co-induction of IL-18 and its natural inhibitor IL-18BP, a decoy-resistant cytokine (DR-18) was engineered and demonstrated ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124099464

Trials in Progress: Decoy-Resistant Interleukin-18 (DR- ... DR-18 immunotherapy may offer effective management of post-HCT relapse while avoiding significant GvHD.

7. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4780.1/529875/Trials-in-Progress-Decoy-Resistant-Interleukin-18

Decoy-Resistant Interleukin-18 (DR-18) for Relapse or Pre ... We found DR-18 overcomes IL18BP mediated immune suppression and reverses CD8+ T cell exhaustion by increasing NK cell activity.

8. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-04811

DR-18 for the Treatment of Relapsed or Persistent Acute ... This phase I trial tests the safety, side effects and best dose of decoy-resistant interleukin-18 (DR-18) and how well it works in treating patients with acute ...

9. withpower.com withpower.com/trial/phase-1-leukemia-8-2024-15de6

DR-18 for Leukemia · Recruiting Participants for Phase ... This phase I trial tests the safety, side effects and best dose of decoy-resistant interleukin-18 (DR-18) and how well it works in treating patients with ...