A Phase I/II, First-in-Human Study of the Menin-KMT2A (MLL1) Inhibitor Bleximenib in Participants With Acute Leukemia

Study Identifier:
75276617ALE1001
CT.gov Identifier:
NCT04811560
EudraCT Identifier:
2020-005967-30
EU Trial (CTIS) Number:
2023-506581-31-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

To determine the recommended Phase 2 dose(s) (RP2D[s]) of bleximenib in phase 1 (Part 1 [Dose Escalation] and to determine the safety and tolerability at RP2D in Phase 1 Part 2 (Dose expansion).

The purpose of the Phase 2 part of the study is to evaluate the efficacy of bleximenib at the RP2D.

To determine the RP2D of bleximenib and establish the safety and tolerability at the RP2D.

To explores the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of bleximenib at the RP2D.

Adverse events (AEs) are graded using the CTCAE v5.0. The safety dataset comprises pts who have received at least one dose of bleximenib. Efficacy responses are investigator-assessed per modified ELN 2017 in pts with R/R NPM1-mutated (NPM1m) or KMT2A-rearranged (KMT2Ar) AL.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Unmapped
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Female & Male
Age
18 - 99 Years
Study Drug
Drug: Experimental: Bleximenib
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Drug: Chinese Generic Name: Bleximenib
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting

Requirements information
Inclusion criteria
  • Inclusion Criteria:
  • Phase 1:
  • Age 2 years to less than (<) 18 years of age (pediatric cohort only), all other cohorts 18 years and aboveRelapsed or refractory (R/R) acute leukemia and has exhausted, or is ineligible for, available therapeutic optionsAcute leukemia harboring histone-lysine N-methyltransferase 2A (KMT2A), nucleophosmin 1 gene (NPM1) or nucleoporin 98 gene or nucleoporin 214 gene (NUP98 or NUP214) alterationsPhase: 2
  • Participants greater than 18 years are eligibleMust have had an initial diagnosis of acute myeloid leukemia (AML) per the WHO 2022 classification criteria and have relapsed/refractory diseaseAML harboring KMT2A-r (gene rearrangement/translocation) or NPM1 mutations onlyFor Both Phase 1 and 2:
  • Pretreatment clinical laboratory values meeting the following criteria: (a) Hematology: white blood cell (WBC) count <= 20*10^9/liter (L) and (b) renal function; For adult participants, estimated or measured glomerular filtration rate >= 30 milliliter per minute (mL/min) per four variable MDRD equation. For pediatric participants an estimated or measured glomerular filtration rate >=40 mL/min per the CKiD (Chronic Kidney Disease in Children) Schwartz formulaEastern Cooperative Oncology Group (ECOG) performance status grade of 0, 1 or 2. Pediatric participants only: Performance status >=70 by Lansky scale (for participants < 16 years of age) or >=70 Karnofsky scale (for participants >=16 years of age)A female of childbearing potential must have a negative highly sensitive serum beta-human chorionic gonadotropin at screening and within 48 hours prior to the first dose of study treatmentParticipant must agree to all protocol required contraception requirements and avoid sperm or egg donations or freezing for future reproductive use while on study and for 90 days (males) or 6 months (females) after the last dose of study treatment 1. ≥18 years of age and with a body weight of ≥ 40 kg.
  • 2. R/R acute leukaemia harbouring KMT2Ar (eg, gene rearrangement/translocation), NPM1m(eg, Exon 12 frameshift), or nucleoporin (NUP98 or NUP214, eg, gene rearrangement/translocation) alterations and has exhausted, or is ineligible for available therapeutic options.
  • 3. Pretreatment clinical laboratory values meeting the following criteria: White blood cell (WBC) count ≤20 x 109/L; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN); Total bilirubin ≤1.5 × ULN; Renal function Estimated or measured glomerular filtration rate ≥60 mL/min per four variable MDRD equation
  • 4. ECOG performance status grade of 0 or 1 (Oken 1982)
  • 5. Regular bowel movements (i.e., average production of at least one stool every 2 days).
  • 6. A woman of childbearing potential must have a negative highly sensitive serum β-human chorionic gonadotropin at screening and within 48 hours prior to the first dose of study treatment.
  • 7. A woman of childbearing potential must agree to all the following during the study and for 6 months after the last dose of study treatment:
  • 7.1. Use a barrier method of contraception
  • 7.2. Use a highly effective, preferably user-independent method of contraception
  • 7.3. Not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction
  • 7.4. Not planning to become pregnant
  • 7.5. Not to breast-feed
  • 8. A male must agree to all the following during the study and for 90 days after the last dose of study treatment:
  • 8.1. Wear a condom when engaging in any activity that allows for the passage of ejaculate to another person.
  • 8.2. Not to donate sperm or freeze for future use for the purpose of reproduction.
  • 8.3. In addition, the participant should be advised of the benefit for a female partner to use a highly effective method of contraception, as a condom may break or leak.
  • 9. Must sign an informed consent form (ICF) indicating participant (or their LAR) understands the purpose of the study and procedures required for the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or
  • procedures that are not part of the standard of care for the participant’s disease.
  • 10. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
Exclusion criteria
  • Exclusion Criteria:
  • Acute promyelocytic leukemia, diagnosis of Down syndrome associated leukemia or juvenile myelomonocytic leukemia according to World Health Organization (WHO) 2016 criteria
  • Active central nervous system (CNS) disease
  • Prior solid organ transplantation
  • QTc according to Fridericia's formula (QTcF) for males >= 450 millisecond (msec) or for females >= 470 msec. Participants with a family history of Long QT syndrome are excluded
  • Exclusion criteria related to stem cell transplant: a. Received prior treatment with allogenic bone marrow or stem cell transplant <=3 months before the first dose of study treatment ; b. Has evidence of graft versus host disease; c. Received donor lymphocyte infusion <=1 month before the first dose of study treatment; d. Requires immunosuppressant therapy (exception: daily doses <=10 milligrams (mg) prednisone or equivalent are allowed for adrenal replacement)
  • Prior cancer immunotherapy within 4 weeks prior to enrollment or blinatumomab within 2 weeks prior to enrollment. Additional prior cancer therapies must not be given within 4 weeks prior to enrollment or 5 half-lives of the agent (whichever is shorter)
  • 1Patients with acute promyelocytic leukemia, diagnosed with Down syndrome-related leukemia, or juvenile myelomonocytic leukemia2Active central nervous system leukemia.3Previous solid organ transplantation.4Cardiovascular disease that may increase the risk of torsades de pointes, or cardiovascular disease diagnosed within 6 months prior to the first administration of the investigational drug.5Any toxicity resulting from previous anticancer treatment that has not subsided to baseline or is ≤ grade 1 (excluding hair loss, stable peripheral neuropathy, thrombocytopenia, neutropenia, and anemia).6Lung damage requiring oxygen therapy to maintain adequate blood oxygen saturation.7Report a body temperature >100.5℉/38℃ within 48 hours prior to the first administration of the study drug.8Known allergies, hypersensitivity reactions, or intolerances to Bleximenib or its excipients.9Exclusion criteria related to stem cell transplantation: a. Received allogeneic bone marrow or hematopoietic stem cell transplantation within ≤3 months prior to the first administration of the investigational drug. b. Evidence of graft-versus-host disease. c. Received donor lymphocyte infusion within ≤1 month prior to the first administration of the investigational drug. d. Required immunosuppressant therapy.10Phase I and II (Cohorts A1 and A2): Patients who have previously received any Menin-KMT2A inhibitors11Patients who have received prior anticancer immunotherapy within 4 weeks prior to enrollment, or who have received belintolimab within 2 weeks prior to enrollment.12Receive the live attenuated vaccine within 4 weeks prior to the first dose of the investigational drug or during the planned administration of the investigational drug; or receive the experimental vaccine within 2 weeks prior to the first dose of the investigational drug.13Those who have received experimental interventions or used invasive experimental medical devices within 2 weeks prior to the planned first dose of the investigational drug, or who are currently enrolled in another clinical study.14Subjects who have undergone major surgery within two weeks prior to the first administration of the investigational drug or who have not yet recovered from surgery must not have major surgery scheduled during the administration of the investigational drug.15It is necessary to use prohibited drugs that cannot be discontinued, substituted, or temporarily interrupted during the study.16Known to be HIV positive or tested positive at screening, unless the viral load is undetectable and the CD4 count is higher than 200 after receiving stable high-efficiency antiretroviral therapy.17The protocol defines active/chronic hepatitis B or hepatitis C infection or clinically active infectious liver disease.18The presence of any serious underlying medical or mental illness, such as epilepsy or mental disorders (such as alcohol or drug abuse), dementia, or altered mental status.19There is evidence that subjects had any active or uncontrolled infection within 7 days prior to the first dose of the investigational drug.20Those who cannot take oral medication, or who have a disease that may affect the absorption of the study drug, or who have undergone previous surgical resection.twenty oneThere are any circumstances where the researcher believes that participation in this study does not provide the maximum benefit to the participants or may hinder, limit, or confound the assessments required by the study protocol.twenty twoThis study investigated active malignant tumors other than those treated with this disease.twenty threePatients diagnosed with Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome, or any other known bone marrow failure syndrome
  • 1. Acute promyelocytic leukemia or diagnosis of Down syndrome associated leukemia, according to WHO 2016 criteria (Arber 2016).
  • 2. Active CNS disease.
  • 3. Recipient of solid organ transplant.
  • 4. Cardiovascular disease that is uncontrolled, increases risk for Torsades de Pointes, or that was diagnosed within 6 months prior to Day1.
  • 5. QTc according to Fridericia’s formula (QTcF) for males ≥450 msec or for females ≥470 msec. Participants with a family history of Long QT syndrome are excluded.
  • 6. Any toxicity (except for alopecia, stable peripheral neuropathy, thrombocytopenia, neutropenia, anemia) from previous anticancer therapy that has not resolved to baseline or to Grade 1 or less.
  • 7. Pulmonary compromise that requires the need for supplemental oxygen use to maintain adequate oxygenation.
  • 8. Reported temperature >100.4ºF/38ºC within 48 hours prior to study Day 1.
  • 9. Known allergies, hypersensitivity, or intolerance to bleximenib or its excipients (refer to IB).
  • 10. Exclusion criteria related to stem cell transplant: prior treatment with allogenic bone marrow or stem cell transplant ≤3 months before first dose of study treatment; evidence of graft versus host disease; received donor lymphocyte infusion ≤1 month before first dose of study treatment; requires immunosuppressant therapy (exception: daily doses ≤10 mg prednisone or equivalent are allowed for adrenal replacement).
  • 11. Any prior treatment with a menin-KMT2A inhibitor. (Participants with R/R acute leukemia and prior menin-KMT2Ainhibitor exposure, without prior evidence of DS, may be considered with Sponsor approval with proper washout.)
  • 12. Prior cancer immunotherapy (ie, CAR-T, inotuzumab, gemtuzumab ozogamicin) within 4 weeks prior to enrollment or blinatumomab within 2 weeks prior to enrollment. Additional prior cancer therapies must not be given within 2 weeks prior to enrollment or 5 half-lives of the agent (whichever is shorter).
  • 13. Administration of: live-attenuated vaccine within 4 weeks before the first dose of study treatment or planned during study treatment; or investigational vaccine within 2 weeks before the first dose of study treatment.
  • 14. Received investigational treatment or used an invasive investigational medical device within 2 weeks before planned first dose of study treatment or is currently receiving active treatment on an investigational study.
  • 15. Major surgery (eg, requiring general anesthesia) within 2 weeks prior to first dose of study treatment or has not recovered from surgery. Must not have major surgery planned during the time the participant is receiving study treatment.
  • 16. Requires prohibited medication that cannot be discontinued or substituted or temporally interrupted during the study.
  • 17. Known to be positive or tests positive at screening for human immunodeficiency virus (HIV), unless viral load is undetectable and CD4 count is above 200 in stable highly active antiretroviral therapy (see Section 6.9.2 for prohibited and restricted medications)
  • 18. Active or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (as defined below) or clinically active infectious liver disease:
  • 18.1. Positive hepatitis B surface antigen (HBsAg). NOTE: Participants with a prior history of hepatitis B virus (HBV) demonstrated by positive hepatitis B core antibody are eligible if they have at screening 1) a negative HbsAg and 2) a HBV DNA (viral load) below the lower limit of quantification, per local testing. Participants with a positive HBsAg due to recent vaccination are eligible if HBV DNA (viral load) is below the lower limit of quantification, per local testing.
  • 18.2. Positive hepatitis C antibody (anti-hepatitis C virus [HCV]). NOTE: Participants with a prior history of HCV, who have completed antiviral
  • treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible.
  • 19. Any serious underlying medical or psychiatric conditions, such as seizure disorder or psychiatric conditions (e.g., alcohol or drug abuse), dementia, or altered mental status.
  • 20. Active infection that is uncontrolled prior to first dose of study treatment and may interfere with the study objectives or expose the participant to undue risk by participating in the trial; an infection controlled with therapy is allowed.
  • 21. Inability to take an orally administered drug, or medical disorder or prior surgical resection that may affect the absorption of the oral study treatment.
  • 22. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant.
  • 23. Active malignancies (those progressing or requiring treatment change in the last 24 months) other than the disease being treated under study.
  • 24. Diagnosis of Fanconi anemia, Kostmann syndrome, Shwachman Diamond syndrome, or any other known bone marrow failure syndrome.
  • 25. Previous participation in an AME study within 3 months before screening.

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (FJD)
Madrid, Spain, 28040
Investigator
Gala Vega Achabal
Status
Recruiting
Condition(s) Treated at Site
Unmapped
Location
START Midwest
Grand Rapids, MI, United States, 49546
Investigator
Andrew Sochacki
Status
Recruiting
Condition(s) Treated at Site
Unmapped