Description:
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).
Title
- Brief Title: (NAVIGATOR) Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors
- 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 IDs
- ORG STUDY ID:
BLU-285-1101
- NCT ID:
NCT02508532
Conditions
- Gastrointestinal Stromal Tumors (GIST)
- Other Relapsed or Refractory Solid Tumors
Interventions
Drug | Synonyms | Arms |
---|
Avapritinib | BLU-285 | Part 1 Avapritinib (formerly BLU-285) 135 mg QD |
Purpose
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).
Trial Arms
Name | Type | Description | Interventions |
---|
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. | |
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. | |
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. | |
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. | |
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. . | |
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. | |
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. | |
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. | |
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. | |
Eligibility Criteria
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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Part 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Avapritinib |
Time Frame: | Cycle 1 (28 days) of treatment |
Safety Issue: | |
Description: | Patients with event(s) of dose-limiting toxicity |
Secondary Outcome Measures
Measure: | Maximum Plasma Drug Concentration (Cmax) |
Time Frame: | Cycle 1 Day 1 |
Safety Issue: | |
Description: | Maximum plasma drug concentration (Cmax) following a single dose of avapritinib |
Measure: | Time to Maximum Plasma Drug Concentration (Tmax) |
Time Frame: | Cycle 1 Day 1 |
Safety Issue: | |
Description: | Cycle 1 Day 1 PK time to maximum plasma drug concentration (Tmax) |
Measure: | Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose (C24) |
Time Frame: | Cycle 1 Day 1 |
Safety Issue: | |
Description: | Plasma drug concentration at 24 hours postdose prior to the next daily dose (C24) following a single dose of avapritinib |
Measure: | Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC 0-24) |
Time Frame: | Cycle 1 Day 1 |
Safety Issue: | |
Description: | Area under the plasma concentration-time curve from time 0 to 24 hours (AUC 0-24) following a single dose of avapritinib |
Measure: | Apparent Oral Clearance Unadjusted for Bioavailability (CL/F) |
Time Frame: | Cycle 1 Day 1 |
Safety Issue: | |
Description: | Apparent oral clearance unadjusted for bioavailability (CL/F) following a single dose of avapritinib |
Measure: | Apparent Volume of Distribution, Unadjusted for Bioavailability (Vz/F) |
Time Frame: | Cycle 1 Day 1 |
Safety Issue: | |
Description: | Apparent volume of distribution, unadjusted for bioavailability (Vz/F) following a single dose of avapritinib |
Measure: | Terminal Elimination Half-life (t1/2) |
Time Frame: | Cycle 1 Day 1 |
Safety Issue: | |
Description: | Terminal elimination half-life (t1/2) following a single dose of avapritinib |
Measure: | Maximum Plasma Drug Concentration (Cmax) at Steady State |
Time Frame: | Cycle 1 Day 15 |
Safety Issue: | |
Description: | Maximum plasma drug concentration (Cmax) at steady state following 15 days of QD dosing |
Measure: | Time of Maximal Concentration (Tmax) at Steady State |
Time Frame: | Cycle 1 Day 15 |
Safety Issue: | |
Description: | Time of maximal concentration (Tmax) at steady state following 15 days of QD dosing |
Measure: | Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose at Steady State (C24,ss) |
Time Frame: | Cycle 1 Day 15 |
Safety Issue: | |
Description: | Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose at steady state (C24,ss) following 15 days of QD dosing |
Measure: | 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 |
Safety Issue: | |
Description: | 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 |
Measure: | 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. |
Safety Issue: | |
Description: | 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. |
Measure: | Apparent Oral Clearance at Steady State, Unadjusted for Bioavailability (CLss/F) |
Time Frame: | Cycle 1 Day 15 |
Safety Issue: | |
Description: | Apparent oral clearance at steady state, unadjusted for bioavailability (CLss/F) following 15 days of QD dosing |
Measure: | 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. |
Safety Issue: | |
Description: | 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. |
Measure: | 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. |
Safety Issue: | |
Description: | 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. |
Measure: | 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. |
Safety Issue: | |
Description: | 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 |
Measure: | Median PFS on Last Prior Anti-cancer Therapy |
Time Frame: | Historical data collected at enrollment, all available data on prior therapy was collected |
Safety Issue: | |
Description: | 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. |
Measure: | Change From Baseline in Levels of KIT and PDGFRα Mutant Allele Fractions in Peripheral Blood |
Time Frame: | Baseline and End of treatment |
Safety Issue: | |
Description: | 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. |
Measure: | KIT, PDGFRA, and Other Cancer-relevant Mutations Present in Tumor Tissue at Baseline and EOT |
Time Frame: | Baseline and end of treatment |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Completed |
Lead Sponsor: | Blueprint Medicines Corporation |
Trial 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
- 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
Last Updated
July 2, 2021