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)
- Conditions
- blood cancerLeukemia10024324
- Registration Number
- NL-OMON55976
- Lead Sponsor
- Biomea Fusion Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 12
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)
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 chro
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Determine the OBD and RP2D of BMF-219 monotherapy (all cohorts).<br /><br>Note that the OBD and RP2D may differ between Arm A and Arm B in Cohort 1.<br /><br><br /><br>-The OBD/RP2D will be determined based on evaluation of all available<br /><br>pharmacokinetics (PK)/pharmacodynamics (PD), target engagement, safety, and<br /><br>tolerability data.<br /><br><br /><br>- Escalation to the maximum tolerated dose (MTD) will not be performed if the<br /><br>OBD/RP2D can be identified at a lower level. Specifically, the maximum dose to<br /><br>be administered will not exceed more than one dose level above the OBD. Should<br /><br>dose limiting toxicity (DLT) be encountered at a dose level below the OBD/RP2D,<br /><br>the MTD will be defined as the highest dose that is not expected to cause DLT<br /><br>in more than 20% of subjects.</p><br>
- Secondary Outcome Measures
Name Time Method