Advanced Systemic Mastocytosis (AdvSM) MedDRA version: 21.1 Level: PT Classification code 10042949 Term: Systemic mastocytosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 26.1 Level: LLT Classification code 10056453 Term: Aggressive systemic mastocytosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: BLU-263
Product Code: BLU-263
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: BLU-263
CAS Number: 2505078-08-8
Current Sponsor code: BLU-263
Concentration unit: mg milli
Sponsors
Blueprint Medicines Corporation
Eligibility
Sex/Gender
All
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 (see Appendix 3). 3. Patient, or legal guardian if permitted by local regulatory authorities, provides informed consent to participate in the study. In Germany, only those patients capable of providing informed consent personally are allowed to be included 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, 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, such as T674I or D842V). A1_2. In France, patients enrolled in the monotherapy arm must have had at least 1 prior standard therapy unless contraindicated. 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 of SM-AHN must be confirmed based on the central pathology laboratory assessment of the BM: a. Chronic myelomonocytic leukemia 2 (per WHO 2016; Appendix 5). b. High or very high risk MDS (per IPSS-R scoring; Appendix 4). 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 syndromes with excessive blasts-2 (10-19% in BM or 5-19% in peripheral blood) (per WHO 2016; Appendix 6). e. Complex karyotype or =3 adverse risk mutations (per the IPSS-R cytogenic prognostic groups of Poor or Very Poor [Appendix 4] Table C.) 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 H
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 procedure within 14 days of the first dose of study drug. Minor surgical procedures such as central venous catheter placement, bone marrow biopsy, and feeding tube placement are not considered
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Arm 1 - Dose Escalation: 1. To determine the RD for BLU-263 monotherapy Arm 1 - Dose Escalation & Dose Expansion: 1. To assess the safety and tolerability of BLU-263 monotherapy 2. To assess clinical efficacy of BLU-263 given as monotherapy at the RD to patients with AdvSM. Arm 2 - Dose Escalation: 1. To determine the RD for BLU-263 in combination with azacitidine in patients with SM-AHN. 2. To assess the safety and tolerability of BLU-263 in combination with azacitidine. Arm 2 - Dose Expansion: 1. To assess the safety and tolerability of BLU-263 in combination with azacitidine. ;Secondary Objective: Arm 1 - Dose Escalation & Dose Expansion: 1. To assess the ORR 2. To characterize the PK profile of BLU263 when given as monotherapy 3. To determine the OS of patients with AdvSM treated with BLU-263 4. To assess additional measures of clinical efficacy of BLU-263 given as monotherapy Arm 2 - Dose Escalation & Dose Expansion: 1. To assess the ORR 2. To assess the PPR rate for SM of BLU-263 given in combination with azacitidine. 3. To assess the PK of BLU-263 and azacitidine when given alone and in combination. ;Primary end point(s): Arm 1 - Dose escalation: 1. The RD will be primarily determined by the number of DLTs in the first 28 days of treatment with BLU-263 monotherapy. Arm 1 - Dose Escalation & Dose Expansion: 1. 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. 2. Pure pathological response rate for SM in selective KIT inhibitor-naïve patients. Arm2 - Dose Escalation: 1. 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. 2. 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, EC | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Arm 1 - Dose Escalation & Dose Expansion: 1. Overall response rate for AdvSM, using mIWG-MRT-ECNM 2. Pharmacokinetic parameters of BLU-263 including: Cmax, Tmax, AUC0-24, Vz/F, t½, CL/F, and accumulation ratio 3. Overall survival 4. Time-to-response, DOR, and PFS. 5. Proportion of patients pursuing stem cell transplant. Arm 2: 1. Overall response rate for SM, using modified IWG-MRT-ECNM 2. Pure pathological response rate for SM 3. Pharmacokinetic parameters of BLU-263 and azacitidine including: Cmax, Tmax, AUC0-24, Vz/F, t½, CL/F, and accumulation ratio;Timepoint(s) of evaluation of this end point: Arm 1 - Dose Escalation & Dose Expansion: 1. C3D1, C7D1, C11D1 and C17D1 and then every 6 cycles (eg. C23, C29, C35 etc); EoT (14 days post last dose); every 6 Month (F/U for PFS) 2. PK Dose Escalation/Dose Expansion: please refer to Table 2 of the study protocol 3. Throughout the study 4. Throughout the study 5. Throughout the study Arm 2: 1. C3D1, C7D1, C11D1 and C17D1 and then every 6 cycles (eg. C23, C29, C35 etc); EoT (14 days post last dose); every 6 Month (F/U for PFS) 2. C3D1, C7D1, C11D1 and C17D1 and then every 6 cycles (eg. C23, C29, C35 etc); EoT (14 days post last dose); every 6 Month (F/U for PFS) 3. PK Dose Escalation/Dose Expansion: please refer to Table 3 of the study protocol | — |
Countries
Belgium, France, Germany, Netherlands, Norway, Spain, United Kingdom, United States
Contacts
Public ContactGemma María García Aguilar
PPD, part of Thermo Fisher Scientific
Outcome results
None listed