(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: Active, not recruiting
• First Posted: July 27, 2015
• Last Update Posted: February 21, 2021
• 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
• Last Update Posted Date: February 21, 2021
• 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: December 22, 2017)

• Part 1: Maximum tolerated dose (MTD) and Recommended Phase 2 dose (RP2D) of avapritinib [ 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 ]
• Parts 1 and 2: 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 ]
• Part 2: Overall response rate [ Time Frame: At Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter. ]
  Either complete response (CR) or partial response (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: January 19, 2021)

• Maximum plasma concentration of avapritinib [ Time Frame: Every cycle (28 days) up to cycle 4 ]
  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
• Time to maximum plasma concentration of avapritinib [ Time Frame: Every cycle (28 days) up to cycle 4 ]
  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
• Duration of response [ Time Frame: Overall median and at 3, 6, and 12 months ]
  CR and PR
• Progression-free survival [ Time Frame: Overall median and at 3, 6, and 12 months ]
• Clinical benefit rate [ Time Frame: 16 weeks ]
  Rate of CR, PR, and SD
• Response rate as defined by Choi Criteria [ Time Frame: At Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter. ]
• Median PFS on last prior anti-cancer therapy [ Time Frame: At Cycle 3 Day 1, then every 2 cycles through Cycle 13, then every 3 cycles thereafter. ]
• KIT, PDGFRα, and other cancer-relevant 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 ]

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: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

• Intervention: Drug: Avapritinib

Study Arms

Experimental: Avapritinib (formerly BLU-285)

Avapritinib tablets for oral administration. Avapritinib will be dosed daily for 28 day cycles.

Intervention: Drug: Avapritinib

Publications *

• Heinrich MC, Jones RL, von Mehren M, Schöffski 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, Schöffski 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: Active, not recruiting
• Actual Enrollment (submitted: October 13, 2017): 250
• Original Estimated Enrollment (submitted: July 23, 2015): 60
• Estimated Study Completion Date: April 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
• Responsible Party: Blueprint Medicines Corporation
• Study Sponsor: Blueprint Medicines Corporation
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Blueprint Medicines Corporation
• Verification Date: January 2021