Evaluation of BLU-263 Monotherapy and BLU-263 Combined with Azacitidine in Patients with KIT-Altered Advanced Systemic Mastocytosis

Trial ID: 2023-510144-20-00
Protocol: BLU-263-2101
Sponsor: Blueprint Medicines Corp.

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Diseases & Conditions

Systemic mastocytosis

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of **BLU-263** as a monotherapy and in combination with **azacitidine** in patients with Advanced Systemic Mastocytosis (AdvSM) and other KIT-altered hematologic malignancies. This is crucial for determining the recommended dose (RD) for both monotherapy and combination therapy, which is essential for optimizing treatment regimens and minimizing adverse effects in this patient population.

Secondary objectives include:

Monotherapy (Arm 1): Assessing the objective response rate (ORR), characterizing the pharmacokinetic (PK) profile of BLU-263, determining overall survival (OS), and evaluating additional measures of clinical efficacy.
Combination (Arm 2): Assessing the ORR, evaluating the pure pathological response (PPR) rate for systemic mastocytosis (SM) when BLU-263 is combined with azacitidine, and assessing the PK of both BLU-263 and azacitidine when administered alone and in combination.

Participants

The clinical trial involves a total of **19 participants** diagnosed with **Advanced Systemic Mastocytosis**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific inclusion criteria, including an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and a confirmed diagnosis of Advanced Systemic Mastocytosis according to World Health Organization (WHO) diagnostic criteria. The trial population includes individuals who have previously received antineoplastic therapy and have discontinued due to disease progression, refractory disease, lack of efficacy, or intolerance. Participants may have been treated with one prior selective KIT inhibitor, provided they meet certain genetic mutation criteria. The study also considers lifestyle factors such as the ability to undergo bone marrow biopsies. The trial includes a vulnerable population, ensuring careful consideration of ethical standards in participant selection and treatment. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed as a **Phase 1/2**, open-label, two-arm study evaluating the efficacy and safety of **BLU-263** as monotherapy and in combination with **azacitidine** in patients with **KIT** altered hematologic malignancies, specifically focusing on **Advanced Systemic Mastocytosis** (AdvSM). The trial employs a dose escalation and expansion approach to determine the recommended dose (RD) and assess the safety, tolerability, and clinical efficacy of the investigational treatments. The study is not categorized as low intervention and is expected to conclude by November 2030, with recruitment having commenced in March 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as **Eastern Cooperative Oncology Group (ECOG)** performance status and recent bone marrow biopsy results. The trial includes two arms: Arm 1 for monotherapy with BLU-263 and Arm 2 for combination therapy with BLU-263 and azacitidine. Each arm will have dose escalation and expansion phases, with primary endpoints focusing on determining the RD and evaluating the safety profile through the assessment of dose-limiting toxicities (DLTs) and adverse events (AEs).

Follow-up visits will be scheduled to monitor participants' response to treatment, including assessments of pharmacokinetic parameters, overall response rate, and safety evaluations through vital signs, ECGs, and laboratory tests. The end-of-study visit will conclude the participant's involvement, which is expected to last until the trial's completion or until early termination conditions are met, such as severe adverse events or withdrawal of consent. Participants who have received prior selective KIT inhibitors may be eligible for the study, provided they meet specific inclusion criteria and have not discontinued previous treatments due to severe adverse events related to those treatments.

Treatment

The clinical trial involves the administration of **Azacitidine**, an experimental medication used in combination therapy. Azacitidine is provided in the form of a **powder for suspension for injection**. The administration routes for Azacitidine are **intravenous (IV)** or **subcutaneous (SC)**. The frequency and dosage of administration are determined based on the specific requirements of the trial protocol, with the aim of evaluating its efficacy and safety in combination with other treatments. Azacitidine is not a pediatric formulation and is classified as a chemical medicinal product.

Another experimental medication used in this trial is **BLU-263 Phosphate**, which is administered as a **film-coated tablet**. The route of administration for BLU-263 Phosphate is **oral**. This medication is evaluated both as a monotherapy and in combination with Azacitidine. The trial aims to determine the recommended dose (RD) for BLU-263 Phosphate and assess its safety, tolerability, and clinical efficacy in patients with KIT-altered hematologic malignancies. BLU-263 Phosphate is also classified as a chemical medicinal product and is not formulated for pediatric use. The trial includes monitoring of participant compliance to ensure adherence to the dosing schedule and to evaluate the outcomes accurately.

Efficacy

The clinical trial will assess the efficacy of **BLU-263** as monotherapy and in combination with **azacitidine** in patients with KIT-altered hematologic malignancies. The primary endpoints for efficacy evaluation include the determination of the recommended dose (RD) based on the number of dose-limiting toxicities (DLTs) observed during the initial 28 days of treatment for both monotherapy and combination therapy arms. Additionally, the safety profile will be assessed by monitoring adverse events (AEs) and serious adverse events (SAEs), along with changes in vital signs, electrocardiograms (ECGs), and safety laboratory tests.

Secondary endpoints include the overall response rate for advanced systemic mastocytosis (AdvSM) and systemic mastocytosis (SM) using the modified International Working Group Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (mIWG-MRT-ECNM) criteria. Pharmacokinetic parameters of BLU-263, such as maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under the curve (AUC0-24), volume of distribution (Vz/F), half-life (t½), clearance (CL/F), and accumulation ratio, will also be evaluated. Additional secondary endpoints include overall survival, time-to-response, duration of response (DOR), progression-free survival (PFS), and the proportion of patients pursuing stem cell transplant.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Key Inclusion Criteria : - Participant has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 - Participant must have a new Bone Marrow (BM) biopsy or may use archival tissue if taken within 56 days prior to C1D1 and participant must be willing to have follow-up BM Biopsies. - Participants receiving antineoplastic therapy within the preceding 12 weeks must have discontinued therapy due to disease progression, refractory disease, lack of efficacy, or intolerance. - Participants treated with 1 prior selective KIT inhibitor (such as avapritinib or CGT9486) will be permitted on study after confirmation of KIT D816V mutation and with written approval of the study Sponsor. Participants who discontinued treatment with a prior selective KIT inhibitor due to a severe AE that was thought to be related to prior treatment will not be eligible to participate in the study. Arm 1 (Monotherapy): Participants must have one of the following AdvSM diagnoses, based on World Health Organization (WHO) diagnostic criteria. Before enrollment, diagnosis of AdvSM must be confirmed based on Central Pathology Laboratory assessment of BM: 1. Aggressive SM (ASM). 2. SM-AHN that in the opinion of the Investigator is not considered to be a candidate for Hypomethylating agent (HMA) monotherapy. Incidental indolent, low-grade lymphoid AHNs (eg, chronic lymphocytic leukemia) not requiring treatment are eligible. 3. Mast cell leukemia (MCL), including diagnoses with an AHN component, that does not require a C-finding. 4. Upon discussion with the Sponsor, other relapsed or refractory hematologic neoplasms with evidence of aberrant KIT or PDGFR may be considered for enrollment. (eg, participants with chronic myeloid neoplasms, such as subvariants of MDS/MPN that harbor activating KIT exon 17 mutations but do not fulfill the diagnostic criteria of SM-AHN, and participants with myeloid/lymphoid neoplasms with PDGFRa/b fusion genes and mutations conferring resistance to imatinib, such as T674I or D842V). Arm 2 (Combination Therapy): A2_1. For Arm 2, patients must have an SM-AHN diagnoses, based on WHO diagnostic criteria. Diagnosis of the AHN component of SM-AHN must be confirmed based on the central pathology laboratory assessment of the BM. Upon discussion with the Sponsor hematologic neoplasms which are felt to have strong rationale to consider the combination treatment of BLU-263 and HMA may be considered for enrollment.

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Exclusion Criteria

Key Exclusion Criteria: - Diagnosis of a Philadelphia chromosome positive malignancy - Acute myeloid leukemia. - If the participant is receiving corticosteroids, and the dose has not been stable for ≥7 days. - Within the 14 days prior to enrollment, participant has received any antineoplastic therapy (including midostaurin, avapritinib and other tyrosine kinase inhibitors [TKIs]) or an investigational agent. - Participant has received hydroxyurea within 7 days prior to the first dose of elenestinib (BLU-263). - Participant received prior HMA therapy (e.g., azacitidine, decitabine) for the current diagnosis. - Participant must not be eligible for allogenic hematopoietic stem cell transplantation. - Participant received prior radiotherapy within 14 days of screening BM biopsy. - Participant received any hematopoietic growth factor (except erythropoietin) within 14 days of screening BM biopsy, or requiring growth factors to maintain adequate neutrophil or platelet levels. Those participants maintained on a chronic dose of erythropoietin, whose hemoglobin is stable, and dose of erythropoietin has not been changed in the prior 28 days are allowed on study. - Participant received >1 prior selective KIT inhibitor (eg: avapritinib or bezuclastinib). - Participant have any of the following laboratory abnormalities on last laboratory assessment within 14 days prior to the first dose of initiation of study drug: a. Alanine aminotransferase and aspartate aminotransferase > 3 × ULN; > 5 × ULN if associated with clinically suspected liver infiltration by mastocytosis or another disease for which the patient enrolled into the study b. Total bilirubin > 1.5 × ULN; > 3 × ULN if associated with liver infiltration by the disease being treated or in the presence of Gilbert's Disease. (In the case of Gilbert's disease, a direct bilirubin > 2.0 ULN would be an exclusion) c. Estimated (Cockcroft-Gault formula) or measured creatinine clearance < 40 mL/min d. Absolute neutrophil count < 0.5 × 10^9/L - Participant has had a major surgical procedure within 14 days of the first dose of study drug. - History of another primary malignancy that has been diagnosed or required therapy within 1 year prior to the first dose of study drug. The following are exempt from the 1-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, GI stromal tumor, and completely resected carcinoma in situ of any site. - Mean resting QTcF > 480 msec, a history of prolonged QT syndrome or Torsades de pointes, or a familial history of prolonged QT syndrome. - Clinically significant, uncontrolled, cardiovascular disease. Arm 1 (Monotherapy): - Myelodysplastic Syndrome (MDS) that is very high- or high-risk as defined by the International Prognostic Scoring System for Myelodysplastic Syndromes-Revised (IPSS-R). - A myeloid AHN with ≥10% BM or peripheral blood blasts. - Platelet count <50 x 10^9/L (within 4 weeks prior to the first dose of study drug) or receiving platelet transfusions or thrombopoietin receptor agonists (TPO-RA) within the prior 14 days. Arm 2 (Combination Therapy): A2_1. Intermediate, low, or very low risk MDS. A2_2. Known hypersensitivity to azacitidine or any of their ingredients. A2_3. Platelet count < 75 x 109/L (within 4 weeks of the first dose of study drug) or receiving platelet transfusions or TPO-RA within the prior 14 days.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	29 Mar 2023	9
France	Not Recruiting	29 Mar 2023	8
Germany	Not Recruiting	29 Mar 2023	11
The Netherlands	Not Recruiting	29 Mar 2023	—
Norway	Not Recruiting	29 Mar 2023	5
Spain	Not Recruiting	29 Mar 2023	4
Netherlands	—	—	4