Clinical trial NCT02508532: (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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Gastrointestinal Stromal Tumors (GIST)
Other Relapsed or Refractory Solid Tumors
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
Lead sponsor: Blueprint Medicines Corporation
Sponsor class: INDUSTRY
First posted: 2015-07-27
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose Escalation and Dose Expansion
Primary purpose: TREATMENT

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).


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.

Primary outcomes:
measure: Part 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Avapritinib
timeFrame: Cycle 1 (28 days) of treatment
measure: Parts 1 and 2: Number of Patients With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: 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
measure: Part 2: Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1
timeFrame: 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:
measure: Maximum Plasma Drug Concentration (Cmax)
timeFrame: Cycle 1 Day 1
measure: Time to Maximum Plasma Drug Concentration (Tmax)
timeFrame: Cycle 1 Day 1
measure: Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose (C24)
timeFrame: Cycle 1 Day 1
measure: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC 0-24)
timeFrame: Cycle 1 Day 1
measure: Apparent Oral Clearance Unadjusted for Bioavailability (CL/F)
timeFrame: Cycle 1 Day 1
measure: Apparent Volume of Distribution, Unadjusted for Bioavailability (Vz/F)
timeFrame: Cycle 1 Day 1
measure: Terminal Elimination Half-life (t1/2)
timeFrame: Cycle 1 Day 1
measure: Maximum Plasma Drug Concentration (Cmax) at Steady State
timeFrame: Cycle 1 Day 15
measure: Time of Maximal Concentration (Tmax) at Steady State
timeFrame: Cycle 1 Day 15
measure: Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose at Steady State (C24,ss)
timeFrame: Cycle 1 Day 15
measure: Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Steady Sate (AUC0-τ,ss) (τ=24 h)
timeFrame: Cycle 1 Day 15
measure: Progression-free Survival Per mRECIST Version 1.1
timeFrame: 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.
measure: Apparent Oral Clearance at Steady State, Unadjusted for Bioavailability (CLss/F)
timeFrame: Cycle 1 Day 15
measure: Clinical Benefit Rate Determined by Central Radiology Assessment Per mRECIST, Version 1.1
timeFrame: 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.
measure: Response Rate Determined by Central Radiology Assessment Per Choi Criteria
timeFrame: 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.
measure: Duration of Response Determined by Central Radiology Assessment Per mRECIST, Version 1.1
timeFrame: 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.
measure: Median PFS on Last Prior Anti-cancer Therapy
timeFrame: Historical data collected at enrollment, all available data on prior therapy was collected
measure: Change From Baseline in Levels of KIT and PDGFRα Mutant Allele Fractions in Peripheral Blood
timeFrame: Baseline and End of treatment
measure: KIT, PDGFRA, and Other Cancer-relevant Mutations Present in Tumor Tissue at Baseline and EOT
timeFrame: Baseline and end of treatment
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Scottsdale Healthcare Hospitals DBA HonorHealth
state: Arizona
city: Santa Monica
country: United States
facility: Sarcoma Oncology Center
state: California
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Cancer Treatment Centers of America
state: Georgia
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Leuven
country: Belgium
facility: Leuven Cancer Institute University Hospitals Leuven
city: Lyon
country: France
facility: Centre Leon Berard
city: Paris
country: France
facility: Institut Gustave Roussy
city: Essen
country: Germany
facility: University of Duisburg-Essen
city: Milan
country: Italy
facility: Fondazione IRCCS - Istituto Nazinale dei Tumori
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC Cancer Institute
city: Warsaw
country: Poland
facility: Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie w Warszawie
city: Barcelona
country: Spain
facility: Vall d' Hebron Institute of Oncology (VHIO)
city: London
country: United Kingdom
facility: Royal Marsden Hospital
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.