Advanced Systemic Mastocytosis Mast cell disease
Conditions
Interventions
Study treatments:
In the Monotherapy Arm, BLU-263 is to be administered once daily for 28 days of
each cycle.
In the Combination Arm, azacitidine will be administered on D1-7 or D1-5, and
D8-9 of
Sponsors
Blueprint Medicines Corporation
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: All patients: 1. Patient is >=18 years of age at the time of signing the informed consent. 2. Patient has Eastern Cooperative Oncology Group performance status of 0-2. 3. Patient, or legal guardian if permitted by local regulatory authorities, provides informed consent to participate in the study. 4. Patient must have a new BM biopsy or may use archival tissue if taken within 56 days prior to C1D1. 5. Patients receiving antineoplastic therapy within the preceding 12 weeks must have discontinued therapy due to disease progression, refractory disease, lack of efficacy, or intolerance. 6. Patient must be willing to have follow-up biopsies of BM and other affected organs to document response. 7. Patients treated with 1 prior selective KIT inhibitor (such as avapritinib or CGT9486) will be permitted on study after confirmation of KIT D816V mutation and with written approval of the study Sponsor. Patients who discontinued treatment with a prior selective KIT inhibitor due to a severe AE that was thought to be related to prior treatment will not be eligible to participate in the study. Arm 1 (Monotherapy): A1_1.For Arm 1, patients must have 1 of the following AdvSM diagnoses, based on WHO diagnostic criteria. Before enrollment, the diagnosis of AdvSM must be confirmed based on central pathology laboratory assessment of BM: a.Aggressive SM b.Systemic mastocytosis-AHN that in the opinion of the Investigator is not considered to be a candidate for HMA monotherapy (Appendix 4). Incidental indolent, low-grade lymphoid AHNs (eg, chronic lymphocytic leukemia) not requiring treatment are eligible. c.Mast cell leukemia, including diagnoses with an AHN component, that does not require a C-finding. d.Upon discussion with the Sponsor, other relapsed or refractory hematologic neoplasms with evidence of aberrant KIT or PDGFR may be considered for enrollment (eg, patients with chronic myeloid neoplasms such as subvariants of MDS/MPN that harbor activating KIT exon 17 mutations but do not fulfill the diagnostic criteria of SM-AHN and patients with myeloid/lymphoid neoplasms with PDGFRa/b fusion genes and mutations conferring resistance to imatinib eg, T674I or D842V). Arm 2 (Combination Therapy): A2_1.For Arm 2, patients must have 1 of the following SM-AHN diagnoses, based on WHO diagnostic criteria. Diagnosis of the AHN component for SM-AHN must be confirmed based on the central pathology laboratory assessment of the BM: a.Chronic myelomonocytic leukemia-2 (per WHO 2016) b.High or very high-risk MDS (per IPSS-R scoring c.Myelodysplastic syndrome/MPN accelerated diagnosis phase as defined by blast count > 10% in BM OR peripheral blood but not meeting diagnostic criteria of AML d.Myelodysplastic syndrome with excessive blasts-2 (10-19% in BM or 5 19% in peripheral blood) (per WHO 2016) e.Complex karyotype or >= 3 adverse risk mutations (per the IPSS-R cytogenic prognostic groups of Poor or Very Poor) f.Upon discussion with the Sponsor and in consultation with the Response Assessment Committee where needed, hematologic neoplasms which are felt to have strong rationale to consider the combination treatment of BLU-263 and HMA may be considered for enrollment (eg, patients with chronic myeloid neoplasms, such as subvariants of MDS/MPN that harbor activating KIT exon 1
Exclusion criteria
Exclusion criteria: All Patients: 1. Diagnosis of a Philadelphia chromosome positive malignancy. 2. Acute myeloid leukemia. 3. If the patient is receiving corticosteroids, and the dose has not been stable for >=7 days. This exclusion criterion is not applicable if a patient has disease that is progressing and there is a safety concern around delaying the patient's study enrollment in order to stabilize the steroid dose and it is in the patient's best interest to enroll in the study rapidly. In such cases, patients may be considered for enrollment following Sponsor Medical Monitor approval. 4. Within the 14 days prior to enrollment, patient has received any antineoplastic therapy (including midostaurin, avapritinib and other TKIs) or an investigational agent. Before obtaining the Screening BM Biopsy, at least 28 days must have elapsed since the most recent dose of Cladribine, interferon alpha, pegylated interferon and any antibody therapy (eg, brentuximab, vedotin). If the site is unsure of the appropriate wash out period for a specific drug product, they should consult the Medical Monitor. 5. Patient has received hydroxyurea within 7 days prior to the first dose of BLU-263. 6. Have any of the following laboratory abnormalities on last laboratory assessment within 14 days prior to the first dose of initiation of study drug: a. Alanine aminotransferase and AST >3 × ULN; >5 × ULN if associated with clinically suspected liver infiltration by mastocytosis or another disease for which the patient enrolled into the study. b. 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.) c. Estimated (Cockcroft-Gault formula) or measured creatinine clearance 1 prior selective KIT inhibitor (eg, avapritinib or CGT9486). 12. Patients who discontinued treatment with a prior selective KIT inhibitor due to a severe AE that was thought to be related to prior treatment will not be eligible to participate in the study. 13. Patient requires therapy with a concomitant medication that is a strong inhibitor, strong inducer, or moderate inducer of CYP3A4. 14. Patient has had a major surgical pr
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Monotherapy (Arm 1): Part 1 (dose escalation): Primary objective: • To determine the RD for BLU-263 monotherapy Primary endpoints: • The RD will be primarily determined by the number of DLTs in the first 28 days of treatment with BLU-263 monotherapy. Part 2 (dose escalation and expansion): Primary objectives: • To assess the safety and tolerability of BLU-263 monotherapy • To assess clinical efficacy of BLU-263 given as monotherapy at the RD to patients with AdvSM. Primary endpoints: • Safety profile of BLU-263, as assessed by the type, frequency, severity, timing, and relationship to study drug of any AEs or SAEs, and changes in vital signs, ECGs, and safety laboratory tests. • Pure pathological response rate for SM in selective KIT inhibitor-naïve patients. Combination (Arm 2): Part 1 (dose escalation): Primary objectives: • To determine the RD for BLU-263 in combination with azacitidine in patients with SM-AHN. • To assess the safety and tolerability of BLU-263 in combination with azacitidine. Primary endpoints: • The RD will be primarily determined by the number of DLTs (during 28 days starting from Day 15 of C1 or Day 15 of C2) with BLU-263 in combination with azacitidine. • Safety profile of BLU-263, as assessed by the type, frequency, severity, timing, and relationship to study drug of any AEs or SAEs, and changes in vital signs, ECGs, and safety laboratory tests. Part 2 (dose expansion): Primary objective: • To assess the safety and tolerability of BLU-263 in combination with azacitidine. Primary endpoints: • Safety profile of BLU-263, as assessed by the type, frequency, severity, timing, and relationship to study drug of any AEs or SAEs, and changes in vital signs, ECGs, and safety laboratory tests. | — |
Secondary
| Measure | Time frame |
|---|---|
| Monotherapy (Arm 1): Dose escalation and expansion: Secundary objectives: • To assess the ORR • To characterize the PK profile of BLU-263 when given as monotherapy • To determine the overall survival (OS) of patients with AdvSM treated with BLU-263 • To assess additional measures of clinical efficacy of BLU-263 given as monotherapy Secundairy endpoints: • Overall response rate for AdvSM, using mIWG-MRT-ECNM • Pharmacokinetic parameters of BLU-263 including: Cmax, Tmax, AUC0-24, Vz/F, t*, CL/F, and accumulation ratio • Overall Survival. • Time-to-response, DOR, and PFS, • Proportion of patients pursuing stem cell transplant. Combination (Arm 2): Dose escalation and expansion: Secundary objectives: • To assess the ORR • To assess the PPR for SM of BLU-263 given in combination with azacitidine. • To assess the PK of BLU-263 and azacitidine when given alone and in combination. Secundairy endpoints: • Overall response rate for SM, using mIWG-MRT-ECNM • Pure pathological response for SM • Pharmacokinetic parameters of BLU-263 and azacitidine including: Cmax, Tmax, AUC0-24, Vz/F, t*, CL/F, and accumulation ratio | — |
Countries
Netherlands
Outcome results
None listed