(Summit) A Study to Evaluate the Efficacy and Safety of CGT9486 Versus Placebo in Patients With Indolent or Smoldering Systemic Mastocytosis

Study Overview
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Brief Summary
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This is a multi-part, randomized, double-blind, placebo-controlled Phase 2 clinical study comparing the safety and efficacy of bezuclastinib (CGT9486) plus best supportive care (BSC) with placebo plus BSC in patients with nonadvanced systemic mastocytosis (NonAdvSM), including indolent systemic mastocytosis and smoldering systemic mastocytosis, whose symptoms are not adequately controlled by BSC. This study will be conducted in three parts. Patients in Parts 1a, 1b and 2 will receive bezuclastinib or placebo, and may roll over onto Part 3 to receive treatment with bezuclastinib.

Official Title
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A Multi-Part, Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Study of The Safety and Efficacy of CGT9486 in Subjects With Nonadvanced Systemic Mastocytosis

Conditions
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SSM, Mastocytosis, Indolent, Mastocytosis, Systemic, Mastocytosis

Intervention / Treatment
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* Drug: Bezuclastinib Tablets (Formulation A)
* Drug: Bezuclastinib Tablets (Formulation B)
* Drug: Placebo Tablets


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosed with 1 of the following diagnoses according to the 2016 World Health Organization (WHO) classification for systemic mastocytosis (SM): Indolent systemic mastocytosis (ISM), including the bone marrow mastocytosis subvariant Smoldering systemic mastocytosis (SSM) Moderate-to-severe symptoms based on a disease-specific PRO and after establishing a stable regimen of at least 2 antimediator therapies over a 14-day eligibility period Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2 For patients receiving corticosteroids, the dose must be ≤10 mg/day of prednisone or equivalent Key Exclusion Criteria: Diagnosed with any of the following WHO SM classifications: bone marrow mastocytosis, advanced systemic mastocytosis including SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia; or mast cell sarcoma Diagnosed with mastocytosis of the skin without systemic involvement Received prior treatment with any targeted KIT inhibitor with the exception of approved agents for the treatment of SM Received prior cytoreductive therapy or investigational agent for <14 days or 5 half- lives of the drug and for cladribine, interferon alpha, pegylated interferon, or antibody therapy <28 days or 5 half-lives of the drug (whichever is longer), before starting screening assessments Received radiotherapy or psoralen and ultraviolet A therapy <14 days before starting screening assessments Received any hematopoietic growth factor support <14 days before starting screening assessments History of clinically significant bleeding event within 30 days before the first dose of study drug or need for therapeutic anticoagulation on study Need for treatment of corticosteroids at >10 mg/day of prednisone or equivalent

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 1a and 1b of the study, patients with NonAdvSM will be randomly assigned to 1 of 2 dose levels of bezuclastinib plus BSC, or to placebo plus BSC. Upon analysis of the Part 1 data, a dose will be selected for Part 2. In Part 2, patients with NonAdvSM will be randomly assigned to the selected dose of bezuclastinib plus BSC, or to placebo plus BSC. Patients who complete Part 1 or Part 2 may participate in Part 3 in which all patients will receive bezuclastinib plus BSC.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (Part 1a) Bezuclastinib Dose 1 + BSC<br> | Drug: Bezuclastinib Tablets (Formulation A)<br>* Bezuclastinib will be administered orally, once daily continuously for 28-day cycles<br>* Other names: PLX9486;|
| Experimental: (Part 1a) Bezuclastinib Dose 2 + BSC<br> | Drug: Bezuclastinib Tablets (Formulation A)<br>* Bezuclastinib will be administered orally, once daily continuously for 28-day cycles<br>* Other names: PLX9486;|
| Placebo Comparator: (Part 1a) Placebo + BSC<br> | Drug: Placebo Tablets<br>* Placebo will be administered orally, once daily continuously for 28-day cycles<br>|
| Experimental: (Part 1b) Bezuclastinib Dose 1 + BSC<br> | Drug: Bezuclastinib Tablets (Formulation B)<br>* Bezuclastinib will be administered orally, once daily continuously for 28-day cycles<br>* Other names: PLX9486;|
| Experimental: (Part 1b) Bezuclastinib Dose 2 + BSC<br> | Drug: Bezuclastinib Tablets (Formulation B)<br>* Bezuclastinib will be administered orally, once daily continuously for 28-day cycles<br>* Other names: PLX9486;|
| Placebo Comparator: (Part 1b) Placebo + BSC<br> | Drug: Placebo Tablets<br>* Placebo will be administered orally, once daily continuously for 28-day cycles<br>|
| Experimental: (Part 2) Bezuclastinib Selected Dose + BSC<br> | Drug: Bezuclastinib Tablets (Formulation B)<br>* Bezuclastinib will be administered orally, once daily continuously for 28-day cycles<br>* Other names: PLX9486;|
| Placebo Comparator: (Part 2) Placebo + BSC<br> | Drug: Placebo Tablets<br>* Placebo will be administered orally, once daily continuously for 28-day cycles<br>|
| Experimental: (Part 3) Bezuclastinib + BSC<br> | Drug: Bezuclastinib Tablets (Formulation A)<br>* Bezuclastinib will be administered orally, once daily continuously for 28-day cycles<br>* Other names: PLX9486;Drug: Bezuclastinib Tablets (Formulation B)<br>* Bezuclastinib will be administered orally, once daily continuously for 28-day cycles<br>* Other names: PLX9486;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Determine recommended dose of bezuclastinib (CGT9486) in subjects with NonAdvSM | Selection of the recommended dose to be used in subsequent parts of the study. | 3 months | 
| Part 2: Efficacy of bezuclastinib at the selected dose versus placebo | Mean absolute change in a disease-specific patient reported outcome (PRO) | 6 months | 
| Part 3: Safety and tolerability of bezuclastinib as assessed by number of adverse events | CTCAE v5 | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of bezuclastinib as assessed by number of adverse events | CTCAE v5 | Up to 24 months | 
| Proportion of subjects who had at least 50% reduction in serum tryptase |  | Up to 24 months | 
| Proportion of subjects who had at least 50% reduction in mast cell burden |  | Up to 24 months | 
| Proportion of subjects who had at least a 50% reduction in peripheral blood D816V allele fraction |  | Up to 24 months | 
| Change and percent change in patient reported outcome (PRO) measures |  | Up to 24 months | 
| Change and percent change in serum tryptase |  | Up to 24 months | 
| Change and percent change in bone marrow mast cells |  | Up to 24 months | 
| Change and percent change in the levels of KIT D816V mutation allele burden |  | Up to 24 months | 
| Assess the pharmacokinetics (PK) of bezuclastinib in subjects with NonAdvSM | Plasma concentrations of CGT9846 | Up to 24 months | 
| Change and percent change in the Mast Cell Quality of Life (MC-QOL) Score | Scale of 0-100, higher numbers represent more severe impairment to quality of life. | up to 24 months | 
| Change and percent change in 12-item Short Form Health Survey (SF-12) | Scale of 0-100, higher numbers represent better symptom outcomes | up to 24 months | 
| Change and percent change in EuroQol 5 Dimensions 5 Levels (EQ 5D-5L) | Scale of 0-100, higher numbers represent better symptom outcomes | up to 24 months | 
| Determine responder rates of subjects treated with bezuclastinib at the selected dose | Response rate based on reduction in disease specific PRO | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Mastocytosis, Immune Complex Diseases, Immune System Diseases, Hypersensitivity, Hematologic Diseases, NonAdvSM, D816V, KIT D816V, Bezuclastinib, CGT9486, CGT, PLX, Nonadvanced Systemic Mastocytosis, PLX9486, Indolent Systemic Mastocytosis, ISM, Smoldering Systemic Mastocytosis