(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis

Blueprint Medicines

Status and phase: Enrolling; Phase 3; Phase 2

Conditions: Monoclonal Mast Cell Activation Syndrome; Smoldering Systemic Mastocytosis; Indolent Systemic Mastocytosis

Treatments: Drug: Placebo; Drug: Elenestinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT04910685

BLU-263-1201

Details and patient eligibility

About

This is a randomized, double-blind, placebo-controlled, Phase 2/3 study comparing the efficacy and safety of elenestinib (BLU-263) + best supportive care (BSC) with placebo + BSC in patients with indolent systemic mastocytosis (ISM) whose symptoms are not adequately controlled by BSC. Parts 1 and 2 will enroll patients with ISM. Patients enrolled in Part 1 or Part 2 will roll over onto Part 3 to receive treatment with elenestinib in an open-label fashion following completion of the earlier Part. Part M will enroll patients with monoclonal mast cell activation syndrome (mMCAS). Part S will enroll participants with smoldering systemic mastocytosis (SSM). The study also includes PK groups that will enroll patients with ISM.

Enrollment: 463 estimated patients

Sex: All

Ages: 16+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria:

All Patients

-1. Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2.

Part 1 and Part 2

• 2. Patient must have moderate-to-severe symptoms based on minimum mean total symptom score (TSS) of the ISM Symptom Assessment Form (ISM-SAF) over the 14-day eligibility screening period.
• 3. Patient has confirmed diagnosis of ISM, confirmed by Central Pathology Review of BM biopsy and central review of B- and C-findings by WHO diagnostic criteria. Archival biopsy may be used if completed within the past 12 months.
• 4. Patient must have failed to achieve adequate symptom control for 1 or more Baseline symptoms, as determined by the Investigator, with at least 2 of the following symptomatic therapies administered: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
• 5. Patients must have BSC for ISM symptom management stabilized for at least 14 days prior to starting screening procedures.
• 6. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days.

Part M

• 7. Patients must have mMCAS, confirmed by Central Pathology Review of BM biopsy. An archival biopsy may be used if completed within the past 12 months.
• 8. Patients must have tryptase < 20 ng/mL.
• 9. Patients must have KIT D816V in peripheral blood (PB) or BM and/or CD25+ Mast cells in BM.
• 10. Patients must have symptoms consistent with mast cell activation (despite BSC) in at least two organ systems characterized by cutaneous flushing, tachycardia, syncope, hypotension, diarrhea, nausea, vomiting and gastro-intestinal cramping) and serum blood tryptase (sBT) levels above 8 ng/mL OR Severe (Ring and Messmer grading ≥ II, recurrent anaphylaxis, including but not limited to hymenoptera venom, drug or food, regardless of sBT levels.

PK Groups

• 11. See inclusion criteria for All patients and Part 1/Part 2
• 12. Accrual may be limited to patients who have specific disease manifestations (ie, GI involvement) or are taking acid-reducing agents to better explore the impact of these features on PK.

Part S:

-13. Patient has confirmed diagnosis of SSM, confirmed by Central Pathology Review of BM biopsy and central review of B- and C-findings by WHO 2022 diagnostic criteria.

Key Exclusion Criteria:

• 1. Patient has been diagnosed with any of the following WHO systemic mastocytosis (SM) sub-classifications: cutaneous mastocytosis only, SM with an associated hematologic neoplasm of non-MC lineage (SM-AHN), aggressive SM, mast cell leukemia, or mast cell sarcoma.
• 2. Patient has been diagnosed with another myeloproliferative disorder.
• 3. Patient has organ damage C-findings attributable to SM.
• 4. Patient has clinically significant, uncontrolled, cardiovascular disease
• 5. Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480 msec.
• 6. Patient has previously received treatment with any targeted KIT inhibitors.
• 7. Patient has a history of a primary malignancy that has been diagnosed or required therapy within 3 years. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
• 8. Time since any cytoreductive therapy including mastinib and midostaurin should be at least 5 half-lives or 14 days (whichever is longer), and for cladribine, interferon alpha, pegylated interferon, or antibody therapy < 28 days or 5 half-lives of the drug (whichever is longer), before beginning the screening period.
• 9.Patient has received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before beginning the screening period.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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463 participants in 10 patient groups, including a placebo group

(Part 1) Elenestinib Dose 1 + BSC

Experimental group

Description:

Patients will receive best supportive care (BSC) and Dose 1 of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally, once daily until completion of Part 1.

Treatment:

Drug: Elenestinib

(Part 1) Elenestinib Dose 2 + BSC

Experimental group

Description:

Patients will receive BSC and Dose 2 of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally, once daily until completion of Part 1.

Treatment:

Drug: Elenestinib

(Part 1) Elenestinib Dose 3 + BSC

Experimental group

Description:

Patients will receive BSC and Dose 3 of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally, once daily until completion of Part 1.

Treatment:

Drug: Elenestinib

(Part 1) Placebo + BSC

Placebo Comparator group

Description:

Patients will receive BSC and matching placebo. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily until completion of Part 1

Treatment:

Drug: Placebo

(Part 2) Elenestinib RD + BSC

Experimental group

Description:

Patients will receive BSC and the recommended dose (RD) of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally, once daily for approximately 24 weeks

Treatment:

Drug: Elenestinib

(Part 2) Placebo + BSC

Placebo Comparator group

Description:

Patients will receive BSC and matching placebo. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily once daily for approximately 24 weeks

Treatment:

Drug: Placebo

(Part 3) Elenestinib RD + BSC

Experimental group

Description:

Patients will receive open-label BSC and the RD of elenestinib for up to approximately 4 years.

Treatment:

Drug: Elenestinib

(Part M) Elenestinib RD + BSC

Experimental group

Description:

Patients will receive BSC and the RD of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally, once daily for the duration of participation in the study.

Treatment:

Drug: Elenestinib

PK Groups (Dose 2 or Dose 3)

Experimental group

Description:

Patients will receive BSC and Dose 2 or Dose 3 of elenestinib. BSC will be determined on a per patient basis. Elenestinib will be administered orally for the duration of participation in the study.

Treatment:

Drug: Elenestinib

(Part S) Elenestinib + BSC

Experimental group

Description:

Participants with Smoldering Systemic Mastocytosis (SSM) will receive open-label BSC and elenestinib for up to approximately 4 years.

Treatment:

Drug: Elenestinib