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

Blueprint Medicines

Status and phase: Completed; Phase 1

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

Treatments: Drug: Avapritinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT02508532

BLU-285-1101

Details and patient eligibility

About

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).

Enrollment: 250 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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250 participants in 9 patient groups

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

Experimental group

Description:

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.

Treatment:

Drug: Avapritinib

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

Experimental group

Description:

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.

Treatment:

Drug: Avapritinib

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

Experimental group

Description:

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.

Treatment:

Drug: Avapritinib

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

Experimental group

Description:

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.

Treatment:

Drug: Avapritinib

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

Experimental group

Description:

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. .

Treatment:

Drug: Avapritinib

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

Experimental group

Description:

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.

Treatment:

Drug: Avapritinib

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

Experimental group

Description:

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.

Treatment:

Drug: Avapritinib

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

Experimental group

Description:

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.

Treatment:

Drug: Avapritinib

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

Experimental group

Description:

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.

Treatment:

Drug: Avapritinib