Blueprint Medicines Announces New Phase 1 Clinical Data for BLU-285 in Advanced Gastrointestinal Stromal Tumors and Plans to Pursue Expedited Development in Patients with a PDGFRα D842V Mutation
"Advanced GIST is a devastating disease marked by rapid disease progression, and patients with PDGFRα-driven GIST and treatment-resistant KIT-driven GIST have limited or no effective treatments," said
New Data from the Ongoing Phase 1 Clinical Trial of BLU-285 in Advanced GIST
BLU-285 is currently being evaluated in a Phase 1 clinical trial in patients with unresectable PDGFRα-driven GIST and patients with treatment-resistant KIT-driven GIST. Following completion of the dose escalation portion of the trial and determination of the maximum tolerated dose (MTD),
As of the data cutoff date of
Pharmacokinetic (PK) data demonstrated a mean half-life of more than 24 hours, supporting a once-daily dosing regimen. Consistent with previously reported preclinical data, PK data from the ongoing clinical trial suggested that exposure at dose levels ranging from 300 to 400 mg QD confers activity against a broad spectrum of disease-driving mutations.
As of the data cutoff date, BLU-285 was observed to be well-tolerated. Most AEs reported by investigators were Grade 1 or 2. Across all grades, AEs reported by investigators most commonly included nausea (60 percent), fatigue (53 percent), vomiting (42 percent), periorbital edema (36 percent), diarrhea (33 percent), and peripheral edema (31 percent). Investigators reported treatment-related Grade ≥3 AEs in 18 patients (25 percent). Grade ≥3 AEs occurring in two or more patients included fatigue, hypophosphatemia, anemia, nausea, vomiting and hyperbilirubinemia. Two patients experienced dose-limiting toxicities at 600 mg QD (Grade 2 hyperbilirubinemia in one patient; Grade 2 rash, Grade 2 hypertension and Grade 2 memory impairment all in one patient), leading to the determination of 400 mg QD as the MTD. Only one patient discontinued treatment with BLU-285 due to a drug-related toxicity (Grade 3 hyperbilirubinemia). An additional 20 patients discontinued treatment, including 19 patients due to progressive disease and one patient due to the investigator's decision. Among all 72 enrolled patients, 51 remained on the trial as of the data cutoff date.
Clinical Activity Data
As of the data cutoff date, 26 patients with PDGFRα-driven GIST were evaluable for response assessment, including 23 patients with a D842V mutation, two patients with other D842 mutations, and one patient with an exon 14 mutation who was excluded from analyses of clinical activity. In addition, 25 patients with KIT-driven GIST were evaluable for response assessment. Patients were evaluable if they had at least one centrally reviewed radiographic scan, and all reported data are based on blinded central radiographic review as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Radiographic scans were also assessed by Choi criteria, a supportive method of response assessment in soft tissue sarcoma. An additional 21 enrolled patients had not been evaluated for response by the data cutoff date.
PDGFRα D842-driven GIST
- Radiographic tumor reductions were observed in 25 of 25 evaluable patients with PDGFRα D842-driven GIST.
- By RECIST criteria, 15 patients had a partial response (PR) (12 confirmed, three pending confirmation), and 10 patients had stable disease (SD), representing a preliminary objective response rate (ORR) of 60 percent and a disease control rate (DCR) of 100 percent.
- By Choi criteria, 25 patients had a PR, representing an ORR of 100 percent.
- Median PFS was not reached and 9-month PFS was estimated to be 87 percent. In contrast, historical data showed a zero percent ORR and median PFS of 2.8 months in patients with PDGFRα D842V–driven GIST treated with imatinib.1
Treatment-resistant KIT-driven GIST
- Radiographic tumor reductions were observed in 10 of 25 evaluable patients, including patients with complex genotypes involving primary and secondary KIT mutations (e.g., mutations in exons 8, 9, 11, 13, 17 and 18).
- In patients treated at dose levels of at least 300 mg QD, eight of 14 patients had tumor reductions per RECIST, including one patient who achieved a PR.
- By RECIST criteria, two patients had a PR (one confirmed, one pending confirmation), and 12 patients had SD, representing a preliminary ORR of eight percent and a DCR of 56 percent.
- By Choi criteria, eight patients had a PR, and six patients had SD, representing a preliminary ORR of 32 percent and a DCR of 56 percent.
- Median PFS among patients treated at dose levels of at least 300 mg QD was 9.3 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.2
Investor Event and Webcast Information
Informational Webinar for the
About the Phase 1 Clinical Trial for BLU-285 in PDGFRα-Driven and KIT-Driven GIST
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 has been determined to be 400 mg QD. The expansion portion is actively enrolling patients in two defined cohorts, including a cohort of patients with a PDGFRα D842V mutation, regardless of line of therapy, and a cohort of patients who have received imatinib and at least one other KIT-directed TKI. Trial objectives include assessing response, pharmacokinetics and pharmacodynamic measures. The two expansion cohorts of the trial are designed to enroll approximately 100 patients at multiple sites in the United States, United Kingdom and European Union. Please refer to www.clinicaltrials.gov for additional details related to this Phase 1 clinical trial (NCT02508532). Patients and physicians may contact the study director for more information about this Phase 1 clinical trial at firstname.lastname@example.org.
GIST is the most common sarcoma, or tumor of bone or connective tissue, of the gastrointestinal (GI) tract. Tumors arise from cells in the wall of the GI tract and occur most often in the stomach or small intestine. Most patients are diagnosed between the ages of 50-80, and diagnosis is typically triggered by GI bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or GI obstruction. Approximately 80 percent of GIST patients have KIT-driven GIST, and Blueprint Medicines estimates that KIT exon 17 mutations occur in approximately 90 percent of GIST patients with KIT-driven GIST following treatment with at least two TKIs. Approximately five percent of all advanced GIST cases are driven by D842V mutant PDGFRα. Patients diagnosed with GIST at an early stage may undergo surgery. For patients with KIT-driven GIST, treatment with the currently approved frontline therapy typically leads to treatment resistance and disease progression. Treatment options for KIT-driven GIST patients whose disease progresses or develops resistance are currently limited, with approved therapies providing a progression free survival of up to six months and a response rate between five percent and seven percent. There are no effective treatment options for patients with PDGFRα D842V-driven GIST, and progression often occurs in as little as three months with available treatment options.
BLU-285 is an orally available, potent and highly selective inhibitor of PDGFRα and KIT. Preclinical data have shown that BLU-285 is active across a broad spectrum of PDGFRα and KIT mutations, including PDGFRα 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.
Blueprint Medicines is developing a new generation of targeted and potent kinase medicines to improve the lives of patients with genomically defined diseases. Its approach is rooted in a deep understanding of the genetic blueprint of cancer and other diseases driven by the abnormal activation of kinases. Blueprint Medicines is advancing four programs in clinical development for subsets of patients with gastrointestinal stromal tumors, hepatocellular carcinoma, systemic mastocytosis, non-small cell lung cancer, medullary thyroid cancer and other advanced solid tumors, as well as multiple programs in research and preclinical development. For more information, please visit www.blueprintmedicines.com.
1 Cassier PA, Fumagalli E, Rutkowski P, et al. Outcome of Patients with Platelet-Derived Growth Factor Receptor Alpha–Mutated Gastrointestinal Stromal Tumors in the Tyrosine Kinase Inhibitor Era.
2 Kang YK, Ryu MH, Ryoo BY, et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1175–82.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding plans and timelines for the clinical development of BLU-285, including plans and timelines for pursuing expedited development in patients with a PDGFRα D842V mutation and plans and timelines for the initiation of a global, pivotal Phase 3 clinical trial of BLU-285;
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Investor Relations: Kristin Hodous, Blueprint Medicines Corporation, 617-714-6674, KHodous@blueprintmedicines.com; Media Relations: Rachel Hutman, W20 Group, 301-801-5540, email@example.com