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

Blueprint Medicines Corporation250 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

250

Conditions

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

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (19)

Scottsdale Healthcare Hospitals DBA HonorHealth

Scottsdale, Arizona, United States

Sarcoma Oncology Center

Santa Monica, California, United States

Sylvester Comprehensive Cancer Center

Miami, Florida, United States

Cancer Treatment Centers of America

Atlanta, Georgia, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Oregon Health and Science University

Portland, Oregon, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

MD Anderson Cancer Center

Houston, Texas, United States

Leuven Cancer Institute University Hospitals Leuven

Leuven, Belgium

...and 9 more locations

Outcomes

Primary Outcomes

Part 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Avapritinib

Patients with event(s) of dose-limiting toxicity

Time frame: 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.

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

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

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.

Secondary Outcomes

Maximum Plasma Drug Concentration (Cmax)

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

Time frame: Cycle 1 Day 1

Time to Maximum Plasma Drug Concentration (Tmax)

Cycle 1 Day 1 PK 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)

Plasma drug concentration at 24 hours postdose prior to the next daily dose (C24) following a single dose of avapritinib

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Cycle 1 Day 1

Terminal Elimination Half-life (t1/2)

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

Time frame: 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

Time frame: 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

Time frame: 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

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)

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

Time frame: 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.

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)

Apparent oral clearance at steady state, unadjusted for bioavailability (CLss/F) following 15 days of QD dosing

Time frame: 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.

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

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.

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

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

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

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.

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

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.

Time frame: 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.

Time frame: Baseline and end of treatment