Date: 2017-12-10
Type of
information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the 59th American Society of Hematology (ASH) Annual Meeting in Orlando
Company: Blueprint Medicines (USA - MA)
Product: avapritinib (BLU-285)
Action
mechanism:
- kinase inhibitor. BLU-285 is a selective KIT and PDGFR? inhibitor.
Disease: advanced systemic mastocytosis
Therapeutic
area: Rare diseases - Hematological diseases
Country: USA
Trial
details:
- The planned Phase 1 clinical trial for BLU-285 for the treatment of advanced systemic mastocytosis will evaluate the safety and tolerability of BLU-285 in multiple ascending doses with the goal of establishing an MTD or a recommended dose if the MTD is not achieved. Blueprint Medicines expects to enroll approximately 60 patients in this clinical trial at multiple sites in the United States and European Union. All patients will be tested retrospectively for KIT D816V mutational status. Once the MTD is reached, or a recommended dose is established, Blueprint Medicines will open expansion cohorts for specific subtypes of systemic mastocytosis. Secondary objectives include assessment of the pharmacokinetic profile of BLU-285, assessment of response rate by the International Working Group Myeloproliferative Neoplasms Research and Treatment criteria, changes in KIT D816V mutant allele fractions in bone marrow and circulating tumor DNA, and changes in patient reported outcomes.
Latest
news:
- • On December 10, 2017, Blueprint Medicines presented new data from its ongoing Phase 1 clinical trial of avapritinib (formerly known as BLU-285) at the 59th American Society of Hematology Annual Meeting and Exposition (ASH). The new data from the dose escalation portion of the Phase 1 trial showed strong clinical activity regardless of advanced systemic mastocytosis subtype, prior treatment with midostaurin or the presence of additional mutations.
- As of the data cutoff date of October 4, 2017, the data showed an overall response rate (ORR) of 72 percent and a disease control rate (DCR) of 100 percent in patients evaluable for response, based on the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria.
- As of the data cutoff date, avapritinib was well-tolerated and most adverse events (AEs) reported by investigators were Grade 1 or 2. In addition, there were no discontinuations due to treatment-related adverse events, and 30 of 32 patients remained on treatment with a median treatment duration of nine months.
- As of the data cutoff date of October 4, 2017, 32 patients had been treated with avapritinib in the dose escalation portion of the Phase 1 clinical trial at seven dose levels (ranging from 30 mg to 400 mg once daily (QD)), including 17 patients with aggressive SM (ASM), nine patients with advanced SM with an associated hematologic neoplasm (SM-AHN) and three patients with mast cell leukemia (MCL). The KIT D816V mutation was confirmed in 28 patients. Overall, 22 patients (69 percent) previously received anti-neoplastic therapy, including four patients (13 percent) who previously received midostaurin.
- Based on pharmacokinetic (PK) data, avapritinib demonstrated a mean half-life of greater than 20 hours, supporting a QD dosing regimen.
- Blueprint Medicines has selected 300 mg QD as the recommended part two dose (RP2D) for the expansion portion of this trial, which was initiated in the second quarter of 2017. A maximum tolerated dose of avapritinib in advanced SM was not determined.
- Safety Data: As of the data cutoff date, avapritinib was generally well-tolerated. Most AEs reported by investigators were Grade 1 or 2. The most common treatment-emergent AEs reported by investigators (?20 percent) across all grades included periorbital edema (59 percent), fatigue (41 percent), peripheral edema (34 percent), nausea (28 percent), anemia (28 percent), thrombocytopenia (28 percent), abdominal pain, diarrhea, respiratory tract infection, dizziness and headache (22 percent each). Investigators reported treatment-related Grade ?3 AEs in 16 patients (50 percent), with only one treatment-related Grade ?3 AE occurring in more than 10 percent of patients (neutropenia, 13 percent).
- No patients discontinued treatment due to a treatment-related AE. Two patients discontinued treatment with avapritinib, including one patient with ASM who had progressive disease with transformation to acute myeloid leukemia and one patient with SM-AHN and no identified KIT mutation (i.e., wild-type KIT). Overall, 30 of 32 patients enrolled in the dose escalation portion of the trial remained on treatment as of the data cutoff date, with a median duration of 9 months (range 4 to 19 months).Clinical Activity Data: IWG-MRT-ECNM Response Assessment - The IWG-MRT-ECNM criteria comprise a rigorous assessment of clinical response in patients with advanced SM. These criteria include objective measures of bone marrow mast cell burden, serum tryptase and improvement in organ damage as measured by a clinical improvement (CI) finding. As of the data cutoff date, 18 patients had advanced SM and were evaluable for response by the IWG-MRT-ECNM criteria.
- Across all 18 evaluable patients with advanced SM, the data showed an ORR of 72 percent and a complete response (CR) + partial response (PR) rate of 56 percent. A detailed summary of response data is provided below.
| Avapritinib in Patients with Advanced SM; Assessment of Response per IWG-MRT-ECNM Criteria |
| Best Response, Number of Patients (%)* |
ASM (n=7) |
SM-AHN (n=8) |
MCL (n=3) |
Overall (n=18) |
| CR |
2 (29%) |
0 |
0 |
2 (11%) |
| PR |
3 (43%) |
4 (50%) |
1 (33%) |
8 (44%) |
| Clinical improvement (CI) |
1 (14%) |
1 (13%) |
1 (33%) |
3 (17%) |
| Stable disease (SD) |
1 (14%) |
3 (38%) |
1 (33%) |
5 (28%) |
| ORR (CR + PR + CI) |
6 (86%) |
5 (63%) |
2 (67%) |
13 (72%) |
| CR + PR |
5 (71%) |
4 (50%) |
1 (33%) |
10 (56%) |
| *Responses pending confirmation: ASM: 2 CR; SM-AHN: 3 PR |
|
Based on these data, Blueprint Medicines plans to engage global regulatory authorities in the first half of 2018 to obtain input on registration pathways for avapritinib in patients with advanced SM and patients with indolent and smoldering SM. Subject to regulatory feedback, the company anticipates initiating a registration-enabling clinical trial of avapritinib in patients with advanced SM in the first half of 2018 and a dose escalation and proof-of-concept clinical trial of avapritinib in patients with indolent and smoldering SM in the second half of 2018. In addition, Blueprint Medicines continues to enroll patients in the expansion portion of the ongoing Phase 1 clinical trial in patients with advanced SM with the goal of generating additional data in 2018.
- Additional Clinical Assessments: In addition, results from individual components of the IWG-MRT-ECNM were reported as of the data cutoff date. Clinically meaningful improvements were observed in all evaluable patients, across all subtypes of advanced SM and at all avapritinib dose levels evaluated. All 32 enrolled patients had decreases in serum tryptase greater than 50 percent.
All 25 patients who had bone marrow mast cell infiltrate of at least 5 percent at baseline (measured by bone marrow biopsy) showed decreases in bone marrow mast cell burden. In this group, 21 patients had at least a 50 percent decrease, and 15 patients achieved a CR for bone marrow mast cell burden.
All 25 patients with centrally reviewed radiographic scans showed decreases in spleen volume. In this group, 14 patients had at least a 35 percent reduction in spleen volume.
In addition, rash improved in 13 of 15 patients with urticaria pigmentosa at baseline, based on investigator assessments. Urticaria pigmentosa is an allergy-mediated rash common in SM patients.
- • On September 10, 2015, Blueprint Medicines announced that the FDA accepted the Company's Investigational New Drug (IND) application to begin a Phase 1 clinical trial of BLU-285 in patients with advanced systemic mastocytosis (SM), a disorder of the mast cells. In this Phase 1 trial, Blueprint Medicines plans to enroll approximately 60 patients with advanced systemic mastocytosis, which includes aggressive systemic mastocytosis with associated hematological non-mast cell disorders (SM-AHNMD) and mast cell leukemia (MCL), and other relapsed or refractory myeloid malignancies at multiple sites in Europe and the United States. The trial will test the safety and tolerability of escalating doses of BLU-285, with the goal of establishing a maximum tolerated dose (MTD), or a recommended dose if the MTD is not achieved. Additional study objectives include assessing early signs of biological activity using disease-specific biomarkers and clinical efficacy as measured by response rate and patient-reported outcomes.
Is
general: Yes
