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

Gastrointestinal Stromal Tumors (GIST) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02508532
• Other study ID #: BLU-285-1101
• Status: Completed
• Phase: Phase 1
• Start date: August 2015
• Est. completion date: June 3, 2021

Study information

• Verified date: July 2021
• Source: Blueprint Medicines Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 250
• Est. completion date: June 3, 2021
• Est. primary completion date: March 6, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 PDGFRa 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 PDGFRa.

• Group 2: Patients must have a confirmed diagnosis of unresectable GIST with a D842V mutation in the PDGFRa gene. The PDGFRa 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 PDGFRa.

• 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.

Related Conditions & MeSH terms

• Gastrointestinal Stromal Tumors
• Gastrointestinal Stromal Tumors (GIST)
• Neoplasms
• Other Relapsed or Refractory Solid Tumors

Intervention

Drug:
• Avapritinib
avapritinib tablets

Locations

Country	Name	City	State
Belgium	Leuven Cancer Institute University Hospitals Leuven	Leuven
France	Centre Leon Berard	Lyon
France	Institut Gustave Roussy	Paris
Germany	University of Duisburg-Essen	Essen
Italy	Fondazione IRCCS - Istituto Nazinale dei Tumori	Milan
Korea, Republic of	Asan Medical Center	Seoul
Netherlands	Erasmus MC Cancer Institute	Rotterdam
Poland	Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie w Warszawie	Warsaw
Spain	Vall d' Hebron Institute of Oncology (VHIO)	Barcelona
United Kingdom	Royal Marsden Hospital	London
United States	Cancer Treatment Centers of America	Atlanta	Georgia
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	MD Anderson Cancer Center	Houston	Texas
United States	Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Sarcoma Oncology Center	Santa Monica	California
United States	Scottsdale Healthcare Hospitals DBA HonorHealth	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Blueprint Medicines Corporation

Countries where clinical trial is conducted

United States,  Belgium,  France,  Germany,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Maximum Plasma Drug Concentration (Cmax)	Maximum plasma drug concentration (Cmax) following a single dose of avapritinib	Cycle 1 Day 1
Secondary	Time to Maximum Plasma Drug Concentration (Tmax)	Cycle 1 Day 1 PK time to maximum plasma drug concentration (Tmax)	Cycle 1 Day 1
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Terminal Elimination Half-life (t1/2)	Terminal elimination half-life (t1/2) following a single dose of avapritinib	Cycle 1 Day 1
Secondary	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
Secondary	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
Secondary	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
Secondary	Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Steady Sate (AUC0-t,ss) (t=24 h)	Area under the plasma concentration-time curve over the dosing interval at steady sate (AUC0-t,ss) (t=24 h) following 15 days of QD dosing	Cycle 1 Day 15
Secondary	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.
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	Change From Baseline in Levels of KIT and PDGFRa 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
Secondary	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