Study of Biomarker-Based Treatment of Acute Myeloid Leukemia

Beat AML, LLC

Status and phase: Enrolling; Phase 3; Phase 2

Conditions: Previously Untreated Relapsed Refractory Acute Myeloid Leukemia

Treatments: Drug: AG-120 (BAML-16-001-S16); Drug: Daunorubicin (BAML-16-001-S1); Drug: Venetoclax (BAML-16-001-S8 Group 2); Drug: Azacitidine (BAML-16-001-S16); Drug: Bleximenib (BAML-16-001-S25/HO181); Drug: ZE46-0134 (BAML-16-001-S21 Group 1); Drug: Venetoclax (BAML-16-001-S24); Drug: Decitabine (BAML-16-001-S14); Drug: Decitabine (BAML-16-001-S8 Group 1); Drug: Entospletinib (BAML-16-001-S4); Drug: Entospletinib (BAML-16-001-S6); Drug: Gilteritinib (BAML-16-001-S8 Group 1); Drug: Venetoclax (BAML-16-001-S10); Drug: AZD5153 (BAML-16-001-S10); Drug: Azacitidine (BAML-16-001-S2); Drug: Pevonedistat (BAML-16-001-S9); Drug: TP-0903 (BAML-16-001-S14); Drug: Gilteritinib (BAML-16-001-S8 Group 2); Drug: Azacitidine (BAML-16-001-S3); Drug: Placebo (BAML-16-001-S26/HO177); Drug: Daunorubicin or Idarubicin (BAML-16-001-S25/HO181); Drug: Entospletinib (BAML-16-001-S5); Drug: Cytarabine (BAML-16-001-S1); Drug: Azacitidine (BAML-16-001-S4); Drug: Decitabine (BAML-16-001-S5); Drug: Cytarabine (BAML-16-001-S6); Drug: ficlatuzumab (BAML-16-001-S24); Biological: Samalizumab (BAML-16-001-S1); Drug: SNDX-5613 (BAML-16-001-S17); Drug: Azacitidine (BAML-16-001-S12 Arm B); Drug: Venetoclax (BAML-16-001-S12 Arm B); Drug: ZE46-0134 (BAML-16-001-S21 Group 2); Drug: Decitabine (BAML-16-001-S8 Group 2); Drug: Azacitidine (BAML-16-001-S18); Drug: AZD5991 (BAML-16-001-S18); Drug: Placebo (BAML-16-001-S25/HO181); Drug: Cytarabine (BAML-16-001-S25/HO181); Other: Laboratory Biomarker Analysis; Drug: Venetoclax (BAML-16-001-S12 Arm A); Drug: Venetoclax (BAML-16-001-S17); Drug: Daunorubicin (BAML-16-001-S6); Drug: Azacitidine (BAML-16-001-S24); Drug: Azacitidine (BAML-16-001-S12 Arm A); Drug: AG-221 (BAML-16-001-S3); Drug: Azacitidine (BAML-16-001-S9); Biological: BI 836858 (BAML-16-001-S2); Drug: Revumenib (BAML-16-001-S26/HO177); Drug: Azacitidine (BAML-16-001-S17)

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT03013998

BAML-16-001

Details and patient eligibility

About

This screening and multi-sub-study Phase 1b/2/3 trial will establish a method for genomic screening followed by assigning and accruing simultaneously to a multi-study "Master Protocol (BAML-16-001-M1)." The specific subtype of acute myeloid leukemia will determine which sub-study, within this protocol, a participant will be assigned to evaluate investigational therapies or combinations with the ultimate goal of advancing new targeted therapies for approval. The study also includes marker negative sub-studies which will include all screened patients not eligible for any of the biomarker-driven sub-studies. Patients with myeloid malignancies [e.g. myelodysplastic syndrome (MDS) or other diseases], will be allowed to enroll to Master protocol if there is an available sub-study.

Enrollment: 3,000 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria (IC):

• Adults, age ≥60 yrs at diagnosis unless in a specific known cytogenetic & genomic group for which treatment in Group A, B, or C is allowed by the substudy where age 18+ is allowed. Patients <60 yrs who are screened but do not fall w/in the cytogenetic & genomic open substudies would still be followed on the M1 Master Protocol (MP) & not considered screen fails
• Patients must be able to understand & provide written informed consent
• Group A: Patients must have previously untreated AML according to WHO classification w/ no prior treatment other than hydroxyurea. Patients w/ myeloid malignancies [eg, myelodysplastic syndrome (MDS) or other disease], will be allowed to enroll to this group. For previously untreated subjects w/ ≥20% blasts in bone marrow or blood only: Prior therapy for MDS, myeloproliferative syndromes (MPD), or aplastic anemia is permitted. For select group, patients who cannot wait or choose not to wait for results of genomic testing, will be allowed to enroll to select substudies that allow enrollment & treatment of all patients regardless of their genomic mutations or cytogenetics. For this group, genomic samples will be collected to be analyzed retrospectively after patients' enrollment
• Group B: Patients must have relapsed or refractory AML according to WHO classification. For study purposes, refractory AML is defined as failure to ever achieve a complete response (CR) or recurrence of AML w/in 6 months of achieving CR; relapsed AML is defined as all others w/ disease after prior remission. For select genomic aberrations specified in substudies, patients ≥18 yrs may be allowed to enroll in this portion of the study. Patients w/ relapsed or refractory myeloid malignancies (eg, MDS or other diseases) will be allowed to enroll to this group
• Group C: For select sites not part of Beat AML core sites. These sites will only participate in select substudies. Patients in this group will enroll under the Beat AML M1 MP w/ the intent to enroll into these select substudies & following screening on Beat M1 MP, they will come off M1 MP

Exclusion Criteria (EC):

• Acute promyelocytic leukemia (APL)
• Clinically active CNS involvement by AML. A patient may be considered eligible if CNS leukemia is showing response to treatment at study entry & should continue to receive intrathecal therapy as clinical indicated. Patients who require or are undergoing craniospinal irradiation of disease control are not eligible for participation
• Signs of leukostasis requiring urgent therapy
• Disseminated intravascular coagulopathy (DIC) w/ active bleeding or signs of thrombosis
• Patients w/ psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol (including failure to collect genomics samples for screening), or complying w/ study treatment & follow-up
• Any other significant medical condition, including psychiatric illness or lab abnormality, that would preclude patient participation in the trial or would confound interpretation of trial results

S17 - IC

1. Age ≥60 yrs at diagnosis w/ untreated AML according to International Consensus Classification (ICC) 2022 & have NPM1 mutated or KMT2A rearrangement disease & are not candidates for or do not wish to pursue intensive chemotherapy
2. Patients must be able to understand & provide written informed consent
3. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
4. Aspartate aminotransferase (AST) <5 x upper limit of normal (ULN), alanine aminotransferase (ALT) <5 x ULN, & total bilirubin <2 x ULN (except for patients w/ known or suspected Gilbert's syndrome & w/ direct bilirubin w/in normal range) for the local lab
5. Adequate renal function as defined by calculated creatinine clearance ≥60 mL/min for the local lab
6. Females must be non-childbearing, postmenopausal, surgically sterile or meet certain criteria if of childbearing potential. Males must adhere to criteria if w/ females of childbearing potential
7. Patients must have previously untreated AML w/ no prior treatment other than hydroxyurea. No chemotherapy for AML outside of hydroxyurea for treatment of leukostasis or ATRA for initially suspected APL (that is ruled out) is allowed as well as 1 dose of intrathecal chemotherapy for suspected CNS involvement (that is ruled out) is allowed. Prior therapy for MDS allowed except for hypomethylating agents
8. If patient has co-morbid illness or malignancy, life expectancy attributed to this must be >2 yrs

S17 - EC

1. Isolated myeloid sarcoma (must have blood or marrow involvement w/ AML)
2. APL (FAB M3)
3. Favorable risk cytogenetics (Core Binding Factor AML)
4. Active CNS involvement by AML
5. Signs of leukostasis requiring urgent therapy
6. WBC ≥25,000/μl (WBC <25,000/μl to begin therapy, Hydroxyurea may be used to obtain this level)
7. Willing & able to receive intensive chemotherapy
8. DIC w/ active bleeding or signs of thrombosis
9. Patients w/ psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or complying w/ study treatment & follow-up
10. Any significant medical condition, including psychiatric illness or lab abnormality, that would preclude the patient participating in the trial or would confound trial result interpretation
11. Known active HIV, active hepatitis B or C infections
12. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (CHF), unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction (MI) as presentation of AML, New York Heart Association (NYHA) Class III or IV heart failure, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients w/ medical comorbidities that will preclude safety evaluation of the combination should not be enrolled
13. Patients w/ uncontrolled infection shall not be enrolled until infection is treated & brought under control
14. Patients who have received an investigational agent (for any indication) w/in 5 half-lives of the agent & until toxicity from this has resolved to ≤ grade 1; if half-life of the agent is unknown, patients must wait 4 wks prior to first dose of study treatment.
15. Patients w/ QTcF >450 ms (males), >468 (females); patients w/ right, left, or partial bundle branch blocks (BBB) or pacemaker that may confound interpretation of this reading excluded provided they lack history of primary arrhythmic events & are cleared by cardiology for enrollment in the trial. Any factors that increase risk of QTc prolongation or risk of arrhythmic event such as congenital long QT syndrome or family history of long QT syndrome

S24 - IC

1. ≥60 yrs at AML diagnosis
2. ECOG score of 0, 1, or 2
3. AST <2.5 x ULN, ALT <2.5 x ULN, & total bilirubin <1.5 x ULN (except for patients w/ known Gilbert's syndrome) for the local lab. If due to disease, higher values may be approved after discussion w/ medical monitor
4. Adequate renal function as defined by calculated creatinine clearance >40 mL/min per the local lab
5. Patients must be able to understand & provide written informed consent
6. Females must be non-childbearing, postmenopausal, surgically sterile or meet certain criteria if of childbearing potential
7. Males must adhere to criteria if w/ females of childbearing potential
8. No prior chemotherapy for leukemia (hydroxyurea to control leukocytosis & ATRA for initially suspected APL allowed). Prior therapy for MDS or myeloproliferative neoplasm (MPN) allowed (except for hypomethylating agents)
9. If patient has co-morbid illness or malignancy, life expectancy attributed to this must be >2 yrs

S24 - EC

1. Patients able & willing to receive intensive chemotherapy for underlying AML
2. Isolated myeloid sarcoma (must have blood or marrow involvement w/ AML)
3. APL
4. Known active CNS involvement by AML
5. Clinical signs/symptoms of leukostasis requiring urgent therapy
6. Known active HIV, active hepatitis B or C infections
7. DIC w/ active bleeding or signs of thrombosis
8. Patients who have received an investigational agent (for any indication) w/in 5 half-lives of the agent; if half-life of the agent is unknown, patients must wait 1 wk prior to first dose of study treatment
9. Systemic antineoplastic therapy (for any indication) w/in 5 half-lives or radiation therapy w/in 1 wk prior to starting protocol except for hydroxyurea, which is allowed to control WBC counts
10. Patients w/ psychological, familial, social, or geographic factors, any other significant medical condition, or a lab abnormality that otherwise precludes them from giving informed consent, following the protocol, or complying w/ study treatment & follow-up, or would confound trial result interpretation
11. Uncontrolled intercurrent illness including, but not limited to, symptomatic CHF, unstable angina pectoris, serious cardiac arrhythmia, MI w/in 6 months prior to enrollment (Troponin leak alone not included if no residual dysfunction) NYHA Class III or IV heart failure, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients w/ medical comorbidities that will preclude safety evaluation of the combination should not be enrolled
12. Patients w/ uncontrolled infection shall not be enrolled until infection is treated & brought under control
13. Patients who require treatment w/ concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A
14. Patients who require treatment w/ concomitant drugs that are strong inhibitors or inducers of P-glycoprotein (P-gp) w/ the exception of drugs that are considered absolutely essential for care of the patient

S25/HO181 IC

1. ≥18 yrs (or legal age of majority in jurisdiction where study is taking place, whichever is greater) at time of informed consent
2. New diagnosis of AML (≥10% blasts in BM or peripheral blood) w/ mutated NPM1 or w/ recurring rearrangements involving KMT2A according to ICC 2022 criteria
3. Considered eligible for intensive chemotherapy
4. WHO/ECOG score ≤2
5. Adequate renal & hepatic functions prior to randomization

S25/HO181 EC

1. Prior (chemo-)therapy for AML, including prior treatment w/ hypomethylating agents

2. Known active leukemic involvement of CNS

3. Recipient of solid organ transplant

4. Cardiac disease:

   1. Any of the following w/in 6 months of randomization: MI, uncontrolled/unstable angina, CHF (NYHA Class III or IV), uncontrolled or symptomatic arrhythmias, stroke, or transient ischemic attack
   2. QTcF ≥470 ms. Prolonged QTc interval associated w/ BBB or pacemaking is permitted
   3. Left ventricular ejection fraction (LVEF) <40% by ECHO or MUGA scan obtained w/in 28 days prior to start of study treatment
   4. Previously received cumulative dose of any combination of anthracyclines or anthracenediones of ≥500 mg/m2

5. Chronic respiratory disease requiring supplemental oxygen

S26/HO177 - IC

1. Patient w/ newly diagnosed NPM1-mutated AML, consistent w/ NPM1c, according to 2022 ICC (ie, ≥10% blasts).

   OR Patient w/ newly diagnosed KMT2A-rearranged AML according to 2022 ICC (ie, ≥10% blasts). KMT2A partial tandem duplications or deletions are NOT eligible

2. Central confirmation of NPM1 mutation or KMT2A rearrangement in 1 of the dedicated central genetic labs

3. Age ≥18 yrs, no upper age limit

4. Patient is ineligible for intensive chemotherapy by meeting at least 1 of the following criteria:

   A. ≥75 yrs: ineligible for intensive chemotherapy per physician's discretion (w/ an ECOG score 0-2)

   B. 18-74 yrs: patient is not eligible for standard chemotherapy because any of the following co-morbidities:

   i. ECOG score 2 or 3 ii. Cardiac history of chronic heart failure requiring treatment; or w/ an ejection fraction ≤50%; or chronic stable angina iii. DLCO ≤65% or FEV1 ≤65% iv. Creatinine clearance ≥30 mL/min to <45 ml/min calculated by Cockcroft Gault formula v. Moderate hepatic impairment w/ total bilirubin >1.5 to <3.0 x ULN vi. Any other comorbidity that local physician assesses to be incompatible w/ intensive chemotherapy must be reviewed & approved by Sponsor's (co-) Principal Investigator

5. Patient must have a projected life expectancy of at least 12 wks (as assessed by treating physician)

6. Patient must have a WBC count of <25 x 109/L. Hydroxyurea can be used prior to study enrollment to reduce WBC count to meet this criterion

7. Adequate renal function as evidenced by serum creatinine ≤2.0 × ULN or creatinine clearance >30 mL/min based on Cockcroft-Gault glomerular filtration rate (GFR)

8. Adequate hepatic function as evidenced by:

   A. Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert's disease, or leukemic involvement following written approval by sponsor (Co-)Principal Investigator B. AST, ALT, & alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following written approval by sponsor (Co-)Principal Investigator

9. Female patient must:

   A. be of nonchildbearing potential: o postmenopausal (defined as at least 1 yr w/out any menses). o documented surgically sterile (eg, documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) or status post hysterectomy (at least 1 month prior to screening) B. or, if of childbearing potential (not surgically sterile & not postmenopausal) agree to avoid pregnancy during the study & for 6 months after the final study drug administration i. and have a negative urine or serum pregnancy test at screening ii. and, if heterosexually active, agree to consistently apply 1 highly effective* method of birth control in combination to a barrier method for the duration of the study & for 6 months after final study drug administration *Highly effective forms of birth control include:

   1. Consistent & correct usage of established hormonal contraceptives that inhibit ovulation for at least 1 month prior to taking study drug. Hormonal contraception qualifies as a highly effective birth control method only when it includes combined estrogen/progestogen contraception or progestogen-only contraception, each associated with inhibition of ovulation
   2. Established intrauterine device (IUD) or intrauterine system (IUS)
   3. Bilateral tubal occlusion
   4. Vasectomy - a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used
   5. Male is sterile due to a bilateral orchiectomy -- Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated w/ the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study & the preferred & usual lifestyle of the patient.

   List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination w/ a barrier method according to locally accepted standards during the protocol defined period C. agree not to breastfeed starting at screening & throughout the study period D. agree not to donate ova starting at screening & throughout the study period, & for 6 months after the final study drug administration

10. Men must use a latex condom during any sexual contact w/ women of childbearing potential, even if they have undergone a successful vasectomy & must agree to avoid fathering a child (while on therapy & for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control

11. Male patient must not donate sperm starting at screening & throughout the study period & for 6 months after the final study drug administration

12. Able to understand & willing to sign an informed consent form (ICF)

13. Institutional Review Board/Independent Ethics Committee-approved written informed consent as per national regulations must be obtained from the patient prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable)

S26/HO177 - EC

1. Previously treated for AML; a treatment period w/ hydroxyurea to control WBC counts allowed; prior treatment w/ a hypomethylating agent for MDS-EB is not allowed; prior treatment w/ erythropoiesis-stimulating agents or luspatercept for MDS is allowed

2. APL w/ t(15;17)(q24.1;q21.2); PML-RARA; or other pathognomonic variant chromosomal translocation/fusion gene

3. AML w/ BCR-ABL1; or myeloid blast crisis of CML

4. Significant active cardiac disease w/in 3 months prior to start of study treatment, including:

   • NYHA class III or IV CHF
   • MI
   • Unstable angina
   • Severe cardiac arrhythmias
   • Congenital long QT syndrome of family member w/ this condition
   • QTcF >450 msec for males & >470 msec for females on screening electrogram (mean of triplicate recordings; calculated using Fridericia's correction)

5. Severe obstructive or restrictive ventilation disorder

6. History of stroke or intracranial hemorrhage w/in 6 months prior to randomization

7. Clinical symptoms suggestive of active CNS leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening

8. Active infection, including hepatitis B or C or HIV infection, that is uncontrolled prior to first dose of study treatment & may interfere w/ study objectives or could expose patient to undue risk through participation in the trial; an infection controlled w/ an approved antibiotic/antiviral/antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients w/ COVID-19 infection can be enrolled if they have no symptoms & tested negative twice by PCR test prior to inclusion in the trial

9. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or DIC

10. Conditions that limit ingestion or gastrointestinal absorption of orally administered drugs

11. Patient w/ currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy & are considered by their physician to be at < 30% risk of relapse w/in 1 yr. However, patients w/ the following history/concurrent conditions are allowed:

    • Basal or squamous cell carcinoma of the skin
    • Carcinoma in situ of the cervix
    • Carcinoma in situ of the breast
    • Incidental histologic finding of prostate cancer

12. Receipt of live, attenuated vaccine w/in 30 days prior to study inclusion (NOTE: patient, if enrolled, should not receive live vaccine during the study & until 6 months after therapy)

13. Severe neurological or psychiatric disorder interfering w/ ability to give informed consent

14. Contraindication to AZA or VEN (as per Summary of Product Characteristics)

15. Weighing <40 kg at registration

16. Participation in other prospective studies w/ anti-leukemic and/or investigational agents

17. Taking Dabigatran, unless patient can be transferred to other medications w/in ≥5 half-lives prior to dosing. Patients taking other P-gP transporter-sensitive medications should be properly monitored during the study if they cannot be transferred to other medications

18. Taking known strong cytochrome P450 (CYP) 3A4 inducers, unless patient can be transferred to other medications w/in ≥5 half-lives prior to dosing

19. Pregnant or lactating woman or plans to become pregnant during the study

20. Patient screened & randomized into this S26/HO177 trial but considered ineligible cannot re-enter this trial at later date

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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3,000 participants in 23 patient groups, including a placebo group

BAML-16-001-S17

Experimental group

Description:

\*\*Active, not Recruiting\*\* This is an open-label Phase 1b dose escalation followed by dose expansion clinical trial to determine the safety and recommended dose of SNDX-5613 combined with azacitidine and venetoclax in newly diagnosed, untreated AML patients age ≥ 60 years who are not candidates or do not wish to pursue intensive induction therapy and who have NPM1 mutated or KMT2A-rearranged disease.

Treatment:

Drug: Azacitidine (BAML-16-001-S17)

Drug: Venetoclax (BAML-16-001-S17)

Other: Laboratory Biomarker Analysis

Drug: SNDX-5613 (BAML-16-001-S17)

BAML-16-001-S12, Arm A (Closed)

Active Comparator group

Description:

This is an open label phase 2 randomized study in which eligible AML patients will be randomly assigned (1:1) to receive either the FDA label-approved regimen of 28-day Venetoclax + Azacitidine (Arm A) or the 14-day regimen of Venetoclax + Azacitidine (Arm B). Newly diagnosed acute myeloid leukemia (AML) patients ≥ 60 years will be enrolled.

Treatment:

Drug: Azacitidine (BAML-16-001-S12 Arm A)

Drug: Venetoclax (BAML-16-001-S12 Arm A)

BAML-16-001-S12, Arm B (Closed)

Experimental group

Description:

This is an open label phase 2 randomized study in which eligible AML patients will be randomly assigned (1:1) to receive either the FDA label-approved regimen of 28-day Venetoclax + Azacitidine (Arm A) or the 14-day regimen of Venetoclax + Azacitidine (Arm B). Newly diagnosed acute myeloid leukemia (AML) patients ≥ 60 years will be enrolled.

Treatment:

Drug: Azacitidine (BAML-16-001-S12 Arm B)

Drug: Venetoclax (BAML-16-001-S12 Arm B)

BAML-16-001-S21, Group 1 (Closed)

Experimental group

Description:

This is a Phase 1, open-label, multicenter, dose escalation, and dose optimization study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ZE46-0134 in adult patients with relapsed or refractory AML with FLT3-ITD and/or FLT3-TKD mutations for Group 1 and with spliceosome (SF3B1, SRSF2, U2AFI and ZRSR2) mutations for Group 2. Patients with AML that are out-patients or hospitalized due to their AML can be enrolled in the study. The study will be run in 2 parts: Part 1 will be dose escalation and determination of the maximum tolerated dose, and Part 2 will be dose expansion.

Treatment:

Other: Laboratory Biomarker Analysis

Drug: ZE46-0134 (BAML-16-001-S21 Group 1)

BAML-16-001-S21, Group 2 (Closed)

Experimental group

Description:

This is a Phase 1, open-label, multicenter, dose escalation, and dose optimization study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ZE46-0134 in adult patients with relapsed or refractory AML with FLT3-ITD and/or FLT3-TKD mutations for Group 1 and with spliceosome (SF3B1, SRSF2, U2AFI and ZRSR2) mutations for Group 2. Patients with AML that are out-patients or hospitalized due to their AML can be enrolled in the study. The study will be run in 2 parts: Part 1 will be dose escalation and determination of the maximum tolerated dose, and Part 2 will be dose expansion.

Treatment:

Other: Laboratory Biomarker Analysis

Drug: ZE46-0134 (BAML-16-001-S21 Group 2)

BAML-16-001-S24

Experimental group

Description:

\*\*Recruiting\*\* This is a multi-center open-label Phase 1b safety run-in study followed by a Phase 2 study of ficlatuzumab given in combination with venetoclax azacitidine, in newly diagnosed untreated acute myeloid leukemia age ≥ 60 years who are not candidates or do not wish to pursue intensive induction therapy.

Treatment:

Drug: Azacitidine (BAML-16-001-S24)

Drug: Venetoclax (BAML-16-001-S24)

Drug: ficlatuzumab (BAML-16-001-S24)

BAML-16-001-S1 (Closed)

Experimental group

Description:

This is an open-label Phase 1b/2 clinical study of Samalizumab given in addition to standard induction chemotherapy/consolidation, followed by Samalizumab maintenance, in newly diagnosed acute myeloid leukemia. Patients that are marker negative, as defined based on the Beat AML Master Protocol assignment or with CBF karyotype/interphase cytogenetics/molecular testing defined by presence of t(8;21)(q22;q22) or the molecular equivalent RUNX1/RUNX1T1 fusion transcript or inv(16)(p13q22) or t(16;16)(p13;q22) or the molecular equivalent CBFB/MYH11 fusion transcript based on the Beat AML will receive Samalizumab in combination with induction therapy followed by Samalizumab maintenance.

Treatment:

Drug: Cytarabine (BAML-16-001-S1)

Drug: Daunorubicin (BAML-16-001-S1)

Biological: Samalizumab (BAML-16-001-S1)

BAML-16-001-S2 (Closed)

Experimental group

Description:

This is an open-label Phase 1b/2 clinical study of BI 836858 given in combination with azacitidine, followed by BI 836858 plus azacitidine maintenance, in newly diagnosed acute myeloid leukemia. The target population is assigned by the Beat AML Master Protocol (the "umbrella" study). Eligible patients will have previously untreated acute myeloid leukemia, age greater than or equal to 60, with any 1 of the following: mutated TET2, IDH1, IDH2, or WT1, or "marker negative" as defined by the overall Beat AML umbrella protocol.

Treatment:

Biological: BI 836858 (BAML-16-001-S2)

Drug: Azacitidine (BAML-16-001-S2)

BAML-16-001-S3 (Closed)

Experimental group

Description:

This is a phase 2 clinical trial to assess the feasibility and efficacy of a stepwise approach to the treatment of IDH2-mutant AML. On day 1 of the trial, all enrolled participants will be initiated on therapy with the IDH2 inhibitor AG-221 for IDH2 R140 and R172-mutant patients. The dosing will be based on phase 1 experience of AG-221, which has established 100 mg daily as a safe and tolerated dose, with preliminary suggestion of efficacy. These will be administered continuously in 28 day cycles. Hydroxyurea will be allowed for the purposes of cytoreduction.

Treatment:

Drug: Azacitidine (BAML-16-001-S3)

Drug: AG-221 (BAML-16-001-S3)

BAML-16-001-S4 (Closed)

Experimental group

Description:

This is a 2 cohort phase 1b/2 clinical trial to assess the feasibility and efficacy of entospletinib (ENTO) stepwise approach to the treatment of patients with balanced translocations of MLL identified cytogenetically (Cohort 1) and patients with MLL-partial tandem duplications identified molecularly (Cohort 2). All enrolled participants will be initiated on monotherapy with ENTO 400 mg PO BID. This dose will be administered continuously in 28 day cycles.

Treatment:

Drug: Entospletinib (BAML-16-001-S4)

Drug: Azacitidine (BAML-16-001-S4)

BAML-16-001-S5 (Closed)

Experimental group

Description:

This is a phase 2 clinical trial to assess the feasibility and efficacy of a stepwise approach to the treatment of patients with TP53 mutations (identified molecularly) with/without complex karyotype (Cohort A) or complex karyotype (3 or greater metaphase abnormalities without TP53) (Cohort B). All enrolled participants will be initiated on entospletinib 400 mg orally twice daily. This dose will be administered continuously in 28 day cycles.

Treatment:

Drug: Entospletinib (BAML-16-001-S5)

Drug: Decitabine (BAML-16-001-S5)

BAML-16-001-S6 (Closed)

Experimental group

Description:

The study is an open-label phase 2 study of entospletinib in younger and older AML patients with NPM1+/FLT3ITD-AML. It includes patients age ≥18 years who are able and willing to receive 7 + 3 intensive chemotherapy. Entospletinib is administered daily with IV daunorubicin (days 1-3 for Cycle 1) and cytarabine (days 1-7 for Cycle 1). If a second induction is required, it is given with IV daunorubicin (days 1-2 for Cycle 2) and cytarabine (days 1-5 for Cycle 2).

Treatment:

Drug: Daunorubicin (BAML-16-001-S6)

Drug: Entospletinib (BAML-16-001-S6)

Drug: Cytarabine (BAML-16-001-S6)

BAML-16-001-S8 (Closed)

Experimental group

Description:

This is an open-label Phase 1b/2 clinical study of gilteritinib monotherapy, gilteritinib in combination with decitabine, or gilteritinib in combination with decitabine and venetoclax in untreated FLT3 mutated AML with high and low variant allele frequency. Initially, the combination of gilteritinib and decitabine was tested (Group 1); however, subsequently the combination of decitabine and venetoclax was shown to be a highly effective therapy for older AML patients, so the triple combination of gilteritinib in combination with decitabine and venetoclax (Group 2) is now being evaluated in this study.

Treatment:

Drug: Gilteritinib (BAML-16-001-S8 Group 2)

Drug: Gilteritinib (BAML-16-001-S8 Group 1)

Drug: Decitabine (BAML-16-001-S8 Group 1)

Drug: Decitabine (BAML-16-001-S8 Group 2)

Drug: Venetoclax (BAML-16-001-S8 Group 2)

BAML-16-001-S9 (Closed)

Experimental group

Description:

This is an open-label phase 2 clinical trial of a stepwise approach to the treatment of patients with TP53 mutation AML. On day 1, all enrolled participants will be initiated on therapy with pevonedistat (20 mg/m2) day 1, 3 and 5 together with azacitidine (75 mg/m2 days 1-7 or day 1-5 then day 8, 9) every 28 days. During cycle 1, patients with rapidly progressive disease or severe organ dysfunction, not correctable by hydroxyurea cytoreduction will not be eligible to continue. Those patients who achieved a response, defined as complete response or complete response with incomplete blood count recovery, by the end of cycle 4 will continue on pevonedistat and azacitidine until disease progression, unacceptable toxicity, or 12 cycles of therapy. After 12 months of combined therapy, pevonedistat will be continued until progression of disease, unacceptable toxicity, or up to 2 years of total therapy.

Treatment:

Drug: Azacitidine (BAML-16-001-S9)

Drug: Pevonedistat (BAML-16-001-S9)

BAML-16-001-S10 (Closed)

Experimental group

Description:

This is a phase 1b/2 clinical trial to assess the safety and efficacy of the combination of AZD5153 and venetoclax. In a phase 1b component, safety and tolerability of the combination will be assessed in relapsed/refractory AML patients ≥ 18 years of age. Following determination of the recommended Phase 2 dose (RP2D), newly diagnosed, marker negative patients age ≥ 60 will be enrolled in the phase 2 component; these patients will be treated at the previously identified RP2D for the combination. The RP2D will be the highest dose level with ≤ 1 out of 6 patients with dose limiting toxicity and defined as the maximum tolerated dose.

Treatment:

Drug: AZD5153 (BAML-16-001-S10)

Drug: Venetoclax (BAML-16-001-S10)

BAML-16-001-S14 (Closed)

Experimental group

Description:

The study is an open-label Phase 1b/2 clinical study of TP-0903 given in addition to decitabine in patients ≥ 60 years with newly diagnosed, previously untreated AML with TP53 mutations and/or complex karyotype. The Phase 1b portion of this study will use a standard 3 + 3 design with dose escalation based upon dose limiting toxicities. The maximum tolerated dose will be defined as the highest dose where at most 1 patient in 6 experiences dose-limiting toxicity, and this is generally the recommended Phase 2 dose (RP2D). Once the RP2D is determined from Phase 1b, patients will be enrolled at this dose level to initiate the Phase 2 portion of the study.

Treatment:

Drug: TP-0903 (BAML-16-001-S14)

Drug: Decitabine (BAML-16-001-S14)

BAML-16-001-S16 (Closed)

Experimental group

Description:

This is an open-label phase 2 clinical study to assess the feasibility and efficacy of a combination based approach to the treatment of IDH1 mutant AML. On day 1 of the trial, all enrolled participants will be initiated on therapy with the IDH1 inhibitor AG-120 given daily together with azacitidine (days 1-5 and 8-9 or 7 consecutive days 1-7) in 28 day cycles for IDH1 mutant patients. Those patients who have achieved a response, defined as complete response or complete response with incomplete blood count recovery, by the end of cycle 6, will continue on combination therapy for a total of 12 cycles and then patients will go onto receive monotherapy with AG-120 until disease progression or unacceptable side effects that mandate discontinuation of therapy. Patients who cannot complete 12 cycles of azacitidine may proceed onto monotherapy with AG-120.

Treatment:

Drug: Azacitidine (BAML-16-001-S16)

Drug: AG-120 (BAML-16-001-S16)

BAML-16-001-S18 (Closed)

Experimental group

Description:

This is an open-label Phase 1b clinical study of AZD5991 + azacitidine in patients aged ≥60 years with newly diagnosed, previously untreated, hypermethylated and marker-negative AML. The phase 1b1 study will adopt a standard 3+3 design with dose escalation based upon dose limiting toxicities. The recommended Phase 2 dose (RP2D) is defined in this study as the highest dose level where less than 2 dose limiting toxicities (DLT) are observed out of 6 patients. Once the RP2D is defined, patients will be enrolled into 2 separate cohorts (hypermethylation and marker negative group) for the phase 1b2 expansion. These 2 groups will both be treated at the RP2D determined from phase 1b1.

Treatment:

Drug: AZD5991 (BAML-16-001-S18)

Drug: Azacitidine (BAML-16-001-S18)

S25/HO181 (Arm 1): Std of care treatment plus bleximenib and also maintenance treatment w/bleximenib

Experimental group

Description:

\*\*Recruiting\*\* Bleximenib in combination with remission induction and consolidation therapy, followed by bleximenib maintenance therapy. Treatment will continue until PD, unacceptable toxicity or other protocol defined criteria for discontinuation (whichever comes first).

Treatment:

Drug: Daunorubicin or Idarubicin (BAML-16-001-S25/HO181)

Drug: Cytarabine (BAML-16-001-S25/HO181)

Drug: Bleximenib (BAML-16-001-S25/HO181)

S25/HO181 (Arm 2): Standard of care treatment plus bleximenib and maintenance treatment w/ a placebo

Experimental group

Description:

\*\*Recruiting\*\* Bleximenib in combination with remission induction and consolidation therapy, followed by placebo maintenance therapy. Treatment will continue until PD, unacceptable toxicity or other protocol defined criteria for discontinuation (whichever comes first)

Treatment:

Drug: Daunorubicin or Idarubicin (BAML-16-001-S25/HO181)

Drug: Cytarabine (BAML-16-001-S25/HO181)

Drug: Placebo (BAML-16-001-S25/HO181)

Drug: Bleximenib (BAML-16-001-S25/HO181)

S25/HO181 (Arm 3): Standard of care treatment plus a placebo and maintenance treatment w/ a placebo

Placebo Comparator group

Description:

\*\*Recruiting\*\* Placebo comparator in combination with remission induction and consolidation therapy, followed by placebo maintenance therapy. Treatment will continue until PD, unacceptable toxicity or other protocol defined criteria for discontinuation (whichever comes first).

Treatment:

Drug: Daunorubicin or Idarubicin (BAML-16-001-S25/HO181)

Drug: Cytarabine (BAML-16-001-S25/HO181)

Drug: Placebo (BAML-16-001-S25/HO181)

BAML-16-001-S26/HO177 (Revumenib-placebo)

Placebo Comparator group

Description:

\*\*Recruiting\*\* day 1-28 Placebo Treatment will be on a continuous 28-day cycle schedule and continued until disease progression, development of unacceptable toxicity, death, withdrawal by subject or other protocol defined criteria for discontinuation (whichever comes first).

Treatment:

Drug: Placebo (BAML-16-001-S26/HO177)

BAML-16-001-S26/HO177 (Revumenib)

Experimental group

Description:

\*\*Recruiting\*\* day 1-28 Revumenib Treatment will be on a continuous 28-day cycle schedule and continued until disease progression, development of unacceptable toxicity, death, withdrawal by subject or other protocol defined criteria for discontinuation (whichever comes first).

Treatment:

Drug: Revumenib (BAML-16-001-S26/HO177)