A Phase 1 Study of BLU-285 in Patients with Advanced Systemic Mastocytosis (advSM) and Relapsed or Refractory Myeloid Malignancies
There are 2 parts to this study: Part 1 (dose escalation) and Part 2 (dose expansion). The goal of Part 1 of this clinical research study is to find the highest tolerable dose of BLU-285 when given to patients with advanced systemic mastocytosis (AdvSM) or relapsed (has come back) or refractory (has not responded to treatment) myeloid malignancies. The goal of Part 2 of this study is to learn if the dose of BLU-285 found in Part 1 is safe and well-tolerated in patients with AdvSM or relapsed or refractory myeloid malignancies. This is one of the first trials using BLU-285 in humans.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: BLU-285
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Blueprint Medicines Corp.
Primary: · To determine the Maximum Tolerated Dose (MTD) and recommended phase 2 dose (RP2D) of BLU-285. · To determine the safety and tolerability of BLU-285. Secondary: · To characterize the pharmacokinetic (PK) profile of BLU-285, and correlate drug exposure with safety assessments. · To assess changes in serum tryptase concentration during treatment with BLU-285. · To assess changes in blood KIT D816V mutant allele fractions during treatment with BLU-285. · To assess changes in patient reported outcomes (PROs). · To assess preliminary evidence of BLU-285 anti-neoplastic activity. Exploratory: · To explore mechanisms of therapeutic resistance by measuring changes in the levels of KIT D816V and other pathway genes in pre- and post-progression bone marrow samples. · To assess additional measures of antitumor activity, including progression free survival (PFS), overall survival (OS), reduction in spleen volume and reduction in liver volume. To identify potential new biomarkers (deoxyribonucleic acid [DNA], ribonucleic acid [RNA], protein) in blood and bone marrow for pharmacodynamic (PD) effects, antitumor activity and safety of BLU-285.
IRB Review and Approval Date: 03/31/2016
Recruitment Status: Open
Projected Accrual: 60
1) Patient is equal to or more than 18 years of age.
2) For Part 1, patients must have one of the following diagnoses: a. ASM as confirmed by WHO diagnostic criteria. b. SM-AHNMD as confirmed by WHO diagnostic criteria, and the patient also has at least 1 C-finding attributable to SM. The AHNMD 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. c. MCL as confirmed per WHO diagnostic criteria. d. Histologically- or cytologically- confirmed myeloid malignancy as confirmed by IWG-MRT or WHO diagnostic criteria 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. e. Upon discussion with the sponsor, other relapsed or refractory, potentially BLU-285-responsive hematologic neoplasms (e.g., evidence of aberrant KIT or PDGFR signaling) may be considered for enrollment. (cont. as #3)
3) Patients may be enrolled based on the local diagnosis. The diagnosis of advSM and the subtype will be confirmed by an independent pathologist retrospectively. Independent confirmation is not required for study entry.
4) For Part 2: o Group 1: ASM as confirmed by WHO diagnostic criteria. o Group 2: SM-AHNMD as confirmed by WHO diagnostic criteria, that also has at least 1 C-finding attributable to SM. The AHNMD 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. o Group 3: MCL as confirmed per WHO diagnostic criteria. Patients may be enrolled based on the local diagnosis. The diagnosis of advSM and the subtype will be confirmed by an independent pathologist retrospectively. Independent confirmation is not required for study entry.
5) Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-3.
6) Patient or legal guardian provides informed consent to participate in the study
1) Patient has any of the following within 14 days prior to the first
dose of study drug: b. Alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) > 3 × 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. c. 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. d. Estimated or measured creatinine clearance <
40 mL/min. e. Platelet count < 25 × 10^9/L. f. Absolute neutrophil
count (ANC) < 0.5 ×10^9/L.
2) Diagnosis of AML, MDS that is very high- or high-risk as defined by the IPSS-R, or a Philadelphia chromosome positive malignancy.
3) If the patient is receiving corticosteroids, the dose must be stable for equal to or more than 7 days, with a maximum daily dose of 10 mg of prednisone (or an equipotent dose of another corticosteroid).
4) Patient received any anti-cancer drug therapy less than 5 half lives or 14 days (whichever is shorter) prior to the first dose of study drug with the exception of hydroxyurea, which the patient may have received less than 7 days prior to the first dose of study drug.
5) Patient received prior radiotherapy less than 14 days prior to the first dose of study drug.
6) Patient requires therapy with a concomitant medication that is a strong inhibitor or strong inducer of CYP3A4
7) Patient has had a major surgical procedure (minor surgical procedures such as central venous catheter placement, bone marrow biopsy, and feeding tube placement are not considered major surgical procedures) within 14 days of the first dose of study drug.
8) History of another primary malignancy that has been diagnosed or required therapy within 1 year prior to the first dose of study drug. The following are exempt from the 1-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
9) QT interval corrected using Fridericia’s formula (QTcF) > 470 milliseconds.
10) Patient has a history of prolonged QT syndrome or Torsades de pointes. Patient has a familial history of prolonged QT syndrome
11) Patient has a history of a seizure disorder (e.g., epilepsy) or requirement for anti-seizure medication.
12) Patient has a history of a cerebrovascular accident or transient ischemic attacks within 1 year prior to the first dose of study drug.
13) Patient has a known risk of intracranial bleeding, such as a brain aneurysm or history of subdural or subarachnoid bleeding.
14) A primary brain malignancy or metastases to the brain.
15) Clinically significant, uncontrolled, cardiovascular disease, including congestive heart failure Grade III or IV according to the New York Heart Association classification, myocardial infarction or unstable angina within the previous 6 months, clinically significant, uncontrolled arrhythmias, or uncontrolled hypertension.
16) Known diagnosis of human immunodeficiency virus infection or active viral hepatitis; viral testing is not required.
17) Patient is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.
18) Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 30 days after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 90 days after the last dose of study drug.
19) Women who are breast feeding
20) Patient has a prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s opinion, could affect the safety of the patient, alter the absorption, distribution, metabolism or excretion of the study drug, or impair the assessment of study results.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
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