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Completed

NCT Number: NCT02508532

(NAVIGATOR) 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).

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Key information

Conditions

Gastrointestinal Stromal Tumors (GIST) Digestive System Diseases Digestive System Neoplasms Gastrointestinal Diseases Gastrointestinal Neoplasms Gastrointestinal Stromal Tumors Neoplasms Neoplasms by Histologic Type Neoplasms, Connective Tissue Neoplasms, Connective and Soft Tissue Other Relapsed or Refractory Solid Tumors

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Leuven Cancer Institute University Hospitals Leuven, Leuven, Belgium

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Avapritinib

Drug

avapritinib tablets

Other names: BLU-285

Primary outcomes

  1. 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

  2. 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.

  3. 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

Secondary outcomes

  1. Maximum Plasma Drug Concentration (Cmax)

    Time frame: Cycle 1 Day 1

    Maximum plasma drug concentration (Cmax) following a single dose of avapritinib

  2. 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)

  3. 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

  4. 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

  5. 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

  6. 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

  7. Terminal Elimination Half-life (t1/2)

    Time frame: Cycle 1 Day 1

    Terminal elimination half-life (t1/2) following a single dose of avapritinib

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

Sponsors and collaborators

Lead sponsor

Blueprint Medicines Corporation

Industry

Registry information

Official study title

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

Important dates

Study start
2015
Primary completion
2020
Study completion
2021
First posted
Jul 27, 2015
Registry last updated
Jun 21, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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