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

NCT02508532 | Completed Phase 1 Results

• 1 other identifier: BLU-285-1101
• Study Type: interventional
• Target: 250
• Locations: 10 countries
• Sites: 19

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

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

Outcome Measures

Primary Outcomes (3)

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

  Patients with event(s) of dose-limiting toxicity

  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.

  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

  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 (19)

• Maximum Plasma Drug Concentration (Cmax)

  Cycle 1 Day 1

• Time to Maximum Plasma Drug Concentration (Tmax)

  Cycle 1 Day 1

• Plasma Drug Concentration at 24 Hours Postdose Prior to the Next Daily Dose (C24)

  Cycle 1 Day 1

• Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC 0-24)

  Cycle 1 Day 1

• Apparent Oral Clearance Unadjusted for Bioavailability (CL/F)

  Cycle 1 Day 1

Study Arms (9)

Part 1 Avapritinib (formerly BLU-285) 30 mg QD

EXPERIMENTAL

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.

Drug: Avapritinib

Part 1 Avapritinib (formerly BLU-285) 60 mg QD

EXPERIMENTAL

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.

Drug: Avapritinib

Part 1 Avapritinib (formerly BLU-285) 90 mg QD

EXPERIMENTAL

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.

Drug: Avapritinib

Part 1 Avapritinib (formerly BLU-285) 135 mg QD

EXPERIMENTAL

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.

Drug: Avapritinib

Part 1 Avapritinib (formerly BLU-285) 200 mg QD

EXPERIMENTAL

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. .

Drug: Avapritinib

Part 1 Avapritinib (formerly BLU-285) 300 mg QD

EXPERIMENTAL

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.

Drug: Avapritinib

Part 1 Avapritinib (formerly BLU-285) 400 mg QD

EXPERIMENTAL

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.

Drug: Avapritinib

Part 1 Avapritinib (formerly BLU-285) 600 mg QD

EXPERIMENTAL

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.

Drug: Avapritinib

Part 1 and Part 2 Avapritinib (formerly BLU-285) 300 mg or 400 mg QD

EXPERIMENTAL

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.

Drug: Avapritinib

Interventions

Avapritinib DRUG

avapritinib tablets

Also known as: BLU-285

Part 1 Avapritinib (formerly BLU-285) 135 mg QD; Part 1 Avapritinib (formerly BLU-285) 200 mg QD; Part 1 Avapritinib (formerly BLU-285) 30 mg QD; Part 1 Avapritinib (formerly BLU-285) 300 mg QD; Part 1 Avapritinib (formerly BLU-285) 400 mg QD; Part 1 Avapritinib (formerly BLU-285) 60 mg QD; Part 1 Avapritinib (formerly BLU-285) 600 mg QD; Part 1 Avapritinib (formerly BLU-285) 90 mg QD; Part 1 and Part 2 Avapritinib (formerly BLU-285) 300 mg or 400 mg QD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Blueprint Medicines Corporation: lead

Study Sites (19)

Scottsdale Healthcare Hospitals DBA HonorHealth

Scottsdale, Arizona, 85258, United States

Location

Sarcoma Oncology Center

Santa Monica, California, 90403, United States

Location

Sylvester Comprehensive Cancer Center

Miami, Florida, 33136, United States

Location

Cancer Treatment Centers of America

Atlanta, Georgia, 30256, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Leuven Cancer Institute University Hospitals Leuven

Leuven, 3000, Belgium

Location

Centre Leon Berard

Lyon, 69008, France

Location

Institut Gustave Roussy

Paris, 94805, France

Location

University of Duisburg-Essen

Essen, 45122, Germany

Location

Fondazione IRCCS - Istituto Nazinale dei Tumori

Milan, 20133, Italy

Location

Erasmus MC Cancer Institute

Rotterdam, 3015, Netherlands

Location

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

Warsaw, 02-781, Poland

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Vall d' Hebron Institute of Oncology (VHIO)

Barcelona, 08305, Spain

Location

Royal Marsden Hospital

London, SW3 6JJ, United Kingdom

Location

Related Publications (6)

• 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.

  PMID: 34343033 DERIVED

• 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.

  PMID: 33740926 DERIVED

• 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.

  PMID: 33465704 DERIVED

• 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.

  PMID: 33301227 DERIVED

• 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.

  PMID: 32615108 DERIVED

• 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.

  PMID: 30274985 DERIVED

MeSH Terms

Conditions

Gastrointestinal Stromal Tumors

Interventions

avapritinib

Condition Hierarchy (Ancestors)

Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases

Results Point of Contact

• Title: Medical Information
• Organization: Blueprint Medicines

medinfo@blueprintmedicines.com

1-888-258-7768

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Model Details: Dose Escalation and Dose Expansion

Study Record Dates

• First Submitted: July 23, 2015
• First Posted: July 27, 2015
• Study Start: August 1, 2015
• Primary Completion: March 6, 2020
• Study Completion: June 3, 2021
• Last Updated: June 21, 2022
• Results First Posted: June 22, 2021

Record last verified: 2021-07

Locations

KR (1); DE (1); IT (1); PL (1); BE (1); FR (2); US (9); NL (1); ES (1); GB (1)