Gastrointestinal Stromal Tumors (GIST)Phase 1NCT02508532
(NAVIGATOR) Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors
A Phase 1 study testing Avapritinib in people with Gastrointestinal Stromal Tumors (GIST) and Other Relapsed or Refractory Solid Tumors, run by Blueprint Medicines Corporation at 19 sites in 10 countries.
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Gastrointestinal Stromal Tumors (GIST), Other Relapsed or Refractory Solid Tumors
- What is being tested?
- Avapritinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 250 participants
- Where
- 19 sitesin 10 countries
- Study dates
- Aug 2015to 3 Jun 2021
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 9Show fewer
- 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.
Trial locations and contacts
19 sites in 10 countries.
19 sites in 10 countries
United States9 sites
Cancer Treatment Centers of America
Atlanta, Georgia, 30256
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
MD Anderson Cancer Center
Houston, Texas, 77030
Sylvester Comprehensive Cancer Center
Miami, Florida, 33136
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Fox Chase Cancer Center
Philadelphia, Pennsylvania, 19111
Oregon Health and Science University
Portland, Oregon, 97239
Sarcoma Oncology Center
Santa Monica, California, 90403
Scottsdale Healthcare Hospitals DBA HonorHealth
Scottsdale, Arizona, 85258
France2 sites
Centre Leon Berard
Lyon, 69008
Institut Gustave Roussy
Paris, 94805
Belgium1 site
Leuven Cancer Institute University Hospitals Leuven
Leuven, 3000
Poland1 site
Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie w Warszawie
Warsaw, 02-781
About this study
Official title: A Phase 1 Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors
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).
- Being tested
- Avapritinib
- Keywords
- 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
- Medical subject headings
- Gastrointestinal Stromal Tumors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AvapritinibDrug
Also called BLU-285
avapritinib tablets
| Study group | Role | What they receive |
|---|---|---|
| Part 1 Avapritinib (formerly BLU-285) 30 mg QD | Experimental | 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. Receives: Drug: Avapritinib |
| Part 1 Avapritinib (formerly BLU-285) 60 mg QD | Experimental | 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. Receives: Drug: Avapritinib |
| Part 1 Avapritinib (formerly BLU-285) 90 mg QD | Experimental | 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. Receives: Drug: Avapritinib |
| Part 1 Avapritinib (formerly BLU-285) 135 mg QD | Experimental | 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. Receives: Drug: Avapritinib |
| Part 1 Avapritinib (formerly BLU-285) 200 mg QD | Experimental | 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. . Receives: Drug: Avapritinib |
| Part 1 Avapritinib (formerly BLU-285) 300 mg QD | Experimental | 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. Receives: Drug: Avapritinib |
| Part 1 Avapritinib (formerly BLU-285) 400 mg QD | Experimental | 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. Receives: Drug: Avapritinib |
| Part 1 Avapritinib (formerly BLU-285) 600 mg QD | Experimental | 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. Receives: Drug: Avapritinib |
| Part 1 and Part 2 Avapritinib (formerly BLU-285) 300 mg or 400 mg QD | Experimental | 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. Receives: Drug: Avapritinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Part 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Avapritinib
Patients with event(s) of dose-limiting toxicity
Measured: 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.
Measured: 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
Measured: 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 outcomes (19)
Maximum Plasma Drug Concentration (Cmax)
Maximum plasma drug concentration (Cmax) following a single dose of avapritinib
Measured: Cycle 1 Day 1
Time to Maximum Plasma Drug Concentration (Tmax)
Cycle 1 Day 1 PK time to maximum plasma drug concentration (Tmax)
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Cycle 1 Day 1
Terminal Elimination Half-life (t1/2)
Terminal elimination half-life (t1/2) following a single dose of avapritinib
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline and end of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jul 2015 (estimated)
- Study startAug 2015
- Primary completion6 Mar 2020
- Study completion3 Jun 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Gastrointestinal Stromal Tumors (GIST)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Model description
- Dose Escalation and Dose Expansion
- Masking
- None (open label)
- Enrolment
- 250 participants (actual)
Sponsor and investigators
- Lead sponsor
- Blueprint Medicines Corporation
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02508532
- Sponsor's protocol ID
- BLU-285-1101
- Status last verified
- Jul 2021
- First submitted
- 23 Jul 2015
- Last updated
- 21 Jun 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Expanded access
- Available
Publications
Kang YK, George S, Jones RL, Rutkowski P, Shen L, Mir O, Patel S, Zhou Y, von Mehren M, Hohenberger P, Villalobos V, Brahmi M, Tap WD, Trent J, Pantaleo MA, Schoffski P, He K, Hew P, Newberry K, Roche M, Heinrich MC, Bauer S. Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. J Clin Oncol. 2021 Oct 1;39(28):3128-3139. doi: 10.1200/JCO.21.00217. Epub 2021 Aug 3.
PubMed 34343033von Mehren M, Heinrich MC, Shi H, Iannazzo S, Mankoski R, Dimitrijevic S, Hoehn G, Chiroli S, George S. Clinical efficacy comparison of avapritinib with other tyrosine kinase inhibitors in gastrointestinal stromal tumors with PDGFRA D842V mutation: a retrospective analysis of clinical trial and real-world data. BMC Cancer. 2021 Mar 19;21(1):291. doi: 10.1186/s12885-021-08013-1.
PubMed 33740926Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, Schoffski P, Cassier PA, Mir O, Chawla SP, Eskens FALM, Rutkowski P, Tap WD, Zhou T, Roche M, Bauer S. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021 Mar;145:132-142. doi: 10.1016/j.ejca.2020.12.008. Epub 2021 Jan 16.
PubMed 33465704Joseph CP, Abaricia SN, Angelis MA, Polson K, Jones RL, Kang YK, Riedel RF, Schoffski P, Serrano C, Trent J, Tetzlaff ED, Si TD, Zhou T, Doyle A, Bauer S, Roche M, Havnaer T. Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors. Oncologist. 2021 Apr;26(4):e622-e631. doi: 10.1002/onco.13632. Epub 2021 Jan 5.
PubMed 33301227Heinrich MC, Jones RL, von Mehren M, Schoffski P, Serrano C, Kang YK, Cassier PA, Mir O, Eskens F, Tap WD, Rutkowski P, Chawla SP, Trent J, Tugnait M, Evans EK, Lauz T, Zhou T, Roche M, Wolf BB, Bauer S, George S. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020 Jul;21(7):935-946. doi: 10.1016/S1470-2045(20)30269-2.
PubMed 32615108Gebreyohannes YK, Wozniak A, Zhai ME, Wellens J, Cornillie J, Vanleeuw U, Evans E, Gardino AK, Lengauer C, Debiec-Rychter M, Sciot R, Schoffski P. Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors. Clin Cancer Res. 2019 Jan 15;25(2):609-618. doi: 10.1158/1078-0432.CCR-18-1858. Epub 2018 Oct 1.
PubMed 30274985
Study at a glance
From the registry record, last updated by the sponsor on 21 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors
- ClinicalTrials.gov ID
- NCT02508532
- Acronym / sponsor ID
- BLU-285-1101
- Keywords
- 2L GIST, GIST second line, GIST gleevec, GIST imatinib, Second-line GIST clinical trial, BLU-285, BLU 285, BLUE-285
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 250 participants (actual)
- Lead sponsor
- Blueprint Medicines CorporationIndustry (pharma, biotech, devices)
- Study start
- Aug 2015 (actual)
- Primary completion
- 6 Mar 2020 (actual)
- Study completion
- 3 Jun 2021 (actual)
- First posted
- 27 Jul 2015 (estimated)
- Results
- Posted 22 Jun 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 9
- Model description
- Dose Escalation and Dose Expansion
| Arm | Type | Receives |
|---|---|---|
| Part 1 Avapritinib (formerly BLU-285) 30 mg QD | Experimental | Drug: AvapritinibPart 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 Avapritinib (formerly BLU-285) 60 mg QD | Experimental | Drug: AvapritinibPart 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 Avapritinib (formerly BLU-285) 90 mg QD | Experimental | Drug: AvapritinibPart 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 Avapritinib (formerly BLU-285) 135 mg QD | Experimental | Drug: AvapritinibPart 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 Avapritinib (formerly BLU-285) 200 mg QD | Experimental | Drug: AvapritinibPart 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 Avapritinib (formerly BLU-285) 300 mg QD | Experimental | Drug: AvapritinibPart 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 Avapritinib (formerly BLU-285) 400 mg QD | Experimental | Drug: AvapritinibPart 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 Avapritinib (formerly BLU-285) 600 mg QD | Experimental | Drug: AvapritinibPart 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 Avapritinib (formerly BLU-285) 300 mg or 400 mg QD | Experimental | Drug: AvapritinibPart 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
- 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.
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AvapritinibAlso: BLU-285avapritinib tablets | Drug | Part 1 Avapritinib (formerly BLU-285) 135 mg QD, Part 1 Avapritinib (formerly BLU-285) 200 mg QD, Part 1 Avapritinib (formerly BLU-285) 30 mg QD, Part 1 Avapritinib (formerly BLU-285) 300 mg QD, Part 1 Avapritinib (formerly BLU-285) 400 mg QD, Part 1 Avapritinib (formerly BLU-285) 60 mg QD, Part 1 Avapritinib (formerly BLU-285) 600 mg QD, Part 1 Avapritinib (formerly BLU-285) 90 mg QD, Part 1 and Part 2 Avapritinib (formerly BLU-285) 300 mg or 400 mg QD |
Primary outcome
Part 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Avapritinib
Time frame: Cycle 1 (28 days) of treatment
Patients with event(s) of dose-limiting toxicity
Parts 1 and 2: Number of Patients With Adverse Events (AE) and Serious Adverse Events (SAE)
Time frame: 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
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.
Part 2: Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1
Time frame: 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.
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
19 secondary outcomes
Maximum Plasma Drug Concentration (Cmax)
Time frame: Cycle 1 Day 1
Time to Maximum Plasma Drug Concentration (Tmax)
Time frame: Cycle 1 Day 1
Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose (C24)
Time frame: Cycle 1 Day 1
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC 0-24)
Time frame: Cycle 1 Day 1
Apparent Oral Clearance Unadjusted for Bioavailability (CL/F)
Time frame: Cycle 1 Day 1
Apparent Volume of Distribution, Unadjusted for Bioavailability (Vz/F)
Time frame: Cycle 1 Day 1
Terminal Elimination Half-life (t1/2)
Time frame: Cycle 1 Day 1
Maximum Plasma Drug Concentration (Cmax) at Steady State
Time frame: Cycle 1 Day 15
Time of Maximal Concentration (Tmax) at Steady State
Time frame: Cycle 1 Day 15
Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose at Steady State (C24,ss)
Time frame: Cycle 1 Day 15
Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Steady Sate (AUC0-τ,ss) (τ=24 h)
Time frame: Cycle 1 Day 15
Progression-free Survival Per mRECIST Version 1.1
Time frame: 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)
Time frame: Cycle 1 Day 15
Clinical Benefit Rate Determined by Central Radiology Assessment Per mRECIST, Version 1.1
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline and End of treatment
KIT, PDGFRA, and Other Cancer-relevant Mutations Present in Tumor Tissue at Baseline and EOT
Time frame: Baseline and end of treatment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jun 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34343033Kang YK, George S, Jones RL, Rutkowski P, Shen L, Mir O, Patel S, Zhou Y, von Mehren M, Hohenberger P, Villalobos V, Brahmi M, Tap WD, Trent J, Pantaleo MA, Schoffski P, He K, Hew P, Newberry K, Roche M, Heinrich MC, Bauer S. Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. J Clin Oncol. 2021 Oct 1;39(28):3128-3139. doi: 10.1200/JCO.21.00217. Epub 2021 Aug 3.
- Derived from this study: PubMed 33740926von Mehren M, Heinrich MC, Shi H, Iannazzo S, Mankoski R, Dimitrijevic S, Hoehn G, Chiroli S, George S. Clinical efficacy comparison of avapritinib with other tyrosine kinase inhibitors in gastrointestinal stromal tumors with PDGFRA D842V mutation: a retrospective analysis of clinical trial and real-world data. BMC Cancer. 2021 Mar 19;21(1):291. doi: 10.1186/s12885-021-08013-1.
- Derived from this study: PubMed 33465704Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, Schoffski P, Cassier PA, Mir O, Chawla SP, Eskens FALM, Rutkowski P, Tap WD, Zhou T, Roche M, Bauer S. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021 Mar;145:132-142. doi: 10.1016/j.ejca.2020.12.008. Epub 2021 Jan 16.
- Derived from this study: PubMed 33301227Joseph CP, Abaricia SN, Angelis MA, Polson K, Jones RL, Kang YK, Riedel RF, Schoffski P, Serrano C, Trent J, Tetzlaff ED, Si TD, Zhou T, Doyle A, Bauer S, Roche M, Havnaer T. Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors. Oncologist. 2021 Apr;26(4):e622-e631. doi: 10.1002/onco.13632. Epub 2021 Jan 5.
- Derived from this study: PubMed 32615108Heinrich MC, Jones RL, von Mehren M, Schoffski P, Serrano C, Kang YK, Cassier PA, Mir O, Eskens F, Tap WD, Rutkowski P, Chawla SP, Trent J, Tugnait M, Evans EK, Lauz T, Zhou T, Roche M, Wolf BB, Bauer S, George S. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020 Jul;21(7):935-946. doi: 10.1016/S1470-2045(20)30269-2.
- Derived from this study: PubMed 30274985Gebreyohannes YK, Wozniak A, Zhai ME, Wellens J, Cornillie J, Vanleeuw U, Evans E, Gardino AK, Lengauer C, Debiec-Rychter M, Sciot R, Schoffski P. Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors. Clin Cancer Res. 2019 Jan 15;25(2):609-618. doi: 10.1158/1078-0432.CCR-18-1858. Epub 2018 Oct 1.
Related trials for Gastrointestinal Stromal Tumors (GIST)
RecruitingPhase 2
A Study to Learn More About How Well Treatment With Sevabertinib (BAY 2927088) Tablets Works and How Safe it is in Participants Who Have a Solid Tumor With Mutations of the Human Epidermal Growth Factor Receptor 2 (HER2)
Advanced Solid Tumors, HER2 Mutation
RecruitingPhase 2
Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015)
Pheochromocytoma/Paraganglioma, Pancreatic Neuroendocrine Tumor
RecruitingObservational study
Surgery in Gastrointestinal Stromal Tumors (GISTs) for Treatment, Tumor Modeling, and Genomic Analysis
Gastric Cancer, Gastric Neoplasm
RecruitingPhase 1
A Study of Ziftomenib in Combination With Imatinib in Patients With Advanced Gastrointestinal Stromal Tumors (GIST)
Gastrointestinal Stromal Tumor (GIST), Gastrointestinal Stromal Cancer
RecruitingPhase 3
A Study to Investigate Velzatinib Compared With Imatinib in Adult Participants With Previously Untreated Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (StrateGIST Frontline)
Gastrointestinal Stromal Neoplasms
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
19 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Avapritinib in people with Gastrointestinal Stromal Tumors (GIST) and Other Relapsed or Refractory Solid Tumors, run by Blueprint Medicines Corporation at 19 sites in 10 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in United States, France, Belgium, Germany, Italy and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Jun 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Avapritinib (time frame: Cycle 1 (28 days) of treatment). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02508532, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jun 2022.