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

• ClinicalTrials.gov Identifier: NCT02508532
• Recruitment Status: Completed
• First Posted: July 27, 2015
• Results First Posted: June 22, 2021
• Last Update Posted: June 21, 2022
• Sponsor: Blueprint Medicines Corporation
• Information provided by (Responsible Party): Blueprint Medicines Corporation

Tracking Information

• First Submitted Date: July 23, 2015
• First Posted Date: July 27, 2015
• Results First Submitted Date: March 5, 2021
• Results First Posted Date: June 22, 2021
• Last Update Posted Date: June 21, 2022
• Actual Study Start Date: August 2015
• Actual Primary Completion Date: March 6, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 27, 2021)

• 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

Original Primary Outcome Measures (submitted: July 23, 2015)

• Maximum tolerated dose (MTD) and Recommended Phase 2 dose (RP2D) of BLU-285 [ Time Frame: During cycle 1 (28 days) of treatment for MTD and at the end of every cycle (28 days) for RP2D for approximately 24 months or earlier if patient terminates from the study ]
• Number of patients with adverse and serious adverse events and changes in physical findings, vital signs, clinical laboratory results and ECG findings [ Time Frame: Every cycle (28 days) for approximately 24 months or earlier if patient terminates from the study ]

Current Secondary Outcome Measures (submitted: May 27, 2021)

• Maximum Plasma Drug Concentration (Cmax) [ Time Frame: Cycle 1 Day 1 ]
  Maximum plasma drug concentration (Cmax) following a single dose of avapritinib
• Time to Maximum Plasma Drug Concentration (Tmax) [ Time Frame: Cycle 1 Day 1 ]
  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) [ Time Frame: Cycle 1 Day 1 ]
  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) [ Time Frame: Cycle 1 Day 1 ]
  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) [ Time Frame: Cycle 1 Day 1 ]
  Apparent oral clearance unadjusted for bioavailability (CL/F) following a single dose of avapritinib
• Apparent Volume of Distribution, Unadjusted for Bioavailability (Vz/F) [ Time Frame: Cycle 1 Day 1 ]
  Apparent volume of distribution, unadjusted for bioavailability (Vz/F) following a single dose of avapritinib
• Terminal Elimination Half-life (t1/2) [ Time Frame: Cycle 1 Day 1 ]
  Terminal elimination half-life (t1/2) following a single dose of avapritinib
• Maximum Plasma Drug Concentration (Cmax) at Steady State [ Time Frame: Cycle 1 Day 15 ]
  Maximum plasma drug concentration (Cmax) at steady state following 15 days of QD dosing
• Time of Maximal Concentration (Tmax) at Steady State [ Time Frame: Cycle 1 Day 15 ]
  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) [ Time Frame: Cycle 1 Day 15 ]
  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) [ 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) following 15 days of QD dosing
• 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. ]
  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) [ Time Frame: Cycle 1 Day 15 ]
  Apparent oral clearance at steady state, unadjusted for bioavailability (CLss/F) following 15 days of QD dosing
• 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. ]
  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.
• 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. ]
  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 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. ]
  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
• Median PFS on Last Prior Anti-cancer Therapy [ Time Frame: Historical data collected at enrollment, all available data on prior therapy was collected ]
  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 From Baseline in Levels of KIT and PDGFRα Mutant Allele Fractions in Peripheral Blood [ Time Frame: Baseline and End of treatment ]
  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.
• KIT, PDGFRA, and Other Cancer-relevant Mutations Present in Tumor Tissue at Baseline and EOT [ Time Frame: Baseline and end of treatment ]
  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.

Original Secondary Outcome Measures (submitted: July 23, 2015)

• Maximum plasma concentration of BLU-285 [ Time Frame: Every cycle (28 days) up to cycle 4 and at end of treatment (approximately 24 months or earlier if patient terminates from the study ]
  Blood samples may be taken at pre-dose, and 0.5, 1, 2, 4, 6, 8 and 24 hrs post dose on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1 and end of treatment (EOT)
• Time to maximum plasma concentration of BLU-285 [ Time Frame: Every cycle (28 days) up to cycle 4 and at end of treatment (approximately 24 months or earlier if patient terminates from the study ]
  Blood samples may be taken at pre-dose, and 0.5, 1, 2, 4, 6, 8 and 24 hrs post dose on Cycle 1 Day 1 and Cycle 1 Day 15, Pre-dose of Cycle 2 to 4, Day 1 and end of treatment (EOT)
• Overall Response Rate [ Time Frame: 16 Weeks ]
  Either complete response (CR) or partial response (PR)
• Duration of Response [ Time Frame: 16 weeks ]
  CR, PR and stable disease (SD)
• KIT and PDGFRα mutations present in tumor tissue at baseline and EOT [ Time Frame: Screening period (Day -31 to Day 0 before first dose) and at the end of treatment ]
• Change from baseline in levels of KIT and PDGFRα mutant allele fractions in peripheral blood [ Time Frame: Baseline, Cycle 1 day 15, Cycle 2 and 3 day 1 and at End of treatment (at approximately 24 months or earlier if patient terminates from the study) and at the EOT ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Dose Escalation and Dose Expansion

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

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

Intervention

Drug: Avapritinib

avapritinib tablets

Other Name: BLU-285

Study Arms

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

  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.

  Intervention: Drug: Avapritinib
• Experimental: Part 1 Avapritinib (formerly BLU-285) 60 mg QD

  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.

  Intervention: Drug: Avapritinib
• Experimental: Part 1 Avapritinib (formerly BLU-285) 90 mg QD

  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.

  Intervention: Drug: Avapritinib
• Experimental: Part 1 Avapritinib (formerly BLU-285) 135 mg QD

  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.

  Intervention: Drug: Avapritinib
• Experimental: Part 1 Avapritinib (formerly BLU-285) 200 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. .

  Intervention: Drug: Avapritinib
• Experimental: Part 1 Avapritinib (formerly BLU-285) 300 mg QD

  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.

  Intervention: Drug: Avapritinib
• Experimental: Part 1 Avapritinib (formerly BLU-285) 400 mg QD

  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.

  Intervention: Drug: Avapritinib
• Experimental: Part 1 Avapritinib (formerly BLU-285) 600 mg QD

  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.

  Intervention: Drug: Avapritinib
• Experimental: Part 1 and Part 2 Avapritinib (formerly BLU-285) 300 mg 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.

  Intervention: Drug: Avapritinib

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.
• von 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.
• Jones 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.
• Joseph 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.
• Heinrich 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. Erratum In: Lancet Oncol. 2020 Sep;21(9):e418.
• Gebreyohannes 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 13, 2017): 250
• Original Estimated Enrollment (submitted: July 23, 2015): 60
• Actual Study Completion Date: June 3, 2021
• Actual Primary Completion Date: March 6, 2020 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, France, Germany, Italy, Korea, Republic of, Netherlands, Poland, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT02508532
• Other Study ID Numbers: BLU-285-1101
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Blueprint Medicines Corporation
• Original Responsible Party: Same as current
• Current Study Sponsor: Blueprint Medicines Corporation
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Blueprint Medicines Corporation
• Verification Date: July 2021