Clinical Trials

Date: 2017-11-10

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the Connective Tissue Oncology Society 2017

Company: Blueprint Medicines (USA - MA)

Product: avapritinib (BLU-285)

Action mechanism:

• kinase inhibitor. BLU-285 is an orally available, potent and highly selective inhibitor of KIT and PDGFR?. Preclinical data have shown that BLU-285 is active across a broad spectrum of KIT and PDGFR? mutations, including PDGFR? D842V and KIT exon 17 mutations for which there are limited or no effective treatment options. Blueprint Medicines is initially developing BLU-285, an investigational medicine, for the treatment of patients with advanced GIST and advanced systemic mastocytosis.
• BLU-285 was discovered by Blueprint Medicines' research team leveraging its proprietary compound library, and the Company retains worldwide development and commercialization rights for BLU-285.
• In June 2017, BLU-285 received Breakthrough Therapy Designation from the FDA for the treatment of patients with unresectable or metastatic GIST harboring the PDGFR? D842V mutation. Previously, the FDA granted orphan drug designation to BLU-285 for the treatment of GIST. The FDA also granted Fast Track designation to BLU-285 for the treatment of patients with unresectable or metastatic GIST that progressed following treatment with imatinib and a second TKI and for the treatment of patients with unresectable or metastatic GIST in patients with the PDGFR? D842V mutation regardless of prior therapy. In addition, the European Medicines Agency has granted orphan drug designation to BLU-285 for the treatment of GIST.

Disease: gastrointestinal stromal tumors (GIST)

Therapeutic area: Cancer - Oncology - Rare diseases

Country: Belgium, France, Germany, Netherlands, UK, USA

Trial details:

• The Phase 1 clinical trial of BLU-285 is designed to evaluate the safety and tolerability of BLU-285 in adults with advanced GIST. The trial consists of two parts, a dose-escalation portion and an expansion portion. The dose-escalation portion is complete, and the MTD was determined to be 400 mg QD. Blueprint Medicines has selected 300 mg QD as the RP2D for the dose expansion portion of the trial. The expansion portion is actively enrolling patients in three defined cohorts at the RP2D consisting of (1) a cohort of patients with a PDGFR? D842V mutation, regardless of line of therapy, (2) a cohort of patients who have received imatinib and at least one other KIT-directed TKI and (3) a cohort of patients who have received imatinib and no other TKI. Trial objectives include assessing response, pharmacokinetics and pharmacodynamic measures. All response assessments use blinded, central radiology review. The three expansion cohorts of the trial are designed to enroll a total of approximately 200 patients at multiple sites in the United States, United Kingdom and European Union. (NCT02508532).

Latest news:

• • On November 10, 2017, Blueprint Medicines presented new Phase 1 clinical data for BLU-285, a potent and highly selective KIT and PDGFR? inhibitor in development as a potential treatment for patients with advanced gastrointestinal stromal tumors (GIST) at the Connective Tissue Oncology Society 2017 Annual Meeting in Maui, Hawaii. The data confirm and build upon data previously presented for BLU-285 in patients with advanced GIST, demonstrating robust clinical activity and a favorable safety profile. The data showed 67 percent of patients with heavily pretreated KIT-driven GIST treated with 300 to 400 mg of BLU-285 once daily (QD) had radiographic tumor reductions. In this population, the data also showed an objective response rate (ORR) of 17 percent and median progression free survival (PFS) of 11.5 months. In patients with PDGFR?-D842 driven GIST, the data showed an ORR of 71 percent and an estimated 12-month PFS of 78 percent. BLU-285 was well-tolerated, and most adverse events (AEs) reported by investigators were Grade 1 or 2.
• Blueprint Medicines plans to pursue expedited development of BLU-285 in patients with PDGFR? D842V-driven GIST, and the company is on track to initiate a global, randomized Phase 3 clinical trial of BLU-285 in third-line GIST in the first half of 2018, with the goal of supporting registration of BLU-285 in a broader GIST patient population. In addition, based on the strength of the data in patients with KIT-driven GIST, Blueprint Medicines also announced  an expansion of the ongoing Phase 1 trial. The company recently increased the enrollment target for patients previously treated with imatinib and at least one additional tyrosine kinase inhibitor (TKI) from 50 to 100 patients and added a new cohort to evaluate BLU-285 in second-line GIST.
• New Data from the Ongoing Phase 1 Clinical Trial of BLU-285 in Advanced GIST:  As of the data cutoff date of October 11, 2017, 116 patients had been treated with BLU-285 in the dose escalation and expansion portions of the Phase 1 clinical trial at eight dose levels (ranging from 30 mg QD to 600 mg QD), including 76 patients with KIT-driven GIST, 39 patients with PDGFR?-driven GIST, and one patient with KIT/PDGFR? wild-type GIST. The median number of prior TKI regimens was four for patients with KIT-driven GIST (ranging from two to 11), and one for patients with PDGFR?-driven GIST (ranging from zero to six). Among patients with KIT-driven GIST, 64 patients (83 percent) previously received regorafenib.
• Blueprint Medicines has selected 300 mg QD as the recommended part 2 dose (RP2D) for the expansion portion of the clinical trial, with an option for investigators to escalate patients to the maximum tolerated dose (MTD) of 400 mg QD following two treatment cycles.
• Safety Data: As of the data cutoff date, BLU-285 was generally well-tolerated. Most AEs reported by investigators were Grade 1 or 2. Across all grades, the most common treatment-emergent AEs reported by investigators (?20 percent) included nausea (56 percent), fatigue (53 percent), periorbital edema (43 percent), vomiting (41 percent), edema peripheral (34 percent), anemia (31 percent), diarrhea (31 percent), increased lacrimation (30 percent), cognitive effects (30 percent), decreased appetite (28 percent), dizziness (23 percent), constipation (22 percent) and hair color changes (22 percent). Cognitive effects are an aggregated category of individual cognitive events, each of which was observed in fewer than 20 percent of patients. Investigators reported treatment-related Grade ?3 AEs in 39 patients (34 percent), including anemia (9 percent), fatigue (7 percent), hypophosphatemia (4 percent), nausea (4 percent) and cognitive effects (3 percent). Six patients (5 percent) discontinued treatment with BLU-285 due to AEs. An additional 43 patients discontinued treatment, with 40 patients due to progressive disease and three patients who withdrew consent. Among all 116 enrolled patients, 67 remained on treatment as of the data cutoff date.
• Clinical Activity Data: As of the data cutoff date, 30 patients with KIT-driven GIST treated at 300 to 400 mg QD were evaluable for response assessments. In addition, 31 patients with PDGFR? D842-driven GIST at all doses were evaluable for response assessments, including 29 patients with a D842V mutation and two patients with other D842 mutations. Two patients with a PDGFR? exon 14 mutation were excluded from analyses of clinical activity. Patients were evaluable if they had at least one centrally reviewed radiographic scan, and all reported data are based on blinded central radiology review as per modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST 1.1 criteria) for GIST. Radiographic scans were also assessed by Choi criteria, a supportive method of response assessment in soft tissue sarcomas that has been shown to be predictive of improved prognosis in patients with advanced GIST.
• Patients with heavily pretreated KIT-driven GIST treated at doses of 300 to 400 mg QD
• Centrally assessed radiographic tumor reductions were observed in 20 of 30 evaluable patients (67 percent) across all common KIT genotypes, including mutations in exons 9, 11, 13, 14 and 17, confirmed by archival tumor biopsy and circulating tumor DNA. By mRECIST 1.1 criteria, five patients had a partial response (PR) (three confirmed, two pending confirmation), and 18 patients had stable disease (SD), representing an ORR of 17 percent and a disease control rate (DCR) of 77 percent. By Choi criteria, 16 patients had a PR and seven patients had SD, representing an ORR of 53 percent and a DCR of 77 percent. Median PFS was 11.5 months. In contrast, historical data showed a zero percent ORR and median PFS of 1.8 months in patients with TKI-resistant advanced GIST re-treated with imatinib in a third-line or later setting. Patients with PDGFR?-driven GIST
• Centrally assessed radiographic tumor reductions were observed in all 31 evaluable patients. By mRECIST 1.1 criteria, one patient had a complete response (CR) (pending confirmation), 21 patients had a PR (18 confirmed, three pending confirmation), and nine patients had SD, representing an ORR of 71 percent and a DCR of 100 percent. By Choi criteria, one patient had a CR and 30 patients had a PR, representing an ORR of 100 percent. Median PFS was not reached, and 12-month PFS was estimated to be 78 percent. In contrast, historical data showed a zero percent ORR and median PFS of 2.8 months in patients with PDGFR? D842V-driven GIST treated with imatinib.

     

Is general: Yes