A Phase 1 first-in-human dose-escalation and dose-expansion study of BMF-219, an oral, covalent, menin inhibitor, in adult patients with acute leukemia (AL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), and chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL)

1. Read, understood, and provided written informed consent and, if applicable,
Health Insurance Portability and Accountability Act (HIPAA) authorization by
subject or legal guardian after the nature of the study has been fully
explained and must be willing to comply with all study requirements and
procedures including DLBCL tumor biopsies (Cohort 2), serial bone marrow and
peripheral blood sampling.
2. Males and females of age: >= 18 years
3. All subjects must have histologically or pathologically confirmed diagnosis
of their malignancy and/or measurable R/R disease, as follows:
a. Cohort 1 only: Refractory or relapsed acute leukemia defined as > 5% blasts
in the bone marrow or reappearance of blasts in the peripheral blood (as
defined by the NCCN in the NCCN Clinical Practice Guidelines in Oncology [NCCN
Guidelines®] for Acute Lymphoblastic Leukemia [Version 2.2021] and Acute
Myeloid Leukemia [Version 3.2021] ) Specific mutational statuses may be
required for allocation to a specific subcohort.
b. Cohort 2 only: Previously treated, pathologically confirmed de novo DLBCL,
or DLBCL transformed from previously indolent lymphoma (e.g., follicular
lymphoma) with documented clinical or radiological evidence of progressive or
persistent disease. At study entry, subjects must have measurable disease as
per the revised criteria for response assessment of lymphoma (Cheson, 2014).
c. Cohort 3 only: Measurable MM based on at least one (1) of the following:
i. Serum M-protein >= 0.5 g/dL by serum protein electrophoresis (SPEP) (for an
IgA-based myeloma, preferably by a quantitative serum IgA level)
ii. Urinary M-protein excretion >= 200 mg/24 hours
iii. Free light chain MM: Serum free light chain (sFLC) >= 10 mg/dL (100 mg/L),
provided serum FLC ratio is abnormal
iv. Of note, subjects without measurable disease in serum or urine, but with
plasmacytoma(s) >= 2.0 cm are eligible
d. Cohort 4 only: Previously treated CLL/SLL with active disease meeting any of
the following
conditions per the iwCLL 2018 criteria
i. Evidence of progressive marrow failure as manifested by the development of,
or worsening of, anemia and/or thrombocytopenia
ii. Massive (i.e., >= 6 cm below the left costal margin) or progressive or
symptomatic splenomegaly
iii. Massive nodes (i.e., >= 10 cm in longest diameter) or progressive or
symptomatic lymphadenopathy
iv. Progressive lymphocytosis with an increase of >= 50% over a 2-month period,
or lymphocyte doubling time (LDT) < 6 months. LDT can be obtained by linear
regression extrapolation of absolute lymphocyte counts obtained at intervals of
2 weeks over an observation period of 2 to 3 months; subjects with initial
blood lymphocyte counts < 30 × 109/L may require a longer observation period to
determine the LDT. Factors contributing to lymphocytosis other than CLL/SLL
(e.g., infections, steroid administration) should be excluded
v. Autoimmune complications including anemia or thrombocytopenia poorly
responsive to corticosteroids
vi. Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung,
spine)
vii. Disease-related symptoms as defined by any of the following:
a. Unintentional weight loss >= 10% within the previous 6 months
b. Significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to
perform usual activities)
c. Fevers >= 100.5°F or 38.0°C for 2 or more weeks without evidence of
infection
d. Night sweats for >= 1 month without evidence of infection
4. Subjects must be refractory or must have progressed on, or following
discontinuation of the most recent anti-cancer therapy, with the following
considerations:
a. Cohort 1 only: Have failed or are ineligible for any approved standard of
care therapies, including HSCT
b. Cohort 2 only: Must have received at least 2 previous systemic regimens for
the treatment of their de novo or transformed DLBCL (i.e., transformed from a
previously diagnosed indolent lymphoma [e.g., follicular lymphoma]) including:
i. at least 1 course of anthracycline-based chemotherapy (unless absolutely
contraindicated due to cardiac dysfunction, in which case other active agents
such as etoposide, bendamustine, or gemcitabine must have been given), and
ii. at least 1 course of anti-CD20 immunotherapy (e.g., rituximab), unless
contraindicated due to severe toxicity
Note: Subjects who were considered ineligible for standard multi-agent
immunochemotherapy must have received at least 2 prior treatment regimens
including at least 1 course of anti-CD20 antibodies and must have been approved
by the Medical Monitor. Prior stem cell transplantation is allowed; induction,
consolidation, stem cell collection, preparative regimen, and transplantation ±
maintenance are considered a single line of therapy. CAR-T therapy is allowed,
and it is considered a prior line of therapy. Subjects with either persistent
or progressive disease after discontinuing the most recent line of therapy may
be eligible for participation.
c. Cohort 3 only: Must have received at least 3 anti-MM regimens including
proteasome inhibitor (e.g., bortezomib or carfilzomib) and immunomodulatory
drug (IMiD) (e.g., lenalidomide or pomalidomide) therapy. Note:
Relapsed-and-refractory MM is defined as relapse of disease in subjects who
must have achieved minimal response (MR) or better, which either becomes
non-responsive while on salvage therapy, or progresses within 60 days of last
therapy.
d. Cohort 4 only: Must have received at least 2 prior systemic treatment
regimens.
5. ECOG PC of 0-2 and an estimated expected life expectancy of > 3 months in
the opinion of the Investigator.
6. Adequate liver function: serum bilirubin <= 1.5x upper limit of normal (ULN)
except for Gilbert*s syndrome or non-hepatic origin such as hemolysis (who must
have a total bilirubin < 3x ULN); aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) <= 2x ULN (those subjects with known liver involvement of
their disease and ALT and AST < 5x ULN may be enrolled, subject to Medical
Monitor approval).
7. Adequate renal function: estimated creatinine clearance (eCrCl) >= 60 mL/min
(Cohort 1) or eCrCl >= 30 mL/min (Cohorts 2, 3, and 4) using the Cockcroft-Gault
equation
8. Subjects in Cohorts 2 ,3 and 4 must have the following hematologic
parameters independent of transfusion and/or blood product support at least 5
days prior to laboratory testing:
a. Absolute neutrophil count (ANC) >= 500 /mm3
b. Platelet count >= 50,000 /mm3 (Cohorts 2 and 3) / >= 30,000 /mm3 (Cohort 4)
(see Section 7.1).
c. Hemoglobin >= 8.0 g/dL.
Note: subjects who have cytopenias due to significant bone marrow infiltration
do not have to meet hematologic eligibility criteria. (Significant bone marrow
infiltration is defined as > 50% disease involvement.)
9. Both men and women of childbearing potential or their partners must use
adequate birth control measures during the course of the trial and for at least
90 days after discontinuing study treatment. Subjects and/or partners who are
surgically sterile or postmenopausal are exempt from this requirement.
• Females are to be not pregnant, non-lactating, and can be postmenopausal
(defined as amenorrheic for at least 1 year while not taking oral
contraceptives [OCPs] without an alternative cause). Females of childbearing
potential must have a negative pregnancy test at screening and be willing to
have additional pregnancy tests during the study and must agree to use adequate
contraception during the study and for approximately 90 days following the last
administration of investigational product to avoid pregnancy. Adequate
contraception is defined as oral, intravaginal, transdermal, implantable or
injectable contraceptives, intrauterine devices, surgical sterilization
(achieved through hysterectomy, oophorectomy, or bilateral salpingectomy or
tubal ligation in addition to/or a combination of an intrauterine
hormone-releasing system (IUS) and spermicid

1. Certain disease subtypes or occurrences, as follows:
a. Cohort 1: APL, CML in blast crisis, iEMR.
b. Cohort 2: PMBCL, DLBCL transformed from diseases other than indolent NHL,
Burkitt Lymphoma
c. Cohort 3: Active plasma cell leukemia, myeloma with amyloidosis, systemic
light chain amyloidosis
d. Cohort 4: Known or suspected history of Richter*s transformation
2. WBC count > 50,000/ µL (uncontrollable with cytoreductive therapy) (Cohort 1
only).
3. Known central nervous involvement, as follows:
a. Cohort 1: Clinically active CNS leukemia. Previously controlled CNS leukemia
is acceptable, however
b. Cohort 2: Active CNS lymphoma or meningeal involvement
c. Cohort 3: Active CNS MM
d. Cohort 4: Active CNS leukemia
4. Prior menin inhibitor therapy (exept for subjects in Cohort 1).
5. Known positive test for human immunodeficiency virus, hepatitis C, or
hepatitis B surface antigen. Of note: HBV core Ab positive but HBV DNA negative
subjects with no prior history of reactivation with prior CD20 monoclonal
antibody exposure and prophylaxis would be allowed with reinstitution of
appropriate prophylaxis; HCV Ab positive after treatment with anti-hepatitis C
medications and viral load negative for at least 6 months would be eligible. If
the subject is known to be cytomegalovirus (CMV) IgG or CMV IgM positive, the
subject must be evaluated for the presence of CMV DNA by PCR. Subjects who are
known to be CMV IgG or CMV IgM positive but who are CMV DNA negative by PCR are
eligible. Antiviral prophylaxis should be considered per institutional protocol.
6. Subjects with a pre-existing disorder predisposing them to a serious or
life-threatening infection (e.g., cystic fibrosis, congenital or acquired
immunodeficiency, bleeding disorder, or cytopenias not related to acute
leukemia, DLBCL, MM, or CLL/SLL).
7. An active uncontrolled acute or chronic systemic fungal, bacterial, or viral
infection.
8. Significant cardiovascular disease including unstable angina pectoris,
uncontrolled hypertension or arrhythmia, history of cerebrovascular accident
including transient ischemic attack within 6 months prior to the first dose of
the study treatment, congestive heart failure (New York Heart Association
[NYHA] Class III or IV) related to primary cardiac disease, ischemic or severe
valvular heart disease, or a myocardial infarction within 6 months prior to the
first dose of study treatment. Additional cardiovascular exclusions include any
evidence of pericardial effusion or LVEF < 45% assessed by echocardiogram
(ECHO), multi-gated acquisition (MUGA), or local standard.
9. Mean QTcF or QTcB of > 470 millisecond (ms) on triplicate ECGs performed
within 5 minutes of each other.
10. Major surgery within 4 weeks prior to the first dose of study treatment.
Surgery requiring local/epidural anesthesia (excluding biopsies) must be
completed at least 72 hours before study drug administration and the subject
should be recovered.
11. Unable to swallow tablets or have gastrointestinal disease or dysfunction
that may interfere with oral absorption of study treatment, such as:
a. Chronic diarrhea or ingestion (e.g., short-gut syndrome, gastroparesis,
etc.).
b. Cirrhosis with a Child-Pugh score of B or C.
c. Post gastrectomy
12. GVHD: Signs or symptoms of acute GVHD of any severity or chronic GVHD other
than disease limited to skin that is adequately controlled with topical
steroids alone within 3 weeks of enrollment. All transplant subjects must have
been off all systemic immunosuppressive therapy and calcineurin inhibitors for
at least 3 weeks prior to enrollment. The use of topical steroids for cutaneous
GVHD is allowed and stable systemic steroid doses less than or equal to 20 mg
of prednisone or equivalent daily is permitted with Medical Monitor approval.
13. Concurrent malignancy in the previous 2 years with the exception of
adequately treated non-melanomatous skin cancer, or carcinoma in situ (e.g.,
breast carcinoma, cervical cancer in situ, melanoma in situ) treated with
potentially curative therapy; superficial bladder cancer not treated with
intravesical chemotherapy or BCG within 6 months, localized prostate cancer and
PSA <1.0 mg/dL on 2 consecutive measurements at least 3 months apart with the
most recent one being within 4 weeks of study entry. Concurrent malignancy must
be in complete response or no evidence of disease during this timeframe.
14. Any underlying medical condition (including uncontrolled diabetes and
muscular glycogenosis) that, in the Investigator*s opinion, will make the
administration of study treatment hazardous or obscure the interpretation of
toxicity determination or AEs.
15. Women who are pregnant or lactating. All female subjects with reproductive
potential must have a negative pregnancy test prior to starting study treatment.
16. Known recent (within the past year) or ongoing alcohol or drug abuse.
17. Live, attenuated vaccine within 4 weeks before the first dose of study
treatment.