DR-18 for Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Fred Hutchinson Cancer Center
Must not be taking: Anti-C5, Anticomplement
Disqualifiers: Thrombotic microangiopathy, Renal insufficiency, Cardiac events, others
No Placebo Group
Trial Summary
What is the purpose of this trial?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 myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that has come back after a period of improvement (relapsed) or that remains despite treatment (persistent) after hematopoietic cell transplantation (HCT). HCT is the only curative therapy for most forms of AML and MDS. However, relapse occurs in a third of patients and is the most common cause of death after HCT. DR-18, a variant of the human cytokine interleukin-18, binds to IL-18 binding probein (IL-18BP) and overcomes the inhibitory effect of the IL-18BP on IL-18, which may boost the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving DR-18 may be safe, tolerable and/or effective in treating patient with relapsed or persistent AML or MDS after HCT.
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.
What data supports the idea that DR-18 for Leukemia is an effective treatment?
The available research does not provide specific data on DR-18 for Leukemia. However, studies on a similar treatment, interleukin-2 (IL-2), show that it can lead to complete remission in some patients with acute myeloid leukemia (AML) who have a low level of disease. For example, one study found that 8 out of 14 patients achieved complete remission, with some maintaining remission for over 30 months. This suggests that IL-2 can be effective in certain cases, but the research also highlights significant side effects and limited success in more advanced cases. Therefore, while IL-2 shows some promise, further research is needed to determine the effectiveness of DR-18 specifically.
12345What safety data is available for DR-18 treatment in leukemia?
The available research does not directly provide safety data for DR-18 or Decoy-resistant interleukin-18 in leukemia. However, a phase 1 study of recombinant human IL-18 (rhIL-18) demonstrated immunomodulatory and clinical activity, which may be relevant since DR-18 is a form of IL-18. No specific safety data for DR-18 in leukemia is mentioned in the provided studies.
36789Eligibility Criteria
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
I have not had severe GvHD after my last stem cell transplant.
My immune suppression has been stable or decreasing without any flare-ups in the last month.
My last stem cell transplant was from a fully matched donor.
No suitable FDA-approved targeted therapy for my AML or MDS, or I couldn't tolerate it.
I can carry out normal activities with minimal symptoms.
I have not had severe chronic graft-versus-host disease after my last stem cell transplant.
My AML or MDS has come back or didn't go away after a stem cell transplant.
Exclusion Criteria
I do not have uncontrolled heart rhythm problems.
I have a severe blood clotting disorder affecting my small blood vessels.
I have needed extra oxygen in the last 2 weeks.
My heart's pumping ability is significantly reduced.
My kidney function is low, with a filtration rate under 30 mL/min.
I have not had a major heart problem that needed ER or hospital care in the last 4 weeks.
I currently have an infection that is not under control.
I have had a seizure or significant neurological disease recently.
My liver tests are not more than 5 times the normal limit.
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (DR-18)Experimental Treatment3 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.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Fred Hutch/University of Washington Cancer ConsortiumSeattle, WA
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Who is running the clinical trial?
Fred Hutchinson Cancer CenterLead Sponsor
Simcha TherapeuticsCollaborator
References
Treatment of acute myeloid leukaemia patients with recombinant interleukin 2: a pilot study. [2019]Twelve patients with acute myeloid leukaemia (AML) with evidence of resistant disease were treated with recombinant interleukin 2 (rIL2) given intravenously by continuous infusion. No objective response to rIL2 alone was documented in the seven patients with advanced disease (20-90% resistant blasts in the marrow), except for a partial response to rIL2 plus chemotherapy in one. Of the five patients with limited disease (8-15% marrow blasts), three obtained a complete disappearance of the blasts following two to four 5d courses of rIL2 alone. One patient persists in fourth complete remission (CR) 30 months later, another obtained a third CR for 4 months, and the last remained in third CR for 9 months before relapsing. This latter patient achieved a fourth CR with low-dose cytarabine. The remissions have been maintained with low-dose monthly courses of rIL2 given on an out-patient basis. Two AML did not respond to rIL2 alone; one, however, obtained a fourth CR with chemotherapy and rIL2. Administration of rIL2 was accompanied by organomegaly and leucocytosis, with a frequent lymphocytosis and increase in eosinophils and large granular lymphocytes, both in the blood and in the marrow. Side effects, though often severe, were controllable using a daily dose escalating protocol and never required intensive care treatment. The results of this pilot study indicate that treatment of AML patients with rIL2 is feasible and may result in the disappearance of chemotherapy-resistant blasts in patients with limited but detectable disease. Further controlled trials in AML in CR appear warranted.
Expression of IL-18 and its receptor in human leukemia cells. [2019]The importance of IL-18, although clearly established in solid tumors, has not been fully elucidated in human hematopoietic neoplasms. Here we examined the mRNA and protein for IL-18 in eight human hematopoietic cell lines representing different lineages and neoplasms including leukemia, lymphoma and others. Our results revealed that IL-18 mRNA was expressed in these cells and that the corresponding protein was found in the cytoplasm. Seven of eight cell lines were also found to express two subunits of the IL-18 receptor (IL-18R) at varied levels. Furthermore, 29 out of 51 leukemia patients tested were observed to express IL-18R with 18/29 (62%) co-expression of both receptor and ligand. By blocking the IL-18 loop using specific antisense oligodeoxynucleotide (ASON) for IL-18 mRNA or anti-human IL-18R monoclonal antibody (McAbR), we were not able to demonstrate a marked inhibition on the most leukemic cell lines growth. Moreover, the potential proliferation in vitro of primary AML cells co-expressing IL-18 and its receptor was not significantly enhanced by recombinant human IL-18, suggesting that IL-18 is not apparently implicated in the proliferation of the leukemia cells via an autocrine loop. Additionally, we also found the effective modulating effect of M-CSF, IFN-alpha and TNF-alpha on IL-18R expression, implying an important in vivo effect of cytokines on IL-18-induced reaction. Moreover, the modulation of IL-18R expression was possibly irrelevant to IFN-gamma secretion induced by these cytokines.
Tocilizumab in combination with a standard induction chemotherapy in acute myeloid leukaemia patients (TOCILAM study): a single-centre, single-arm, phase 1 trial. [2023]In acute myeloid leukaemia (AML), interleukin-6 (IL-6) promotes chemo-resistance and its levels correlate with poor prognosis. IL-6 blockade may represent a promising therapeutic strategy. We aimed to test, tocilizumab, an anti-IL-6 receptor (R) monoclonal antibody in combination with standard intensive AML induction chemotherapy.
Interleukin-2 may induce prolonged remissions in advanced acute myelogenous leukemia. [2021]The administration of interleukin-2 (IL-2) may induce complete remissions in acute myelogenous leukemia (AML) patients with a low proportion of residual bone marrow (BM) blasts. To confirm this preliminary observation, we treated 14 AML patients with advanced disease and with a residual BM blastosis that ranged between 7% and 24% with repeated 5-day cycles of high-dose recombinant IL-2 administered by daily continuous intravenous infusion. Patients who responded have been subsequently submitted to a monthly maintenance scheme with subcutaneous IL-2 at lower doses. While using this schedule and closely monitoring clinical and laboratory conditions, side effects were acceptable and no toxic deaths recorded. Eight of the 14 patients treated with high-dose IL-2 obtained a complete remission (CR). Five remain in persistent CR (four in third CR and one in fourth CR) after a median follow-up time of 32 months (14, 30, 32, 33, and 68 months, respectively). In all five patients, the IL-2-induced remission is the longest in the natural history of the disease. These findings show that IL-2 displays an antileukemic effect in AML with limited residual disease, and suggest that IL-2 should be considered a therapeutic option for resistant or relapsed AML patients.
A phase II study of interleukin-2 in 49 patients with relapsed or refractory acute leukemia. [2019]In this report we present the results of a multicenter phase II study of high-dose recombinant Interleukin-2 (rIL-2) in patients with refractory or relapsed acute leukemia. Forty-nine patients with acute myeloid leukemia (AML: 30 patients) or acute lymphoblastic leukemia (ALL: 19 patients) were included. Median age was 30 years (range: 4-71). Four patients were treated for primary refractory disease and 45 for relapsed disease (16 patients > 2nd relapse). Twenty-four patients (49%) had previously received bone marrow transplantation (allogeneic: 5, autologous: 19). Patients were scheduled to receive three 5-day cycles of rIL-2 given every other week. rIL-2 was administered as bolus I.V. infusion of 8 x 10(6) UI/m2 every 8 hours during cycle I and every 12 hours during cycles 2 and 3. Patients received a mean of 76% of rIL-2 planned dose. Main toxicity was hematologic (grade IV thrombopenia: 84%). Hemodynamic and metabolic toxicities lead to treatment discontinuation in 10 patients (20%). Strong immune activation was achieved including a significant increase in activated T-cells and Lymphokine-Activating-Killer cell (LAK) activity. Twenty-seven out of 30 AML patients could be evaluated for response: 2(7%) achieved complete remission (CR) which lasted 3 and 4 months. No response was observed in the 18 assessable ALL patients, most of whom (77 %) presented absolute drug resistance. These results show that this high dose rIL-2 regimen induces significant biological effects and provides some anti-leukemic activity in patients with advanced leukemia. Considering the severe toxicity observed and the limited remission rate achieved here, rIL-2 does not appear to be a valuable therapeutic option for such patients. However, the undoubted anti-leukemic activity of this cytokine invites further investigation especially in the minimal residual disease situation.
A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma. [2021]Phase 1 studies demonstrated evidence of recombinant human IL-18 (rhIL-18)-mediated immunomodulatory and clinical activity, and defined a biologically active dose range.
Interleukin-2 receptor-directed therapies: antibody-or cytokine-based targeting molecules. [2021]With the exception of certain hematologic malignancies, the high affinity interleukin-2 (IL-2) receptor is only transiently expressed during the brief antigen-triggered proliferative burst of lymphocytes. Hence, we wondered whether administration of anti-IL-2 receptor (IL-2R) monoclonal antibody (mAb) or chimeric IL-2 toxins would provide a utilitarian way to achieve immunosuppression aimed directly at activated lymphocytes, or whether this approach could be used to treat IL-2R+ leukemia/lymphoma. Studies in preclinical autoimmune and transplant models indicate that this approach can be effective. The results of open, uncontrolled studies provide preliminary evidence that a chimeric IL-2 toxin is well tolerated at doses that may induce improvement in patients with IL-2R+ leukemia/lymphoma, as well as in patients with refractory rheumatoid arthritis or new-onset diabetes mellitus.
A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. [2022]To evaluate the hematologic effects of recombinant human interleukin-6 (rhIL-6, Escherichia coli, SDZ ILS 969, IL-6), and determine its toxicity profile, we performed a phase I trial of IL-6 in 22 patients with various myelodysplastic syndromes (MDS), platelet counts
Modulation of the systemic inflammatory response by recombinant human interleukin-11: a prospective randomized placebo controlled clinical study in patients with hematological malignancy. [2015]The immunomodulatory activities of recombinant human interleukin-11 (rhIL-11) were investigated in a clinical trial among patients with hematological malignancy, randomized to either rhIL-11 or placebo throughout chemotherapy. Daily serum concentrations of sTNFRI, IL-6, IL-8, TNFalpha, and CRP were measured. Higher sTNFRI levels [mean pg/ml (95% CI)] were detected in patients receiving rhIL-11 compared to placebo [1749.7 (1626-1882.9) versus 1038.5 (953.3-1131.3)] respectively (P = 0.01) for all 898 observations and during febrile days [2327.6 (2142.6-2528.2) versus 1308.9 (1163-1473.2), P = 0.12] and during days without infection [1406.6 (1266.1-1563) versus 871.3 (774.9-979.6), P
The -137G/C Polymorphism in Interleukin-18 Gene Promoter Contributes to Chronic Lymphocytic and Chronic Myelogenous Leukemia Risk in Turkish Patients. [2018]Interleukin-18 (IL-18) is a cytokine that belongs to the IL-1 superfamily and is secreted by various immune and nonimmune cells. Evidence has shown that IL-18 has both anticancer and procancer effects. The aim of this study was to evaluate the relationship between IL-18 gene polymorphisms and susceptibility to chronic lymphocytic leukemias (CLL) and chronic myelogenous leukemias (CML) in Turkish patients.
Exogenous IL-33 overcomes T cell tolerance in murine acute myeloid leukemia. [2023]Emerging studies suggest that dominant peripheral tolerance is a major mechanism of immune escape in disseminated leukemia. Using an established murine acute myeloid leukemia (AML) model, we here show that systemic administration of recombinant IL-33 dramatically inhibits the leukemia growth and prolongs the survival of leukemia-bearing mice in a CD8+ T cell dependent manner. Exogenous IL-33 treatment enhanced anti-leukemia activity by increasing the expansion and IFN-γ production of leukemia-reactive CD8+ T cells. Moreover, IL-33 promoted dendritic cell (DC) maturation and activation in favor of its cross presentation ability to evoke a vigorous anti-leukemia immune response. Finally, we found that the combination of PD-1 blockade with IL-33 further prolonged the survival, with half of the mice achieving complete regression. Our data establish a role of exogenous IL-33 in reversing T cell tolerance, and suggest its potential clinical implication into leukemia immunotherapy.
Cancer-killing, decoy-resistant interleukin-18. [2020]A recent paper by Zhou et al. describes a new engineered decoy-resistant interleukin-18 with potent antitumor activity and translational potential for cancer immunotherapy.
[Expression of interleukin-18 in human leukemia cell line J6-1 and its significance]. [2006]To elucidate the expression and regulation of interleukin-18 (IL-18) in human leukemia cell line J6-1, and investigate its possible role in leukemogenesis.