IRB Study Number 22-247
Status Recruiting
Phase Phase 1
Institute Taussig Cancer Institute
Description
5.1 Primary Objectives
The primary objectives of the study are to:
Determine the optimal biological dose(s) [OBD(s)] and recommended Phase 2 dose (RP2D) of BMF-219 monotherapy administered daily based on evaluation of all available PK/ PD, target engagement, safety, and tolerability data.
Note that the OBD and RP2D may differ between arms and/or cohorts.
5.2 Secondary Objectives
The secondary objectives of the study are to:
Evaluate the safety as expressed by treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). [Time Frame: During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first.] (all cohorts)
Determine maximum observed plasma concentration (Cmax) of BMF-219; Time to reach maximum observed concentration (Tmax); Area under plasma-concentration time curve from time 0 to time of last quantifiable concentration (AUC0-last). [Time Frame: Blood samples for determination of BMF-219 concentration will be collected during Cycle 1 and Cycle 2] (all cohorts)
Evaluate the efficacy of BMF-219 as measured by complete response rate (CRR) (Cohort 1) or objective response rate (ORR) (Cohorts 2, 3, and 4) per Investigator assessment based on:
− Cohort 1: per modified Cheson (2003) criteria in AML or the NCCN Clinical Practice Guidelines, ALL (Version 1.2022) (Appendix 14.11)
− Cohort 2: Revised criteria for response assessment of lymphoma (Cheson, 2014)
− Cohort 3: International Myeloma Working Group (IMWG) response criteria (Kumar, 2016)
− Cohort 4: iwCLL guidelines (Hallek, 2018)
- Assess additional evidence of antitumor activity as measured by the following based on the applicable guidelines above:
− Cohort 1: Complete response rate (CRR), complete response rate composite (CRRc), duration of complete response (DOCR), duration of complete response composite (DOCRc), duration of response (DOR), time to relapse, relapse-free survival (RFS), time to response, time to complete response (TTCR), and overall survival (OS)
− Cohort 2: CRR, DOCR, DOR, disease control rate (DCR), duration of DC (DDC), time to progression (TTP), progression-free survival (PFS), time to response, TTCR, and OS
− Cohort 3: CRR, DOCR, DOR, DCR, DDC, TTP, progression-free survival (PFS), time to response, TTCR, and OS
− Cohort 4: CRR, CRRc, DOCR, DOCRc, DOR, DCR, DDC, time to progression (TTP), progression-free survival (PFS), time to response, TTCR, and OS
Inclusion Criteria
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.
Males and females of age: > 18 years
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 1.2022] and Acute Myeloid Leukemia [Version 3.2021] ). Specific mutational statuses may be required for allocation to a specific subcohort (see Table 9).
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 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 the 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
- 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 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.
ECOG PS of 0-2 and an estimated expected life expectancy of > 3 months in the opinion of the Investigator.
Adequate liver function: serum bilirubin ≤ 1.5 × 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 lanine aminotransferase (ALT) ≤ 2× ULN (those subjects with known liver involvement of their disease and ALT and AST < 5x ULN may be enrolled, subject to Medical Monitor approval).
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
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. ANC ≥ 500 / mm3
b. Platelet count ≥ 50,000 / mm3 (Cohorts 2 and 3) / ≥ 30,000 /mm3 (Cohort 4).
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.)
- 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
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 the 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
- 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.
ECOG PS of 0-2 and an estimated expected life expectancy of > 3 months in the opinion of the Investigator.
Adequate liver function: serum bilirubin ≤ 1.5 × 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) ≤ 2× ULN (those subjects with known liver involvement of their disease and ALT and AST < 5x ULN may be enrolled, subject to Medical Monitor approval).
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
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. ANC ≥ 500 / mm3
b. Platelet count ≥ 50,000 / mm3 (Cohorts 2 and 3) / ≥ 30,000 /mm3 (Cohort 4).
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.)
- 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 spermicide for at least 90 days.
• Females must be willing to refrain from egg donation, and in vitro fertilization during treatment and until the end of contraception requirement. If needed, female subjects should be advised to seek guidance about egg donation and cryopreservation of germ cells before treatment.
• Males with partners who are female with reproductive potential must agree to commit to either continued abstinence from sexual intercourse or that they or their partners will use at least 2 effective contraceptive methods (when engaging in reproductive sexual activity throughout the study) and will avoid conceiving for 90 days after the last dose of BMF-219. Males must be willing to refrain from sperm donation during treatment and until the end of contraception requirement. If needed, male subjects should be advised to seek advice about sperm donation and cryopreservation of germ cells before treatment.
Any prior treatment-related toxicities resolved to ≤ Grade 2 prior to enrollment
Subjects must have adequate washout period from prior anticancer therapy(ies) of a minimum duration prior to first dose of BMF-219, as detailed below:
a. Radiation Therapy: At least 60 days from prior total body irradiation (TBI), craniospinal radiation and/or ≥ 50% radiation of the pelvis. Palliative localized radiation therapy is allowed provided all radiation-related toxicities are resolved to grade 1 or baseline, excluding alopecia skin pigmentation change, or other clinically insignificant events, e.g., small area radiation dermatitis or rectal or urinary urgency. Note: For Cohort 2 only, the lesions being assessed for response of lymphoma via Lugano Classification (Cheson, 2014) must be outside of the radiation portal or they must have demonstrated radiological progression and irradiation must have not occurred within 3 months of baseline assessment.
b. Stem Cell Infusion: At least 60 days must have elapsed from HSCT and at least 4 weeks (from last dose) must have elapsed from donor lymphocyte infusion (DLI) without conditioning.
c. Immunotherapy: At least 21 days must have lapsed since prior immunotherapy, including tumor vaccines and checkpoint inhibitors, and at least 30 days since receipt of chimeric antigen receptor therapy or other modified T-cell therapy.
d. Chemotherapy: At least 14 days since the completion of cytotoxic/myelosuppressive therapy. Note: Hydroxyurea will be allowed prior to enrollment and after the start of BMF-219 to control and maintain peripheral white blood cell (WBC) counts ≤50,000/μL. Subjects can continue on hydroxyurea through Cycle 1 Day 28 or until first disease assessment. After which, subjects should be titrated off of therapy.
e. Biologics and targeted therapeutic agents: At least 7 days or 5 half-lives, whichever is shorter since the completion of therapy.
f. Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing (equivalent to ≤ 20 mg prednisone daily) or cytoreductive therapy.
g. Investigational agents: At least 14 days or 5 drug half-lives, whichever is shorter, must have lapsed since receipt of all chemotherapy, immunotherapy, or radiotherapy or any ancillary therapy considered to be investigational (i.e., used for non-approved indication(s) and in the context of a research investigation)
- Adhere to the CYP3A4 inhibitor concomitant therapy use requirements, as follows:
• Arm A: Subjects must not have received a moderate or strong CYP3A4 inhibitor for at least 7 days prior to enrollment and are not anticipated to require such agents in the near term (at least 4 weeks).
• Arm B: Subjects must have received a moderate or strong CYP3A4 inhibitor for at least 7 days prior to enrollment and be able to continue such inhibitor(s) while on BMF-219 treatment for at least 4 weeks.
Exclusion Criteria
- Certain disease subtypes or occurrences, as follows:
a. Cohort 1: acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML) in blast crisis, isolated extramedullary relapse (iEMR).
b. Cohort 2: Primary mediastinal B-cell lymphoma (PMBCL), DLBCL transformed from diseases other than indolent non-Hodgkin’s Lymphoma (NHL)
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
WBC count > 50,000/ μL (uncontrollable with cytoreductive therapy) (Cohort 1 only).
Known central nervous involvement, as follows:
a. Cohort 1: Clinically active central nervous system (CNS) leukemia. Previously controlled CNS leukemia is acceptable
b. Cohort 2: Active CNS lymphoma or meningeal involvement
c. Cohort 3: Active CNS MM
d. Cohort 4: Active CNS leukemia
Prior menin inhibitor therapy.
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 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.
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).
An active uncontrolled acute or chronic systemic fungal, bacterial, or viral infection.
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 (CV) exclusions include any evidence of pericardial effusion or LVEF <45% assessed by echocardiogram (ECHO), multi-gated acquisition (MUGA), or local standard.
Mean QTcF or QTcB of > 470 millisecond (ms) on triplicate ECGs performed.
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.
Unable to swallow tablets or 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
Graft-Versus-Host Disease (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.
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, thyroid cancer; 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.
Any underlying medical condition that, in the Investigator’s opinion, will make the administration of study treatment hazardous or obscure the interpretation of toxicity determination or AEs.
Women who are pregnant or lactating. All female subjects with reproductive potential must have a negative pregnancy test prior to starting study treatment.
Known recent (within the past year) or ongoing alcohol or drug abuse.
Live, attenuated vaccine within 4 weeks before the first dose of study treatment.
