Elenestinib for Blood Cancers

(AZURE Trial)

No longer 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called elenestinib (BLU-263) for individuals with certain blood cancers, such as advanced systemic mastocytosis (AdvSM) and related conditions. Researchers aim to determine the optimal dose, assess its safety, and evaluate its effectiveness. Participants will be divided into two groups: one will receive elenestinib alone, while the other will receive it with azacitidine, a chemotherapy drug. Suitable candidates have blood cancer that did not respond well to previous treatments or have a specific genetic mutation called KIT D816V. 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 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.

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

Research shows that elenestinib, when used alone, is generally safe and well-tolerated by patients. In earlier studies, elenestinib reduced symptoms in patients with systemic mastocytosis and managed side effects effectively. Some patients experienced unwanted effects, but these were mostly manageable and less severe than those from traditional treatments.

The combination of elenestinib with azacitidine remains under study. Early trials are examining patient tolerance of this mix, aiming to treat blood cancers more effectively. While specific safety information is still being gathered, researchers are closely monitoring for any side effects to ensure patient safety.

Both treatments are in the early stages of clinical trials, focusing on understanding safety and dosage. This phase is crucial to observe patient responses and to identify and address any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for advanced systemic mastocytosis, like midostaurin and imatinib, which generally target multiple pathways, Elenestinib (BLU-263) is unique because it specifically targets the KIT D816V mutation. This mutation is present in the majority of cases, making Elenestinib potentially more precise and effective. Researchers are also excited about its potential versatility, as it can be used both as a monotherapy and in combination with azacitidine to address different risk profiles within blood cancers. This targeted approach could lead to better outcomes and fewer side effects for patients.

What evidence suggests that elenestinib (BLU-263) could be an effective treatment for blood cancers?

Research has shown that elenestinib targets a common change in systemic mastocytosis (SM) called KIT D816V, present in about 95% of cases. This change causes abnormal mast cell growth, and elenestinib works to halt this growth. Earlier studies found that elenestinib may improve symptoms and is safer than traditional treatments. In this trial, some participants will receive elenestinib as monotherapy.

For the combination of elenestinib and azacitidine, research is ongoing, but this mix is under study in this trial for its potential to be more effective in treating advanced cases. Azacitidine is known to slow cancer cell growth, and when combined with elenestinib, it might offer a stronger treatment against these blood cancers. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05609942

Study of Elenestinib (BLU-263) in Advanced Systemic ... The goal of this clinical trial is to evaluate elenestinib (BLU-263) in participants with Advanced Systemic Mastocytosis (AdvSM), SM with an associated ...

2. onclive.com onclive.com/view/elenestinib-may-be-safer-than-traditional-kit-inhibitors-in-indolent-systemic-mastocytosis

Elenestinib May Be Safer Than Traditional KIT Inhibitors in ... Tsewang Tashi, MD, discusses how elenestinib could be an effective option with a manageable safety profile in ISM.

3. blueprintmedinfo.com blueprintmedinfo.com/uploads/Livindeanu-et-al._Harbor-TiP-poster_EACCI_FINAL-1.pdf

HARBOR: A phase 2/3 study of elenestinib (BLU-263) in ... Systemic mastocytosis (SM) is a clonal mast cell disease driven by the. KIT D816V mutation in ~95% of cases1–5. • The KIT D816V mutation leads to increased ...

4. rarediseaseadvisor.com rarediseaseadvisor.com/news/new-clinical-trial-will-investigate-blu-263-efficacy-and-safety-in-advanced-sm/

New Clinical Trial Will Investigate BLU-263 Efficacy and ... A new phase 1/2, open-label, 2-arm study (AZURE) will investigate the efficacy and safety of BLU-263 in patients with advanced systemic mastocytosis (SM)

5. blueprintmedicines.com blueprintmedicines.com/wp-content/uploads/2023/12/Blueprint-Medicines-ASH-2023-Elenestinib-Systemic-Mastocytosis-HARBOR-Trial-Analysis-Oral-Presentation-2.pdf

Elenestinib, an Investigational, Next Generation KIT D816V ... Targeting KIT D816V in Indolent Systemic Mastocytosis results in deepening symptom improvement. -3.0. -2.5. -2.0. -1.5. -1.0. -0.5. 0.0. Avapritinib 25 mg QD, ...

6. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/76/503377/Elenestinib-an-Investigational-Next-Generation-KIT

Elenestinib, an Investigational, Next Generation KIT D816V ... Elenestinib, an investigational, next generation KIT D816V inhibitor, reduces mast cell burden, improves symptoms, and has a favorable safety profile in ...

7. jacionline.org jacionline.org/article/S0091-6749(21)02544-6/fulltext

A Phase 2/3 Study of BLU-263 in Patients with Indolent ... Systemic mastocytosis (SM) is a rare, clonal mast cell neoplasm driven by the KIT D816V mutation in ∼95% of cases. Indolent SM (ISM) is characterized by ...