Clinical trial NCT02561988: (EXPLORER) Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies
Official title: A Phase 1 Study of BLU-285 in Patients With Advanced Systemic Mastocytosis (AdvSM) and Relapsed or Refractory Myeloid Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Aggressive Systemic Mastocytosis
Systemic Mastocytosis-associated Hematologic Non-mast Cell Disease
Mast Cell Leukemia
Relapsed or Refractory Myeloid Malignancies
Lead sponsor: Blueprint Medicines Corporation
Sponsor class: INDUSTRY
First posted: 2015-09-29
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase 1, open-label, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antineoplastic activity of avapritinib (also known as BLU-285), administered orally (PO), in adult patients with advanced systemic mastocytosis and other relapsed or refractory myeloid malignancies. The study consists of 2 parts:, dose-escalation (Part 1) and expansion (Part 2).


Eligibility criteria: Inclusion Criteria:

For Part 1:Patients must have one of the following diagnoses based on World Heath Organization (WHO) diagnostic criteria:

* Aggressive systemic mastocytosis (ASM).
* Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) and at least 1 C-finding attributable to systemic mastocytosis (SM). The AHN must be myeloid, with the following exceptions that are excluded: Acute myeloid leukemia (AML), Myelodysplastic syndrome (MDS) that is very high- or high-risk as defined by the International prognostic scoring system for myelodysplastic syndromes (IPSS-R) and Philadelphia chromosome positive malignancies.
* Mast cell leukemia (MCL).
* Histologically- or cytologically- confirmed myeloid malignancy that is relapsed or refractory to standard treatments. AML, MDS that is very high- or high-risk as defined by the IPSS-R, and Philadelphia chromosome positive malignancies are excluded.
* Upon discussion with the sponsor, other relapsed or refractory, potentially avapritinib-responsive hematologic neoplasms (e.g., evidence of aberrant KIT or platelet derived growth factor receptor (PDGFR) signaling) may be considered for enrollment.

For Part 2, patients must have one of the following diagnoses, based on WHO diagnostic criteria:

* ASM.
* SM-AHN. The AHN must be myeloid, with the following exceptions that are excluded: AML, MDS that is very high- or high-risk as defined by the IPSS-R, and Philadelphia chromosome positive malignancies.
* MCL.

For Part 2, Cohort 2, patients must have at least 1 measurable C-finding per modified IWG-MRT-ECNM criteria at Baseline, attributed to SM unless diagnosis is MCL, which does not require a C-finding.

* Cytopenias: ANC \< 1.0 × 10⁹/L or hemoglobin \< 10 g/dL or platelet count \< 75 × 10⁹/L.
* Symptomatic ascites or pleural effusion requiring medical intervention such as: use of diuretics (Grade 2) or ≥ 2 therapeutic paracenteses or thoracenteses (Grade 3) at least 28 days apart over the 12 weeks before study entry and 1 of the procedures is performed during the 6 weeks before study start (C1D1).
* ≥ Grade 2 abnormalities in direct bilirubin (\> 1.5 × upper limit of normal \[ULN\]), aspartate aminotransferase (AST; \> 3.0 × ULN), alanine aminotransferase (ALT; \> 3.0 × ULN), or alkaline phosphatase (\> 2.5 × ULN) with 1 of the following present: ascites or clinically relevant portal hypertension or liver mast cell infiltration that is biopsy-proven or no other identified cause of abnormal liver function.
* ≥ Grade 2 hypoalbuminemia (\< 3.0 g/dL).
* A spleen that is palpable ≥ 5 cm below the left costal margin.
* Transfusion-dependent anemia defined as: transfusion of ≥ 6 units packed red blood cells (PRBCs) in the 12 weeks before start of treatment (C1D1) and most recent transfusion occurring during the preceding 4 weeks and transfusion administered for hemoglobin ≤ 8.5 g/dL and reason for transfusion is not bleeding, hemolysis, or therapy-related.

Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.

Exclusion Criteria:

* QT interval corrected using Fridericia's formula (QTcF) \>480 milliseconds
* Platelet count \<50,000/μL (within 4 weeks of the first dose of study drug) or receiving platelet transfusion(s)
* Absolute neutrophil count \<500/μL
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \>3 x the upper limit of normal (ULN); \>5 × ULN if associated with clinically suspected liver infiltration by mastocytosis or another disease for which the patient enrolled into the study
* Total bilirubin \>1.5 × ULN; \>3 × ULN if associated with liver infiltration by the disease being treated or in the presence of Gilbert's Disease (In the case of Gilbert's disease, a direct bilirubin \> 2.0 ULN would be an exclusion.)
* 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
* Known risk of intracranial bleeding, such as a brain aneurysm or history of subdural or subarachnoid bleeding
* Eosinophilia and known positivity for the FIP1L1-PGDFRA fusion, unless the patient has demonstrated relapse or progressive disease on prior imatinib therapy

Primary outcomes:
measure: Maximum tolerated dose (MTD) of avapritinib (also known as BLU-285)
timeFrame: During cycle 1 (28 days) of treatment
measure: Number of patients with adverse and serious adverse events and changes in physical findings, vital signs, clinical laboratory results and ECG findings
timeFrame: Approximately 24 months
measure: Recommended Phase 2 dose (RP2D) of avapritinib
timeFrame: Approximately 24 months
Secondary outcomes:
measure: Maximum plasma concentration of avapritinib
timeFrame: Every cycle (28 days) up to cycle 4
measure: Time to maximum plasma concentration of avapritinib
timeFrame: Every cycle (28 days) up to cycle 4
measure: Overall Response Rate
timeFrame: 8, 24, 40, 68 and every 24 weeks until patient terminates from the study (approximately 24 months)
measure: Morphologic response
timeFrame: ≥ 12 weeks
measure: Changes in levels of serum tryptase and levels of V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) D816V allele burden in blood
timeFrame: Cycle (C)1Day (D)1, C1D15, C2D1, C3D1, C5D1, C7D1, C11D1, C18D1 every 6 cycles thereafter and at disease progression. (approximately 24 months)
measure: Changes in patient reported symptoms and quality of life using the Patient Global Impression of Symptom Severity (PGIS) scale
timeFrame: Part 2 only - Day 1 of Cycles 1-12
measure: Changes in patient reported quality of life using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C-30)
timeFrame: Part 2 only - Day 1 of Cycles 1-12
measure: Changes in patient reported outcomes using the advanced SM symptom assessment form (AdvSM-SAF)
timeFrame: Part 2 only - daily from Day -7 through Cycle 12
measure: Change in liver volume by imaging
timeFrame: Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days)
measure: Change in spleen volume by imaging
timeFrame: Day 1 of Cycles 5-18, and every 6 cycles thereafter (each cycle is 28 days)
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Denver
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Guy's Hospital
Study officials:
References:
citation: Reiter A, Gotlib J, Alvarez-Twose I, Radia DH, Lubke J, Bobbili PJ, Wang A, Norregaard C, Dimitrijevic S, Sullivan E, Louie-Gao M, Schwaab J, Galinsky IA, Perkins C, Sperr WR, Sriskandarajah P, Chin A, Sendhil SR, Duh MS, Valent P, DeAngelo DJ. Efficacy of avapritinib versus best available therapy in the treatment of advanced systemic mastocytosis. Leukemia. 2022 Aug;36(8):2108-2120. doi: 10.1038/s41375-022-01615-z. Epub 2022 Jul 5.
citation: Reiter A, Schwaab J, DeAngelo DJ, Gotlib J, Deininger MW, Pettit KM, Alvarez-Twose I, Vannucchi AM, Panse J, Platzbecker U, Hermine O, Dybedal I, Lin HM, Rylova SN, Ehlert K, Dimitrijevic S, Radia DH. Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis. Blood Adv. 2022 Nov 8;6(21):5750-5762. doi: 10.1182/bloodadvances.2022007539.
citation: DeAngelo DJ, Radia DH, George TI, Robinson WA, Quiery AT, Drummond MW, Bose P, Hexner EO, Winton EF, Horny HP, Tugnait M, Schmidt-Kittler O, Evans EK, Lin HM, Mar BG, Verstovsek S, Deininger MW, Gotlib J. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat Med. 2021 Dec;27(12):2183-2191. doi: 10.1038/s41591-021-01538-9. Epub 2021 Dec 6.