(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

Phase 2Active Not RecruitingNCT03731260

Blueprint Medicines Corporation251 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

251

Conditions

Indolent Systemic Mastocytosis

Interventions

AvapritinibDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Part 1: Recommended Phase 2 dose (RP2D) in patients with ISM

Time frame: 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)

Time frame: 6 months

Part 3: Number of Participants with Adverse Events

Time frame: Up to 5 years

Secondary Outcomes

Part 2: Proportion of patients with a ≥50% reduction in serum tryptase

Time frame: 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

Time frame: 6 months

Part 2: Proportion of patients with ≥50% reduction in ISM-SAF TSS

Time frame: 6 months

Part 2: Proportion of patients with ≥30% reduction in ISM-SAF TSS

Time frame: 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

Time frame: 6 months

Parts 1, 2, and 3: Change in serum tryptase

Time frame: Up to 5 years

Parts 1, 2, and 3: Change in KIT D816V allele burden in blood

Time frame: Up to 5 years

Parts 1, 2, and 3: Change in bone marrow mast cells

Time frame: Up to 5 years

Parts 1, 2, and 3: Change in best supportive care (BSC) concomitant medication usage

Time frame: Up to 5 years

Parts 1, 2, and 3: Change from Baseline in ISM-SAF Score

Time frame: Up to 5 years

Parts 1, 2, and 3: Change in Mastocytosis Quality of Life Questionnaire (MC-QoL)

Time frame: Up to 5 years

Parts 1, 2, and 3: Change in Patient's Global Impression of Symptom Severity (PGIS)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: Up to 5 years

Parts 1, 2, and 3: Safety of avapritinib as assessed by number of adverse events

CTCAE version 5.0

Time frame: Up to 5 years

(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

Overview

Conditions

Interventions

Eligibility

Locations (49)

Outcomes

Primary Outcomes

Secondary Outcomes