Elenestinib for Blood Cancers

(AZURE Trial)

Recruiting at 10 trial locations

Overseen By Blueprint Medicines

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Blueprint Medicines Corporation

Must not be taking: Corticosteroids, Hydroxyurea, HMAs, others

Disqualifiers: Philadelphia chromosome, AML, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

9 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to evaluate elenestinib (BLU-263) in participants with Advanced Systemic Mastocytosis (AdvSM), SM with an associated hematologic neoplasm (SM-AHN), and other hematologic malignancies. The main questions it aims to answer are: * Determine Recommended Dose of elenestinib (BLU-263) monotherapy for participants with AdvSM * Safety and tolerability of elenestinib (BLU-263) monotherapy * Efficacy of elenestinib (BLU-263) monotherapy in participants with AdvSM * Determine Recommended Dose of elenestinib (BLU-263) in combination with azacitidine in participants with AdvSM * Safety and tolerability of elenestinib (BLU-263) in combination with azacitidine * Efficacy of elenestinib (BLU-263) in combination with azacitidine in participants with AdvSM The estimated study duration for each participant will be approximately 4 years: 2 years of treatment followed by 2 years of follow-up. Participants may be required to attend monthly visits for the first six months, followed by quarterly visits for the remainder of the study.

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

The trial protocol does not specify if you must stop all current medications. However, you cannot have received any antineoplastic therapy or investigational agents within 14 days before enrollment, and you must not have taken hydroxyurea within 7 days before the first dose of elenestinib. If you're on corticosteroids, the dose must be stable for at least 7 days. Please consult with the trial team for specific guidance on your medications.

What data supports the idea that Elenestinib for Blood Cancers is an effective treatment?

The available research does not provide specific data supporting the effectiveness of Elenestinib for Blood Cancers. Instead, it discusses other treatments like elotuzumab, which targets specific cells in myelofibrosis, and ruxolitinib, which shows significant activity in myelofibrosis. These treatments are compared to hydroxyurea, which has concerns about long-term safety. While Elenestinib is mentioned, there is no direct evidence in the provided information about its effectiveness for blood cancers. ^{1 2 3 4 5}

What safety data exists for Elenestinib in blood cancers?

The provided research does not contain safety data for Elenestinib (BLU-263) or its other names like Azacitidine, Vidaza, or 5-azacytidine in blood cancers. The studies focus on other drugs and conditions, primarily related to breast cancer treatments. ^{6 7 8 9 10}

Is the drug Elenestinib (BLU-263) a promising treatment for blood cancers?

The information provided does not directly mention Elenestinib (BLU-263) or its effectiveness in treating blood cancers. Therefore, we cannot determine if it is a promising treatment based on the given data. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for people with advanced systemic mastocytosis or related blood cancers, who are not responding to current treatments. They must be able to perform daily activities (with varying degrees of difficulty), have a recent bone marrow biopsy, and agree to follow-up tests. It's not suitable for those already on effective cancer treatment.

Inclusion Criteria

My condition is aggressive systemic mastocytosis.

My blood cancer may respond to BLU-263 treatment, as discussed with the sponsor.

I stopped my cancer treatment in the last 12 weeks because it wasn't working or caused side effects.

Exclusion Criteria

I had major surgery less than 14 days before starting the study drug.

I have a serious heart condition that is not under control.

My cancer is Philadelphia chromosome positive.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive elenestinib (BLU-263) as monotherapy or in combination with azacitidine for 2 years

2 years

Monthly visits for the first six months, followed by quarterly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Quarterly visits

Treatment Details

Interventions

• Azacitidine
• Elenestinib (BLU-263)

Trial Overview The study is testing elenestinib (BLU-263) alone and combined with azacitidine in patients with advanced systemic mastocytosis. It aims to find the right dose, check safety and tolerability, and measure how well these treatments work over a period of up to four years.

Participant Groups

Group I: Monotherapy Experimental Treatment 1 Intervention

Participants with AdvSM (ASM, SM-AHN, or MCL) will receive BLU-263 monotherapy.

Group II: Combination therapy Experimental Treatment 2 Interventions

Participants with high risk and very high risk systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) of non-MC lineage will receive BLU-263 in combination with azacitidine.

Who Is Running the Clinical Trial?

Blueprint Medicines Corporation

Lead Sponsor

Trials

31

Recruited

6,000+

Findings from Research

In patients with myelofibrosis (MF) and the JAK2V617F mutation, there is a significant increase in SLAMF7high monocytes, which correlates with the severity of the mutation, suggesting these monocytes could serve as noninvasive markers for MF onset.

The anti-SLAMF7 antibody elotuzumab (Elo) not only inhibited fibrocyte differentiation in vitro but also showed potential therapeutic effects in reducing MF and splenomegaly in a mouse model, indicating its promise as a treatment for MPN patients with MF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab. Maekawa, T., Kato, S., Kawamura, T., et al.[2021]

Pegylated interferon (IFN), particularly ropeginterferon-α-2b, shows promise as a frontline therapy for high-risk polycythemia vera (PV), demonstrating efficient count control and tolerability in early-phase studies.

Novel therapies, including combinations of ruxolitinib and IFN, as well as MDM2 inhibitors, are being explored to potentially change the treatment approach for newly diagnosed PV patients from reactive to proactive interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapeutic approaches in polycythemia vera. Foucar, CE., Stein, BL.[2021]

In a study of 63 patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), elevated levels of PD-1 and PD-L1 were found in CD34+ progenitor cells, suggesting a potential target for therapy.

Despite no significant differences in PD-1 and PD-L1 levels among different MPN subtypes, the overall higher expression in stem cells indicates that PD-1 and PD-L1 pathway inhibitors could be a promising treatment avenue for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death Receptor (PD-1) Ligand (PD-L1) expression in Philadelphia chromosome-negative myeloproliferative neoplasms. Wang, JC., Chen, C., Kundra, A., et al.[2019]

In a double-blind trial involving 309 patients with intermediate-2 or high-risk myelofibrosis, ruxolitinib significantly reduced spleen volume by 35% or more in 41.9% of patients compared to only 0.7% in the placebo group, demonstrating its efficacy (P<0.001).

Ruxolitinib also improved overall survival, with a hazard ratio of 0.50 for death compared to placebo, while common side effects included anemia and thrombocytopenia, which were manageable and rarely led to discontinuation of the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. Verstovsek, S., Mesa, RA., Gotlib, J., et al.[2022]

The study established a preclinical model using JAK2-V617F transgenic mice to test drugs for myeloproliferative neoplasms, revealing that the JAK2-V617F mutation enhances erythropoiesis without affecting platelet or granulocyte levels.

When comparing treatments, the dual JAK1/JAK2 inhibitor INC424 effectively reduced spleen size and normalized red blood cell and neutrophil levels without significant weight loss, while hydroxyurea (HU) caused weight loss and increased JAK/STAT signaling, potentially counteracting its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model. Kubovcakova, L., Lundberg, P., Grisouard, J., et al.[2021]

Eribulin is an effective and safe third-line chemotherapy option for patients with advanced HER2-negative breast cancer, showing a median overall survival of 13.6 months and a median progression-free survival of 4 months in a study of 59 heavily pre-treated patients.

The treatment significantly reduced circulating tumor cells (CTCs) in patients, with lower baseline CTC levels correlating with longer overall survival, indicating that CTC dynamics may serve as a useful biomarker for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of eribulin as third-line chemotherapy in HER2-negative, advanced breast cancer pre-treated with taxanes and anthracycline: OnSITE study. Manso, L., Moreno Antón, F., Izarzugaza Perón, Y., et al.[2019]

A total of 1611 individual case safety reports were analyzed, revealing that palbociclib and ribociclib were associated with serious adverse drug reactions (ADRs) like leukopenia and thrombocytopenia, although most patients recovered from these conditions.

In contrast, abemaciclib was linked to mostly non-serious ADRs, indicating a potentially better safety profile, especially when combined with treatments like fulvestrant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematological Events Potentially Associated with CDK4/6 Inhibitors: An Analysis from the European Spontaneous Adverse Event Reporting System. Martins, V., Jesus, M., Pereira, L., et al.[2023]

Abemaciclib, used for treating advanced breast cancer, was generally well tolerated, with the most common adverse event being diarrhea, affecting 42.8% of patients, which was manageable with medications and dose adjustments.

Importantly, dose reductions or early onset of adverse events like diarrhea and neutropenia did not negatively impact progression-free survival, indicating that patients can continue treatment effectively despite these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Abemaciclib-Associated Adverse Events in Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Safety Analysis of MONARCH 2 and MONARCH 3. Rugo, HS., Huober, J., García-Sáenz, JA., et al.[2023]

Eribulin significantly improves overall survival in patients with locally advanced or metastatic breast cancer compared to non-eribulin treatments, with a hazard ratio of 0.77, indicating a 23% reduction in the risk of death.

The only notable adverse event associated with eribulin was an increased incidence of all-grade neutropenia, suggesting that while it has a manageable toxicity profile, monitoring for this side effect is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness and safety of eribulin in advanced or metastatic breast cancer: a systematic review and meta-analysis. Tanni, KA., Truong, CB., Johnson, BS., et al.[2021]

In the phase II PALOMA-1/TRIO-18 trial involving 165 postmenopausal women with advanced ER-positive, HER2-negative breast cancer, palbociclib combined with letrozole significantly improved progression-free survival (PFS) to 20.2 months compared to 10.2 months with letrozole alone, indicating its efficacy as a first-line treatment.

While Grade 3-4 neutropenia was the most common adverse event associated with the palbociclib and letrozole combination, the incidence of neutropenia decreased over time, and most patients did not experience severe infections, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. Finn, RS., Crown, JP., Ettl, J., et al.[2022]

In a Phase 1 study involving 57 patients with relapsed or refractory chronic or acute myeloid leukemia, rebastinib demonstrated safety with a maximum tolerated dose of 150 mg taken twice daily, but dose-limiting toxicities included dysarthria and muscle weakness.

Rebastinib showed some clinical activity, achieving complete hematologic responses in 8 out of 40 chronic myeloid leukemia patients, including 4 with the resistant T315I mutation, but overall clinical benefits were insufficient to warrant further development for these leukemias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia. Cortes, J., Talpaz, M., Smith, HP., et al.[2019]

Bosutinib is an effective treatment for chronic myeloid leukemia, particularly in patients who have developed resistance or intolerance to other tyrosine kinase inhibitors, demonstrating sustained efficacy in the chronic phase of the disease.

The safety profile of bosutinib includes distinct but manageable side effects, and it can be used without absolute contraindications in most patients, except those with specific mutations (T315I and V299L).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib: a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia. Rassi, FE., Khoury, HJ.[2021]

Bosutinib is an effective oral treatment for chronic myeloid leukemia (CML) that works against all phases of the disease, except for cases with specific mutations (T315I or V299LABL).

The drug is well tolerated with a manageable toxicity profile, and its absorption is enhanced when taken with food, showing dose-proportional increases in plasma concentration from 200 to 800 mg.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib. Abbas, R., Hsyu, PH.[2022]

Bosutinib is a dual inhibitor of Src and Abl kinases, showing strong efficacy against the Bcr-Abl fusion protein, which is critical in chronic myeloid leukaemia (CML), with lower concentrations needed to inhibit Bcr-Abl phosphorylation compared to imatinib.

In ongoing clinical trials, bosutinib has demonstrated effectiveness in CML patients who are resistant or intolerant to imatinib, and it is currently being compared to imatinib in a phase III study for first-line therapy in CML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib. Keller, G., Schafhausen, P., Brümmendorf, TH.[2017]

In a phase 2 study involving 67 patients with Philadelphia chromosome-negative myeloid disorders, dasatinib showed a 33% overall response rate in patients with systemic mastocytosis, particularly benefiting those without the KIT-D816V mutation.

While dasatinib improved symptoms for some patients, it did not lead to complete disease elimination in those with the KIT-D816V mutation, indicating that its efficacy may be limited based on genetic factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis. Verstovsek, S., Tefferi, A., Cortes, J., et al.[2021]

References

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

Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab. [2021]

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

Novel therapeutic approaches in polycythemia vera. [2021]

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

Programmed Cell Death Receptor (PD-1) Ligand (PD-L1) expression in Philadelphia chromosome-negative myeloproliferative neoplasms. [2019]

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

A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. [2022]

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

Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model. [2021]

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

Safety of eribulin as third-line chemotherapy in HER2-negative, advanced breast cancer pre-treated with taxanes and anthracycline: OnSITE study. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Hematological Events Potentially Associated with CDK4/6 Inhibitors: An Analysis from the European Spontaneous Adverse Event Reporting System. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Management of Abemaciclib-Associated Adverse Events in Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Safety Analysis of MONARCH 2 and MONARCH 3. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Comparative effectiveness and safety of eribulin in advanced or metastatic breast cancer: a systematic review and meta-analysis. [2021]

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

Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. [2022]

11. Italy pubmed.ncbi.nlm.nih.gov

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia. [2019]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Bosutinib: a SRC-ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia. [2021]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib. [2022]

14. Germany pubmed.ncbi.nlm.nih.gov

Bosutinib. [2017]

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

Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis. [2021]