Neoplasms

Digestive System Diseases

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Gastrointestinal Stromal Tumors

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Tyrosine Kinase Inhibitors

Imatinib Mesylate

Tyrosine

Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.

avapritinib

Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).

regorafenib

This is an open-label, randomized, Phase 3 study in patients with locally advanced unresectable or metastatic GIST (advanced GIST) of avapritinib (also known as BLU-285) versus regorafenib in patients previously treated with imatinib and 1 or 2 other TKIs.

(VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST

An International, Multicenter, Open-label, Randomized, Phase 3 Study of BLU-285 vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST)

To demonstrate the efficacy of avapritinib based on progression-free survival (PFS) determined by central radiological assessment per modified Response Evaluation Criteria in Solid Tumors (mRECIST), version 1.1 in patients with advanced GIST following 2 or 3 regimens of prior treatment with a tyrosine kinase inhibitor (TKI), including imatinib, compared to patients treated with regorafenib. 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.

To evaluate objective response rate (ORR) determined by central radiology assessment per mRECIST, version 1.1 in patients with advanced GIST treated with avapritinib compared to patients treated with regorafenib. A complete response (CR) per modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) is defined as complete disappearance of all target lesions. A partial response (PR) 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

To evaluate overall survival (OS) in patients with advanced GIST treated with avapritinib compared to patients treated with regorafenib

The Global Health Status Score is derived from question 29 and 30 on the EORTC-QLQ-C30 tool. The change in score was assessed between baseline and week 12 in patients treated with advanced GIST treated with avapritinib compared to patients treated with regorafenib. The Global Health Status Score score range is 0 to 100 with a higher score indicating better global health status. A positive change indicates improvement in global health status.

Blueprint Medicines Corporation

The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.

300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.

Avapritinib

160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).

Regorafinib

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Singapore

Hungary

United States

Czechia

United Kingdom

Spain

Canada

Austria

Netherlands

South Korea

Sweden

Belgium

China

Poland

Italy

Australia

France

Germany

Region of Enrollment

Both height and weight measurements are needed for body mass index calculation. Some patients had missing height and/or weight measurements. Only patients with both a height and a weight measurement are included in the body mass index calculation

Body Mass Index (BMI)

Medical Information Call Center

Intent-to-Treat Population that included all patients randomized to study.

Efficacy of Avapritinib Based on Progression-free Survival (PFS) Determined by Central Radiological Assessment Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST), Version 1.1

Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1

Overall Survival (OS) in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib

Intent-to-Treat Population with both a baseline and a Week 12 measurements.

European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30). Change in Individual Scores in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib

Overall Study

Connective Tissue Diseases

Sunitinib

Participants with unresectable or metastatic GIST who will receive orally administered THE-630.

Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib, regorafenib and ripretinib who will receive orally administered THE-630 at the recommended Phase 2 dose based on the dose escalation phase.

Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib and 0-1 additional lines of therapy in the advanced/metastatic setting, who will receive orally administered THE-630 at the recommended Phase 2 dose based on the dose escalation phase.

Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib (including in the adjuvant setting) and who have not received additional systemic therapy for advanced GIST, who will receive orally administered THE-630 at the recommended Phase 2 dose based on the dose escalation phase.

Oral THE-630 administered once daily in a continuous regimen

THE-630

Stew Kroll

This study will assess the safety, efficacy, and pharmacokinetics of THE-630 in participants with advanced gastrointestinal stromal tumors (GIST).

The drug being tested in this study is called THE-630, an orally administered KIT tyrosine kinase inhibitor. The study will be conducted in two parts: a dose escalation phase, followed by an expansion phase. The patient population of the initial dose escalation phase (Phase 1) of the trial will include patients with unresectable or metastatic GIST. Patients must have disease progression on or be intolerant to imatinib therapy and have also received at least 1 of the following: sunitinib, regorafenib, ripretinib, or avapritinib. The primary objective of the dose escalation phase is to determine the safety profile of oral THE-630, including the dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D).

Once a recommended dose has been determined in the escalation phase, the expansion phase (Phase 2) will enroll 3 cohorts of patients with unresectable or metastatic GIST defined by prior therapy:

* Cohort 1: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib, regorafenib and ripretinib (≥5th Line).
* Cohort 2: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib, sunitinib and 0-1 additional lines of therapy in the advanced/metastatic setting (3rd-4th Line).
* Cohort 3: Patients with unresectable or metastatic GIST who have progressed on or are intolerant to imatinib (including in the adjuvant setting) and who have not received additional systemic therapy for advanced GIST (2nd Line).

The safety and tolerability of orally administered THE-630 will continue to be assessed in the expansion cohorts. However, the primary objective of the expansion component of the trial is to evaluate the anti-tumor activity of THE-630 in these GIST patient populations.

A Study of THE-630 in Patients With Advanced Gastrointestinal Stromal Tumors (GIST)

A Phase 1/2 Study of the Safety, Pharmacokinetics and Anti-Tumor Activity of the Oral KIT Inhibitor THE-630 in Patients With Advanced Gastrointestinal Stromal Tumors (GIST)

Cmax of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses

Tmax of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses

AUC 0-24 of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses

AUC 0-t of THE-630 and its active metabolite after single oral dose and at steady state after multiple oral doses

Theseus Pharmaceuticals

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.

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.

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.

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.

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. .

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.

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.

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.

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.

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).

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

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

Patients with event(s) of dose-limiting toxicity

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.

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

Maximum plasma drug concentration (Cmax) following a single dose of avapritinib

Cycle 1 Day 1 PK time to maximum plasma drug concentration (Tmax)

Plasma drug concentration at 24 hours postdose prior to the next daily dose (C24) following a single dose of avapritinib

Area under the plasma concentration-time curve from time 0 to 24 hours (AUC 0-24) following a single dose of avapritinib

Apparent oral clearance unadjusted for bioavailability (CL/F) following a single dose of avapritinib

Apparent volume of distribution, unadjusted for bioavailability (Vz/F) following a single dose of avapritinib

Terminal elimination half-life (t1/2) following a single dose of avapritinib

Maximum plasma drug concentration (Cmax) at steady state following 15 days of QD dosing

Time of maximal concentration (Tmax) at steady state following 15 days of QD dosing

Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose at steady state (C24,ss) following 15 days of QD dosing

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

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.

Apparent oral clearance at steady state, unadjusted for bioavailability (CLss/F) following 15 days of QD dosing

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.

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.

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

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.

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.

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.

Experimental: Part 1 Avapritinib (Formerly BLU-285) 30 mg QD

Experimental: Part 1 Avapritinib (Formerly BLU-285) 60 mg QD

Experimental: Part 1 Avapritinib (Formerly BLU-285) 90 mg QD

Experimental: Part 1 Avapritinib (Formerly BLU-285) 135 mg QD

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.

Experimental: Part 1 Avapritinib (Formerly BLU-285) 200 mg QD

Experimental: Part 1 Avapritinib (Formerly BLU-285) 600 mg QD

Experimental: Part 1 and Part 2 Avapritinib (Formerly BLU-285) 300 or 400 mg QD

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.

Includes 13 patients from Part 1

Part 1 and Part 2 Avapritinib (Formerly BLU-285) 300 mg or 400 mg QD

Body Mass Index was only calculated for patients with both a height and weight measurement at Baseline

Medical Information

Experimental: Part 1 Avapritinib (Formerly BLU-285) 300 mg QD

Experimental: Part 1 Avapritinib (Formerly BLU-285) 400 mg QD

Patients that completed Part 1 or had a DLT

Part 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Avapritinib

Participants with an Adverse Event

Participants with a Serious Adverse Event

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. 13 patients in this group were enrolled in Part 1

Patients received avapritinib in continuous 28 day cycles until discontinuation.

Experimental: Part 1 and Part 2 Avapritinib (Formerly BLU-285) 300 mg or 400 mg QD

Safety Population - all patients that received at least one dose of avapritinib

Parts 1 and 2: Number of Patients With Adverse Events (AE) and Serious Adverse Events (SAE)

Patients with a PDGFRA D842V Mutation, any line of treatment

Patients With a PDGFRA D842V Mutation

Patients that do not have a PDGFRA D842V mutation and have received 1 prior line of therapy

2L Patients Without a PDGFRA D842V Mutation

Patients that do not have a PDGFRA D842V mutation and have had 2 or more prior lines of therapy

3L Patients Without a PDGFRA D842V Mutation

patients enrolled in Part 1 or Part 2 with a starting dose of 300 or 400 mg, including 13 patients enrolled in Part 1

Part 2: Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1

Part 1 and Part 2: Patients received a starting dose of 300 mg QD. Patients received avapritinib in continuous 28 day cycles until discontinuation.

Part 1 Avapritinib (Formerly BLU-285) 300 mg QD

Part 1 and Part 2: Patients received a starting dose of 400 mg QD. Patients received avapritinib in continuous 28 day cycles until discontinuation.

Part 1 Avapritinib (Formerly BLU-285) 400 mg QD

Patients enrolled in Part 1 and Part 2 with a starting dose of 300 or 400 mg QD and available samples for PK

Maximum Plasma Drug Concentration (Cmax)

Part 1 and Part 2: Avapritinib (Formerly BLU-285) 300 mg QD

Part 1 and Part 2: Avapritinib (Formerly BLU-285) 400 mg QD

Patients enrolled in Part 1 and Part 2 with available samples for PK

Time to Maximum Plasma Drug Concentration (Tmax)

Patients enrolled in Part 1 or Part 2 with a starting dose of 300 or 400 mg QD and available PK samples

Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose (C24)

Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC 0-24)

Apparent Oral Clearance Unadjusted for Bioavailability (CL/F)

Patients enrolled in Part 1 and Part 2 with a starting dose of 300 or 400 mg QD and available PK samples

Apparent Volume of Distribution, Unadjusted for Bioavailability (Vz/F)

Terminal Elimination Half-life (t1/2)

Maximum Plasma Drug Concentration (Cmax) at Steady State

Time of Maximal Concentration (Tmax) at Steady State

Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose at Steady State (C24,ss)

Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Steady Sate (AUC0-τ,ss) (τ=24 h)

Patients with a PDGFRA D842V mutation, any line of treatment

Patients enrolled in Part 1 or Part 2 with a starting dose of 300 or 400 mg QD

Progression-free Survival Per mRECIST Version 1.1

Apparent Oral Clearance at Steady State, Unadjusted for Bioavailability (CLss/F)

patients with a starting dose of 300 or 400 mg QD

Clinical Benefit Rate Determined by Central Radiology Assessment Per mRECIST, Version 1.1

Patients enrolled in Part 1 or Part 2 with a starting dose of 300 or 400 mg

Response Rate Determined by Central Radiology Assessment Per Choi Criteria

Patients With PDGFRA D842V Mutation

Patients in Part 1 and Part 2 with a starting dose of 300 or 400 mg QD. Only patients that achieved a CR or PR are included in this analysis

Duration of Response Determined by Central Radiology Assessment Per mRECIST, Version 1.1

Patients enrolled on any dose (Part 1 and Part 2) with data on progression-free survival for the most recent prior therapy

Median PFS on Last Prior Anti-cancer Therapy

Change in PDGFRA MAF

Change in KIT MAF

Change From Baseline in Levels of KIT and PDGFRα Mutant Allele Fractions in Peripheral Blood

Patients with pre-and post-treatment tumor biopsies. No patients provided a post-treatment biopsy.

KIT, PDGFRA, and Other Cancer-relevant Mutations Present in Tumor Tissue at Baseline and EOT

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
(VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST	NCT03465722	GIST	avapritinib regorafenib	18 Years -	Blueprint Medicines Corporation
A Study of THE-630 in Patients With Advanced Gastrointestinal Stromal Tumors (GIST)	NCT05160168	Gastrointestina... Neoplasms, Conn... Neoplasms, Conn... Neoplasms by Hi... Neoplasms Gastrointestina... Digestive Syste... Digestive Syste... Gastrointestina...	THE-630	18 Years -	Theseus Pharmaceuticals
(NAVIGATOR) Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors	NCT02508532	Gastrointestina... Other Relapsed ...	Avapritinib	18 Years -	Blueprint Medicines Corporation
(VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST	NCT03465722	GIST	avapritinib regorafenib	18 Years -	Blueprint Medicines Corporation

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