(PIONEER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, Versus Placebo in Patients With Indolent Systemic Mastocytosis

Study Overview
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Brief Summary
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This is a Phase 2, randomized, double-blind, placebo-controlled study comparing the efficacy and safety of avapritinib + best supportive care (BSC) with placebo + BSC in patients with indolent systemic mastocytosis (ISM) whose symptoms are not adequately controlled by BSC. The study will be conducted in 3 parts. All patients will receive treatment with avapritinib during Part 3 including those rolling over from the placebo group.

Official Title
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A 3-Part, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Evaluate Safety and Efficacy of Avapritinib (BLU-285), a Selective KIT Mutation-Targeted Tyrosine Kinase Inhibitor, in Indolent and Smoldering Systemic Mastocytosis With Symptoms Inadequately Controlled With Standard Therapy

Conditions
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Indolent Systemic Mastocytosis

Intervention / Treatment
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* Drug: Avapritinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 1. Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and central review of B- and C-findings by WHO diagnostic criteria. 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 must have failed to achieve adequate symptom control for 1 or more Baseline symptoms. 4. For patients receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days. 5. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2. Key Exclusion Criteria: 1. Patient has been diagnosed with any of the following WHO SM subclassifications: cutaneous mastocytosis only, smoldering SM, SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia, or mast cell sarcoma. 2. Patient must not have received prior treatment with avapritinib. 3. Patient must not have had any cytoreductive therapy including but not limited to masitinib and midostaurin, or investigational agent for < 14 days or 5 half-lives of the drug (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 14-day ISM-SAF eligibility TSS assessment. 4. Patient must not have received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment. 5. Patient must not have received any hematopoietic growth factor the preceding 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment. 6. Patient must not have a QT interval corrected using Fridericia's formula (QTcF) of > 480 msec.

Ages Eligible for Study
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Minimum Age: 18 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 will be randomly assigned to 1 of 3 doses of avapritinib or to placebo + BSC. Once the recommended phase 2 dose (RP2D) of avapritinib is identified in Part 1, patients in Part 2 will be randomly assigned to receive avapritinib at the RP2D + BSC or matching placebo + BSC. In Part 3, patients who have completed treatment in Part 1 or Part 2 of the study (including those initially randomized to placebo) may participate in a long-term open-label extension, receiving avapritinib at the RP2D + BSC.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (Part 1) Avapritinib Dose 1 + BSC<br>Avapritinib will be administered orally in continuous 28-day cycles | Drug: Avapritinib<br>* Avapritinib tablet<br>* Other names: BLU-285;|
| Experimental: (Part 1) Avapritinib Dose 2 + BSC<br>Avapritinib will be administered orally in continuous 28-day cycles | Drug: Avapritinib<br>* Avapritinib tablet<br>* Other names: BLU-285;|
| Experimental: (Part 1) Avapritinib Dose 3 + BSC<br>Avapritinib will be administered orally in continuous 28-day cycles | Drug: Avapritinib<br>* Avapritinib tablet<br>* Other names: BLU-285;|
| Placebo Comparator: (Part 1) Placebo + BSC<br>Placebo will be administered orally in continuous 28-day cycles | Drug: Placebo<br>* Placebo tablet<br>|
| Experimental: (Part 2) Avapritinib RP2D + BSC<br>Avapritinib will be administered orally in continuous 28-day cycles | Drug: Avapritinib<br>* Avapritinib tablet<br>* Other names: BLU-285;|
| Placebo Comparator: (Part 2) Placebo + BSC<br>Placebo will be administered orally in continuous 28-day cycles | Drug: Placebo<br>* Placebo tablet<br>|
| Experimental: (Part 3) Avapritinib RP2D + BSC<br>Avapritinib will be administered orally in continuous 28-day cycles | Drug: Avapritinib<br>* Avapritinib tablet<br>* Other names: BLU-285;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Recommended Phase 2 dose (RP2D) in patients with ISM |  | 9 months | 
| Part 2: Mean change in ISM Symptom Assessment Form (ISM-SAF) total symptom score (TSS) as compared to placebo | 0 - 110 points (higher value represents worse symptom outcomes) | 6 months | 
| Part 3: Number of Participants with Adverse Events |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Proportion of patients with a ≥50% reduction in serum tryptase |  | 6 months | 
| Part 2: Proportion of patients with a ≥50% reduction in peripheral blood V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog aspartate 816 valine (KIT D816V) allele fraction or undetectable for patients with detectable mutation at Baseline |  | 6 months | 
| Part 2: Proportion of patients with ≥50% reduction in ISM-SAF TSS |  | 6 months | 
| Part 2: Proportion of patients with ≥30% reduction in ISM-SAF TSS |  | 6 months | 
| Part 2: Proportion of patients with a ≥50% reduction in bone marrow mast cells or no aggregates for patients with aggregates at Baseline |  | 6 months | 
| Parts 1, 2, and 3: Change in serum tryptase |  | Up to 5 years | 
| Parts 1, 2, and 3: Change in KIT D816V allele burden in blood |  | Up to 5 years | 
| Parts 1, 2, and 3: Change in bone marrow mast cells |  | Up to 5 years | 
| Parts 1, 2, and 3: Change in best supportive care (BSC) concomitant medication usage |  | Up to 5 years | 
| Parts 1, 2, and 3: Change from Baseline in ISM-SAF Score |  | Up to 5 years | 
| Parts 1, 2, and 3: Change in Mastocytosis Quality of Life Questionnaire (MC-QoL) |  | Up to 5 years | 
| Parts 1, 2, and 3: Change in Patient's Global Impression of Symptom Severity (PGIS) |  | Up to 5 years | 
| Parts 1, 2, and 3: Change in 12-item Short Form Health Survey (SF-12) | 0 - 100 points (higher value represents better symptom outcomes) | Up to 5 years | 
| Parts 1, 2, and 3: Change in Patients' Global Impression of Change (PGIC) | 1 - 7 (higher value represents worse symptom outcomes) | Up to 5 years | 
| Parts 1, 2, and 3: Change in EuroQuol 5 Dimensions 5 Levels (EQ 5D-5L) | 0 - 100 (higher value represents better symptom outcomes) | Up to 5 years | 
| Parts 1, 2, and 3: Safety of avapritinib as assessed by number of adverse events | CTCAE version 5.0 | Up to 5 years |