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

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, Phase 2/3 study comparing the efficacy and safety of 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 BLU-263 in an open-label fashion following completion of the earlier Part. Part M will enroll patients with monoclonal mast cell activation syndrome (mMCAS). The study also includes PK groups that will enroll patients with ISM.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study of BLU-263 in Indolent Systemic Mastocytosis

Conditions
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Indolent Systemic Mastocytosis, Monoclonal Mast Cell Activation Syndrome

Intervention / Treatment
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* Drug: BLU-263
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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. Key Exclusion Criteria: 1. Patient has been diagnosed with any of the following WHO systemic mastocytosis (SM) sub-classifications: cutaneous mastocytosis only, smoldering SM, SM with associated hematologic neoplasm, 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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In Part 1 of the study, patients with ISM will be randomly assigned to 1 of 3 doses of BLU-263 + BSC or to placebo + BSC. Once the recommended dose (RD) of BLU-263 is identified in Part 1, patients with ISM in Part 2 will be randomly assigned to receive BLU-263 at the RD + BSC or matching placebo + BSC. Patients will be randomized 2:1 to BLU-263:placebo. In Part 3, patients who have completed treatment in Part 1 or Part 2 of the study (including those initially randomized to placebo) will participate in a long-term open-label extension, receiving BLU-263 at the RD + BSC. In Part M of the study patients with monoclonal mast cell activation syndrome will receive BLU-263 + BSC at the RD in an open-label fashion. The study also includes PK groups that will enroll patients with ISM
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (Part 1) BLU-263 Dose 1 + BSC<br>Patients will receive best supportive care (BSC) and Dose 1 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1. | Drug: BLU-263<br>* BLU-263 tablet<br>|
| Experimental: (Part 1) BLU-263 Dose 2 + BSC<br>Patients will receive best supportive care (BSC) and Dose 2 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1. | Drug: BLU-263<br>* BLU-263 tablet<br>|
| Experimental: (Part 1) BLU-263 Dose 3 + BSC<br>Patients will receive best supportive care (BSC) and Dose 3 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily until completion of Part 1. | Drug: BLU-263<br>* BLU-263 tablet<br>|
| Placebo Comparator: (Part 1) Placebo + BSC<br>Patients will receive best supportive care (BSC) and matching placebo tablets. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily until completion of Part 1 | Drug: Placebo<br>* Placebo Tablet<br>|
| Experimental: (Part 2) BLU-263 RD + BSC<br>Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily for approximately 24 weeks | Drug: BLU-263<br>* BLU-263 tablet<br>|
| Placebo Comparator: (Part 2) Placebo + BSC<br>Patients will receive best supportive care (BSC) and matching placebo tablets. BSC will be determined on a per patient basis. Placebo will be administered orally, once daily once daily for approximately 24 weeks | Drug: Placebo<br>* Placebo Tablet<br>|
| Experimental: (Part 3) BLU-263 RD + BSC<br>Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablet in an open-label fashion for up to 5 years. | Drug: BLU-263<br>* BLU-263 tablet<br>|
| Experimental: (Part M) BLU-263 RD + BSC<br>Patients will receive best supportive care (BSC) and the recommended dose (RD) of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally, once daily for the duration of participation in the study. | Drug: BLU-263<br>* BLU-263 tablet<br>|
| Experimental: PK Groups (Dose 2 or Dose 3)<br>Patients will receive best supportive care (BSC) and Dose 2 or Dose 3 of BLU-263 tablets. BSC will be determined on a per patient basis. BLU-263 will be administered orally for the duration of participation in the study. | Drug: BLU-263<br>* BLU-263 tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Recommended Dose (RD) in patients with ISM | Selection of the RD to be used in Part 2, Part 3 and Part M of the study | 3 months | 
| Part 2: Proportion of responders, defined as ≥30% reduction in ISM-Symptom in Assessment Form (ISM-SAF) Total Symptom Score (TSS) | Response rate in patients with ISM | 6 months | 
| Part 3: Long-term safety and tolerability of BLU-263 as assessed by the number of adverse events and serious adverse events |  | up to 5 years | 
| Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) | The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Mean change in measures of mast cell burden |  | 3 Months | 
| Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) | The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms | 3 Months | 
| Part 1: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores | Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms | 3 months | 
| Part 1: Time to achieve 30% reduction inIndolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) scores | Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-110 and a lower score represents lower symptom burden | 3 months | 
| Part 2: Proportion of patients with a ≥50% reduction in serum tryptase |  | 6 months | 
| Part 2: The proportion of patients who achieve at least a 50% reduction in peripheral blood KIT D816V allele fraction, or a reduction to undetectable levels. |  | 6 months | 
| Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Total Symptom Score (TSS) | The ISM-SAF has a scale of 0-110. A decrease in score corresponds to improvement in symptoms | 6 months | 
| Part 2: Proportion of patients with a ≥50% reduction in bone marrow mast cells or reduction to no aggregates for patients with aggregates at Baseline |  | 6 months | 
| Part 2: Mean change in measures of mast cell burden |  | 6 months | 
| Part 2: Change in number of best supportive care medications |  | 6 Months | 
| Part 2: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom scores | Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms | 6 months | 
| Part 2: Change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) leading symptom score | Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms | 6 months | 
| Part 2: Time to achieve 30% reduction in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) scores | Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-10 and a lower score represents lower symptom burden | 6 months | 
| Part 2: Mean change in the Mast Cell Quality of Life (MC-QoL) score | The MC-QoL has a scale of 0-100, higher numbers represent more severe impairment to quality of life. | 6 months | 
| Part 2: Safety of BLU-263 as assessed by number of adverse events and serious adverse events |  | up to 5 years | 
| Part 3: Mean change in measures of mast cell burden |  | approximately 5 years | 
| Part 3: Change in number of best supportive care medications |  | approximately 5 years | 
| Part 3: Mean change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) individual symptom score | Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms | approximately 5 years | 
| Part 3: Change in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) leading symptom score | Each symptom in the ISM-SAF has a scale of 0-10. A decrease in score corresponds to improvement in symptoms | approximately 5 years | 
| Part 3: Mean change in the Mast Cell Quality of Life (MC-QoL) score | The MC-QoL has a scale of 0-100, higher numbers represent more severe impairment to quality of life. | approximately 5 years | 
| Part 3: Time to achieve 30% reduction in Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) Scores | Time to achieve a 30% reduction in scores generated by the ISM-SAF. The ISM-SAF uses a score from 0-110 and a lower score represents lower symptom burden | 12 months |