A Phase 1/2, open-label, 2-arm study evaluating BLU-263 as monotherapy and in combination with azacitidine, in patients with KIT altered hematologic malignancies

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 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.

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.