(NAVIGATOR) Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antineoplastic activity of avapritinib (formerly BLU-285), administered orally (PO), in adult patients with unresectable GIST or other relapsed or refractory solid tumors. The study consists of 2 parts, a dose-escalation part (Part 1) and an expansion part (Part 2).

Official Title
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A Phase 1 Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors

Conditions
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Gastrointestinal Stromal Tumors (GIST), Other Relapsed or Refractory Solid Tumors

Intervention / Treatment
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* Drug: Avapritinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Part 1: Histologically- or cytologically-confirmed diagnosis of unresectable GIST or another advanced solid tumor. Patients with unresectable GIST must have disease that has progressed following imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib or an experimental kinase-inhibitor agent, or disease with a D842 mutation in the PDGFRα gene. Patients with an advanced solid tumor other than GIST must have relapsed or refractory disease without an available effective therapy. OR For Part 2: Group 1: Patients must have a confirmed diagnosis of unresectable GIST that has progressed following imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib, or an experimental kinase-inhibitor agent, and the patient does not have a D842V mutation in PDGFRα. Group 2: Patients must have a confirmed diagnosis of unresectable GIST with a D842V mutation in the PDGFRα gene. The PDGFRα mutation will be identified by local or central assessment, either in an archival tissue sample or a new tumor biopsy obtained prior to treatment with avapritinib. Group 3: Patients must have a confirmed diagnosis of unresectable GIST that has progressed and/or patients must have experienced intolerance to imatinib and not received additional kinase-inhibitor therapy. Patients must not have a known D842V mutation in PDGFRα. Groups 1, 2 and 3: At least 1 measurable lesion defined by mRECIST 1.1 for patients with GIST. Groups 1 and 2: A tumor sample (archival tissue or a new tumor biopsy) has been submitted for mutational testing. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Exclusion Criteria: QT interval corrected using Fridericia's formula (QTcF) >450 milliseconds Platelet count <90,000/mL Absolute neutrophil count <1000/mL Hemoglobin <9 g/dL Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 x the upper limit of normal (ULN) if no hepatic metastases are present; >5 × ULN if hepatic metastases are present Total bilirubin >1.5 × ULN; >3 × ULN with direct bilirubin, >1.5 × ULN in the presence of Gilbert's Disease Estimated (Cockroft-Gault formula) or measured creatinine clearance <40 mL/min Brain malignancy or metastases to the brain History of a seizure disorder or requirement for anti-seizure medication Group 3: Patients known to be KIT wild type.

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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose Escalation and Dose Expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Avapritinib (formerly BLU-285) 30 mg QD<br>Part 1: Patients received a starting dose of 30 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued. Patients received avapritinib in continuous 28 day cycles until discontinuation. | Drug: Avapritinib<br>* avapritinib tablets<br>* Other names: BLU-285;|
| Experimental: Part 1 Avapritinib (formerly BLU-285) 60 mg QD<br>Part 1: Patients received a starting dose of 60 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued. Patients received avapritinib in continuous 28 day cycles until discontinuation. | Drug: Avapritinib<br>* avapritinib tablets<br>* Other names: BLU-285;|
| Experimental: Part 1 Avapritinib (formerly BLU-285) 90 mg QD<br>Part 1: Patients received a starting dose of 90 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued. Patients received avapritinib in continuous 28 day cycles until discontinuation. | Drug: Avapritinib<br>* avapritinib tablets<br>* Other names: BLU-285;|
| Experimental: Part 1 Avapritinib (formerly BLU-285) 135 mg QD<br>Part 1: Patients received a starting dose of 135 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued. Patients received avapritinib in continuous 28 day cycles until discontinuation. | Drug: Avapritinib<br>* avapritinib tablets<br>* Other names: BLU-285;|
| Experimental: Part 1 Avapritinib (formerly BLU-285) 200 mg QD<br>Part 1: Patients received a starting dose of 200 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued. Patients received avapritinib in continuous 28 day cycles until discontinuation. . | Drug: Avapritinib<br>* avapritinib tablets<br>* Other names: BLU-285;|
| Experimental: Part 1 Avapritinib (formerly BLU-285) 300 mg QD<br>Part 1: Patients received a starting dose of 300 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued. Patients received avapritinib in continuous 28 day cycles until discontinuation. Patients that received at least one dose of avapritinib were included in the Part 2 analysis. | Drug: Avapritinib<br>* avapritinib tablets<br>* Other names: BLU-285;|
| Experimental: Part 1 Avapritinib (formerly BLU-285) 400 mg QD<br>Part 1: Patients received a starting dose of 400 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued. Patients received avapritinib in continuous 28 day cycles until discontinuation. Patients that received at least one dose of avapritinib were included in the Part 2 analysis. | Drug: Avapritinib<br>* avapritinib tablets<br>* Other names: BLU-285;|
| Experimental: Part 1 Avapritinib (formerly BLU-285) 600 mg QD<br>Part 1: Patients received a starting dose of 600 mg QD for 28 days and they were assessed for dose limiting toxicities (DLT). If no DTLs were observed the dose escalation continued. Patients received avapritinib in continuous 28 day cycles until discontinuation. | Drug: Avapritinib<br>* avapritinib tablets<br>* Other names: BLU-285;|
| Experimental: Part 1 and Part 2 Avapritinib (formerly BLU-285) 300 mg or 400 mg QD<br>Part 1 and Part 2: Patients enrolled in Part 1 and Part 2 at a starting dose of 300 or 400 mg QD were included in the Part1/Part 2 safety and efficacy analysis. Patients received avapritinib in continuous 28 day cycles until discontinuation. | Drug: Avapritinib<br>* avapritinib tablets<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: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Avapritinib | Patients with event(s) of dose-limiting toxicity | Cycle 1 (28 days) of treatment | 
| Parts 1 and 2: Number of Patients With Adverse Events (AE) and Serious Adverse Events (SAE) | The overall safety profile of the drug was assessed by reviewing the number of patients with AEs, SAEs and other events. There was no formal statistical analysis. Safety assessments continued for the duration of treatment. | AEs were collected from the start of study drug until 30 days after the last dose, SAEs were collected from the date of the informed consent signature until 30 days after the last dose of study drug, up to 5 years | 
| Part 2: Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1 | To evaluate objective response rate (ORR) determined by central radiology assessment per mRECIST, version 1.1 in patients with advanced GIST treated with avapritinib. A complete response per modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) is defined as complete disappearance of all target lesions. A partial response is defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Overall Response (OR) = CR + PR | Tumor assessments were performed at screening, Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter up to approximately 4 years. Each cycle is 28 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Drug Concentration (Cmax) | Maximum plasma drug concentration (Cmax) following a single dose of avapritinib | Cycle 1 Day 1 | 
| Time to Maximum Plasma Drug Concentration (Tmax) | Cycle 1 Day 1 PK time to maximum plasma drug concentration (Tmax) | Cycle 1 Day 1 | 
| Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose (C24) | Plasma drug concentration at 24 hours postdose prior to the next daily dose (C24) following a single dose of avapritinib | Cycle 1 Day 1 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC 0-24) | Area under the plasma concentration-time curve from time 0 to 24 hours (AUC 0-24) following a single dose of avapritinib | Cycle 1 Day 1 | 
| Apparent Oral Clearance Unadjusted for Bioavailability (CL/F) | Apparent oral clearance unadjusted for bioavailability (CL/F) following a single dose of avapritinib | Cycle 1 Day 1 | 
| Apparent Volume of Distribution, Unadjusted for Bioavailability (Vz/F) | Apparent volume of distribution, unadjusted for bioavailability (Vz/F) following a single dose of avapritinib | Cycle 1 Day 1 | 
| Terminal Elimination Half-life (t1/2) | Terminal elimination half-life (t1/2) following a single dose of avapritinib | Cycle 1 Day 1 | 
| Maximum Plasma Drug Concentration (Cmax) at Steady State | Maximum plasma drug concentration (Cmax) at steady state following 15 days of QD dosing | Cycle 1 Day 15 | 
| Time of Maximal Concentration (Tmax) at Steady State | Time of maximal concentration (Tmax) at steady state following 15 days of QD dosing | Cycle 1 Day 15 | 
| Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose at Steady State (C24,ss) | Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose at steady state (C24,ss) following 15 days of QD dosing | Cycle 1 Day 15 | 
| Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Steady Sate (AUC0-τ,ss) (τ=24 h) | Area under the plasma concentration-time curve over the dosing interval at steady sate (AUC0-τ,ss) (τ=24 h) following 15 days of QD dosing | Cycle 1 Day 15 | 
| Progression-free Survival Per mRECIST Version 1.1 | Progression-free survival is defined as the time in months from the start of treatment to the date of first documented progression or death due to any cause. Progression-free survival determined by central radiological assessment per modified Response Evaluation Criteria in Solid Tumors (mRECIST), version 1.1 in patients with advanced GIST. A progressively growing tumor must meet the following criteria: a) the target lesions must be greater or equal to 2cm in size and be a new GIST active lesion or b) the target lesions must be expanding on at least 2 sequential imaging studies. | Tumor assessments were performed at screening, Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter up to approximately 4 years. Each cycle is 28 days. | 
| Apparent Oral Clearance at Steady State, Unadjusted for Bioavailability (CLss/F) | Apparent oral clearance at steady state, unadjusted for bioavailability (CLss/F) following 15 days of QD dosing | Cycle 1 Day 15 | 
| Clinical Benefit Rate Determined by Central Radiology Assessment Per mRECIST, Version 1.1 | Percent of patients with a complete response, partial response or stable disease lasting more than 16 weeks. A complete response per modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) is defined as complete disappearance of all target lesions. A partial response is defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Stable disease is defined as a tumor that does not meet the criteria for progression or for response. A progressively growing tumor must meet the following criteria: a) the target lesions must be greater or equal to 2cm in size and be a new GIST active lesion or b) the target lesions must be expanding on at least 2 sequential imaging studies. | Tumor assessments were performed at screening, Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter up to approximately 4 years. Each cycle is 28 days. | 
| Response Rate Determined by Central Radiology Assessment Per Choi Criteria | A complete response is defined as complete disappearance of all target lesions. A partial response is ≥10% decrease tumor size at computed tomography (CT) or ≥15% decrease in tumor attenuation at computed tomography (CT) and no new lesions. The response rate is defined as complete response plus partial response. | Tumor assessments were performed at screening, Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter up to approximately 4 years. Each cycle is 28 days. | 
| Duration of Response Determined by Central Radiology Assessment Per mRECIST, Version 1.1 | Duration from time to first documented CR/PR to date of first documented disease progression or death. A complete response per modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) is defined as complete disappearance of all target lesions. A partial response is defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Overall Response (OR) = CR + PR | Tumor assessments were performed at screening, Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter up to approximately 4 years. Each cycle is 28 days. | 
| Median PFS on Last Prior Anti-cancer Therapy | Progression Free Survival (PFS) is defined as the time in months from the start of treatment to the date of first documented disease progression or death due to any cause, which ever occurs first. PFS on last prior anti-cancer therapy is defined as the time in months from the start of last prior anti-cancer therapy to progression on that therapy. | Historical data collected at enrollment, all available data on prior therapy was collected | 
| Change From Baseline in Levels of KIT and PDGFRα Mutant Allele Fractions in Peripheral Blood | Change of mutant allele fraction (MAF) summarizes the largest fold change. Change from baseline only displayed for patients with pre and post treatment MAF measurements. A positive number represents an increase in MAF. Data is only provided for patients that had both a baseline measurement and an end of treatment measurement. | Baseline and End of treatment | 
| KIT, PDGFRA, and Other Cancer-relevant Mutations Present in Tumor Tissue at Baseline and EOT | Change in mutations in tumor tissue at baseline and end of treatment (EOT). EOT tumor biopsies were optional and there were no EOT samples collected. | Baseline and end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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2L GIST, GIST second line, GIST gleevec, GIST imatinib, Second-line GIST clinical trial, BLU-285, BLU 285, BLUE-285, BLUE 285, Avapritinib, GIST imatinib relapse, GIST gleevec relapse, GIST KIT, GIST relapse, GIST refractory, GIST imatinib intolerance, GIST TKI treatment, GIST tyrosine kinase inhibitor treatment, GIST TKI, GIST tyrosine kinase inhibitor, Advanced GIST, GIST mutations, GIST treatments, Blueprint GIST, Relapsed GIST clinical trial, Refractory GIST clinical trial, KIT-mutant GIST, cancer gist, gastrointestinal stromal tumor, gist cancer, PDGFRA