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

NCT ID: NCT02508532

Last Updated: 2022-06-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 250 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-08-31
• Study Completion Date: 2021-06-03

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).

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Avapritinib

Intervention Type: DRUG

avapritinib tablets

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.

Group Type: EXPERIMENTAL

Avapritinib

Intervention Type: DRUG

avapritinib tablets

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.

Group Type: EXPERIMENTAL

Avapritinib

Intervention Type: DRUG

avapritinib tablets

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.

Group Type: EXPERIMENTAL

Avapritinib

Intervention Type: DRUG

avapritinib tablets

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. .

Group Type: EXPERIMENTAL

Avapritinib

Intervention Type: DRUG

avapritinib tablets

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.

Group Type: EXPERIMENTAL

Avapritinib

Intervention Type: DRUG

avapritinib tablets

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.

Group Type: EXPERIMENTAL

Avapritinib

Intervention Type: DRUG

avapritinib tablets

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.

Group Type: EXPERIMENTAL

Avapritinib

Intervention Type: DRUG

avapritinib tablets

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.

Group Type: EXPERIMENTAL

Avapritinib

Intervention Type: DRUG

avapritinib tablets

Interventions

Avapritinib

avapritinib tablets

Intervention Type: DRUG

Other Intervention Names

BLU-285

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Blueprint Medicines Corporation

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

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

Centre Leon Berard

Lyon, , France

Institut Gustave Roussy

Paris, , France

University of Duisburg-Essen

Essen, , Germany

Fondazione IRCCS - Istituto Nazinale dei Tumori

Milan, , Italy

Erasmus MC Cancer Institute

Rotterdam, , Netherlands

Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie w Warszawie

Warsaw, , Poland

Asan Medical Center

Seoul, , South Korea

Vall d' Hebron Institute of Oncology (VHIO)

Barcelona, , Spain

Royal Marsden Hospital

London, , United Kingdom

Countries

United States; Belgium; France; Germany; Italy; Netherlands; Poland; South Korea; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 34343033 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33740926 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33465704 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33301227 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32615108 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30274985 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

BLU-285-1101

Identifier Type: -

Identifier Source: org_study_id