| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Systemic Mastocytosis (AdvSM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Systemic Mastocytosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10042949 |
| E.1.2 | Term | Systemic mastocytosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 26.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056453 |
| E.1.2 | Term | Aggressive systemic mastocytosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
|
|
| E.2.2 | Secondary objectives of the trial |
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.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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, the diagnosis of AdvSM must be confirmed based on central pathology laboratory assessment of BM:
a. Aggressive SM.
b. Systematic 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 (Shahin et al. 2021).
d. Myelodysplastic syndromes with excessive blasts-2 (MDS-EB-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 HMA 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). The RAC will retrospectively assess the eligibility of enrolled patients during the study. |
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| E.4 | Principal 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 <40 mL/min.
d. Absolute neutrophil count <0.5 × 109/L.
7. Patient received prior HMA therapy (e.g., azacitidine, decitabine) for the current diagnosis.
8. At the time of enrollment, patient must not be eligible for allogeneic hematopoietic stem cell transplantation, in the opinion of the Investigator. However, patients who may become eligible for transplant after cytoreduction while on study are eligible to participate.
9. Patient received prior radiotherapy within 14 days of screening BM biopsy. Prior radiotherapy given to palliate specific sites of disease (eg, bone lesion) may be allowed with written approval of the Sponsor Medical Monitor.
10. Patient received any hematopoietic growth factor (except erythropoietin) within 14 days of screening BM biopsy, or requiring growth factors to maintain adequate neutrophil or platelet levels. Those patients maintained on a chronic dose of erythropoietin, whose hemoglobin is stable, and dose of erythropoietin has not been changed in the prior 28 days are allowed on study.
11. Patient received >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 major surgical procedures and may be performed within the 14-day window.
15. 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, GI stromal tumor, and completely resected carcinoma in situ of any site.
16. Tryptase <20 except in patients with MCL.
17. Mean resting QTcF >480 msec, a history of prolonged QT syndrome or Torsades de pointes, or a familial history of prolonged QT syndrome.
18. Patient has a history of a seizure disorder (eg, epilepsy) or requirement for antiseizure medication
19. Patient has a history of a cerebrovascular accident or transient ischemic attacks within 1 year prior to the first dose of study drug.
20. Patient has a known risk of intracranial bleeding, such as a brain aneurysm or history of subdural or subarachnoid bleeding.
21. A primary brain malignancy or metastases to the brain.
22. 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.
Please refer to the study protocol for the complete list.
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| E.5 End points |
| E.5.1 | 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, ECGs, and safety laboratory tests.
Arm 2 - 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Arm 1 - Dose escalation:
1. In the first 28 days of treatment with BLU-263 monotherapy.
Arm 1 - Dose Escalation & Dose Expansion:
1. Throughout the study
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)
Arm2 - Dose Escalation:
1. During 28 days starting from Day 15 of C1 or Day 15 of C2.
2. Throughout the study.
Arm 2 - Dose Expansion:
1. Throughout the study |
|
| E.5.2 | Secondary end point(s) |
Arm 1 - Dose Escalation & Dose Expansion:
1. Overall response rate for AdvSM, using modified IWG-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 |
|
| E.5.2.1 | 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 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| 2 arms, dose escalation - dose expansion study |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Netherlands |
| Norway |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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