On November 30, 2016 Blueprint Medicines Corporation (NASDAQ: BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported data from its ongoing Phase 1 clinical trial evaluating BLU-285, an investigational medicine for the treatment of patients with advanced gastrointestinal stromal tumors (GIST). These data provide proof-of-concept for BLU-285, a potent, highly selective inhibitor of D842V mutant PDGFRα and Exon 17 mutant KIT. The data will be presented on Thursday, December 1, 2016 at the 28th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany (EORTC-NCI-AACR) (Free EORTC-NCI-AACR Whitepaper).

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"The clinical activity observed to date in the dose escalation portion of this Phase 1 study is promising," said Michael Heinrich, M.D., Oregon Health & Science University, an investigator for the clinical trial. "Advanced GIST is a devastating illness, marked by rapid disease progression. Seeing tumor shrinkage in 14 out of 15 PDGFRα-driven GIST patients at this point in the study is notable. I am also excited to see tumor shrinkage in four out of the six KIT-driven GIST patients treated at the higher dose levels, indicating the potential for increased clinical activity as we continue to dose-escalate. Given these encouraging early data for this investigational medicine, I believe BLU-285 could be transformative for patients with advanced GIST."

"These data help to validate Blueprint Medicines’ ability to craft targeted kinase inhibitors and to achieve rapid proof-of-concept for our investigational therapies in genomically-defined populations," said Andy Boral, M.D., Chief Medical Officer at Blueprint Medicines. "We are encouraged by the early evidence of clinical activity, with the majority of patients achieving stable disease or a partial response, and some patients having durable tumor reduction lasting at least eight months. I am also pleased that BLU-285 has been well-tolerated to date and that the pharmacokinetic profile supports once daily dosing. We continue to believe that BLU-285 has the potential to significantly impact the treatment paradigm for patients with GIST."

Data from the Ongoing Phase 1 Clinical Trial

BLU-285 is currently being evaluated in the dose escalation stage of a Phase 1 clinical trial in patients with unresectable PDGFRα-driven GIST and patients with treatment-resistant KIT-driven GIST. As of the data cutoff date of November 1, 2016, 36 patients had been treated in the dose escalation portion of the Phase 1 clinical trial at seven dose levels (ranging from 30 mg once daily (QD) to 400 mg QD), including 18 patients with PDGFRα-driven GIST and 18 patients with KIT-driven GIST. The median age was 61 (ranging from 41 to 77), and the median number of prior tyrosine-kinase inhibitor (TKI) regimens was 3.5 (ranging from zero to 12).

Preliminary pharmacokinetic analysis demonstrated relatively rapid absorption of BLU-285 and a mean half-life of over 24 hours that supports once daily dosing.

Preliminary Safety Data

As of the data cutoff date of November 1, 2016, BLU-285 was observed to be well-tolerated at all doses. The majority of adverse events (AEs) reported by investigators were Grade 1 or 2. Across all grades, AEs reported by investigators most commonly included nausea (42%), vomiting (33%), peripheral edema (31%), fatigue (28%) and constipation (22%). Investigators reported treatment-related Grade 3 AEs in three patients: nausea and vomiting (one patient); anemia and intratumoral hemorrhage (one patient); and hypophosphatemia (one patient). No dose-limiting toxicities or drug-related Grade 4 or 5 AEs were reported, and no patients discontinued BLU-285 due to treatment-related adverse events. A maximum tolerated dose (MTD) has not been reached, and enrollment in the dose escalation portion of the Phase 1 clinical trial is ongoing.

Preliminary Clinical Activity Data

As of the data cutoff date of November 1, 2016, 28 patients in the first six cohorts of the dose escalation portion of the clinical trial (at doses ranging from 30 mg QD to 300 mg QD) had completed at least two 28-day dosing cycles and were evaluable for response assessment. CT and MRI imaging was used to measure clinical activity by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.

In PDGFRα-driven GIST, investigators observed radiographic tumor reduction in 14 of 15 evaluable patients with six patients achieving a partial response (PR) by RECIST (five confirmed, one unconfirmed). Tumor reduction was observed at the first dose level in the PDGFRα-driven subgroup of advanced GIST.
In KIT-driven GIST, investigators observed radiographic tumor reduction in five of the 13 evaluable patients, including one who achieved a PR by RECIST (confirmed). At the higher dose levels (greater than or equal to 135 mg), four out of six patients had tumor reduction, including the patient with a PR, suggesting increased clinical activity with increased dose. Tumor shrinkage was first observed at the fourth dose level in the KIT-driven subgroup of advanced GIST.
Among all 36 patients treated, 27 patients remained on BLU-285, including all 18 patients with PDGFRα-driven GIST, with a duration of treatment ranging from 0.8 months to 12.3 months.
Nine patients discontinued treatment with BLU-285 due to progressive disease.
Clinical Development Plans for BLU-285 in GIST

Based on the favorable safety profile and encouraging clinical activity observed to date in the Phase 1 clinical trial for BLU-285 for the treatment of advanced GIST, Blueprint Medicines will continue to enroll patients in the dose escalation portion of this clinical trial until a MTD or a lower recommended dose for further clinical evaluation has been established. Enrollment in the expansion cohorts for this Phase 1 clinical trial is expected to begin in the first half of 2017. Blueprint Medicines plans to enroll approximately 35 patients with advanced GIST in the expansion cohorts. We also plan to accelerate our evaluation of expanded development options for BLU-285 in GIST, including opportunities to move to earlier lines of therapy and possible combinations.

In January 2016, the U.S. Food and Drug Administration (FDA) granted orphan drug designation to BLU-285 for the treatment of GIST, and in October 2016, the FDA 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 with the PDGFRα D842V mutation regardless of prior therapy. Blueprint Medicines plans to seek regulatory guidance on potential pathways for expedited clinical development of BLU-285 for the treatment of advanced GIST.