NCT03013998 · Beat AML, LLC
Study of Biomarker-Based Treatment of Acute Myeloid Leukemia
What this study is about
This screening and multi-sub-study Phase 1b/2 trial will establish a method for genomic screening followed by assigning and accruing simultaneously to a multi-study "Master Protocol (BAML-16-001-M1).
View original scientific description
This screening and multi-sub-study Phase 1b/2 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.
Interventions
BIOLOGICAL
Samalizumab (BAML-16-001-S1)
300 mg/m2, IV, on days 1, 3, and 24; followed by 300 mg/m2, IV, every 21 days for 2 years in the absence of toxicity or disease progression. Dose may be de-escalated to 150 mg/m2 or escalated to 600 mg/m2 based on occurrence of dose-limiting toxicity.
BIOLOGICAL
BI 836858 (BAML-16-001-S2)
20 mg/m2, IV, on days 9, 16, and 23 of a 28-day cycle; followed 20 by mg/m2, IV, on days 1, 8, 15 and 22 of each 28-day cycle for 2 years in the absence of toxicity or disease progression (reduced to monthly administration in event of complete response or complete response with incomplete blood count recovery). Dose may be escalated to a maximum dose of 320 mg/m2 or de-escalated to 10 mg/m2 based on occurrence of dose-limiting toxicity.
OTHER
Laboratory Biomarker Analysis
Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia
DRUG
Daunorubicin (BAML-16-001-S1)
60 mg/m2, IV, on days 4, 5, and 6 of the induction cycle
DRUG
Cytarabine (BAML-16-001-S1)
100 mg/m2, IV, on days 4 through 10 of the 24-day induction cycle; 1000 mg/m2, IV, on days 2, 4, and 6 of the consolidation cycle 1 and days 1, 3, and 5 of consolidation cycles 2 through 4
DRUG
Azacitidine (BAML-16-001-S2)
75 mg/m2, IV, on days 1 through 7 of each 28-day cycle for 2 years in the absence of toxicity or disease progression
DRUG
AG-221 (BAML-16-001-S3)
100 mg, oral, daily until time of intolerance or disease progression. Dose may be de-escalated to 50 mg based on occurrence of dose-limiting toxicity.
DRUG
Azacitidine (BAML-16-001-S3)
75 mg/m2, IV or SC, on days 1 through 7 of each 28-day cycle starting with cycle 6 and ending after 12 cycles for patients not attaining complete remission or complete remission with incomplete blood count recovery after 5 cycles of monotherapy with AG-221
DRUG
Entospletinib (BAML-16-001-S4)
200 mg, oral, twice daily for 5 years until time of intolerance or disease progression. Dose may be escalated to 400 mg.
DRUG
Azacitidine (BAML-16-001-S4)
75 mg/m2, IV or SC, on days 1 through 7 of each 28-day cycle and continuing for 12 cycles. Treatment starts after 1 cycle of monotherapy with entospletinib for patients not attaining complete remission or complete remission with incomplete blood count recovery or after later cycles of monotherapy with entospletinib for patients with disease progression.
DRUG
Entospletinib (BAML-16-001-S5)
400 mg, oral, twice daily for 2 years on study until time of intolerance or disease progression. Dose may be de-escalated to 200 mg twice daily or 200 mg once daily based on occurrence of dose-limiting toxicity.
DRUG
Decitabine (BAML-16-001-S5)
20 mg/m2, IV, on days 1 through 5 or 10 of each 28-day cycle and continuing for up to 11 cycles. During the first induction cycle, and the 2nd and 3rd induction cycles if they are needed, administration occurs on days 1 through 10 of each 28-day cycle. During subsequent consolidation, decitabine is administered on days 1 through 5 of each 28-day cycle and continuing for up to 11 cycles. Duration may be reduced by 1 day based on occurrence of dose-limiting toxicity, and patients may switch to entospletinib monotherapy maintenance at any time if they develop toxicity or are unwilling to continue decitabine during consolidation therapy.
DRUG
Entospletinib (BAML-16-001-S6)
400 mg, oral, twice daily for 2 years until time of intolerance or disease progression.
DRUG
Daunorubicin (BAML-16-001-S6)
60 mg/m2, IV, on days 1-3 or 1-2 of each 28-day cycle for the first and second induction cycle, respectively
DRUG
Cytarabine (BAML-16-001-S6)
100 mg/m2, IV, on days 1 through 7 or 1 through 5 of each 28-day cycle for the first and second induction cycle, respectively; then 1000 mg/m2 (patients ≥60 years) or 3000 mg/m2 (younger patients with creatinine clearance \>30 mL/min and \<50 mL/min), IV, every 12 hours on days 1, 3, and 5 of each 28-day cycle for up to 4 consolidation cycles
DRUG
Pevonedistat (BAML-16-001-S9)
20 mg/m2, IV, on days 1, 3, and 5 of each 28-day cycle and continuing for 24 cycles in the absence of toxicity or disease progression
DRUG
Azacitidine (BAML-16-001-S9)
75 mg/m2, IV or SC, on days 1 through 7 or days 1 through 5 and then 8 through 9 (based on institutional guidelines) of each 28-day cycle and continuing for 12 cycles in the absence of toxicity or disease progression
DRUG
AG-120 (BAML-16-001-S16)
500 mg, oral, daily until time of intolerance or disease progression. Dose may be de-escalated to 250 mg based on occurrence of dose-limiting toxicity.
DRUG
Azacitidine (BAML-16-001-S16)
75 mg/m2, IV or SC, on days 1 through 7 or days 1 through 5 and then 8 through 9 (based on institutional guidelines) of each 28-day cycle and continuing for 12 cycles in the absence of toxicity or disease progression
DRUG
Gilteritinib (BAML-16-001-S8 Group 1)
120 mg, oral, daily, with treatment continuing based on bone marrow results at 28 and 56 days. Patients with partial response at 28 days continue treatment for an additional 28 days. Patients with complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) at 28 or 56 days continue treatment for 5 years until time of intolerance or disease progression. Patients with less than partial response at 28 days or partial response at 28 days followed by less than CR or CRi at 56 days proceed to combination treatment with decitabine or non-study alternative. The combination dose is 80 mg, oral, daily, for 5 years until time of intolerance or disease progression (patients who do not achieve CR or CRi after 3 cycles will discontinue study treatment). The combination dose may be escalated to 120 mg daily or de-escalated to 80 mg daily given after decitabine rather than in combination with decitabine based on absence or occurrence of dose-limiting toxicity.
DRUG
Decitabine (BAML-16-001-S8 Group 1)
20 mg/m2, IV, on days 1 through 10 of each 28-day cycle and continuing for up to 3 cycles. Treatment starts after 1-2 cycles of monotherapy with gilteritinib if patients do not attain complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) with monotherapy. Patients who do not achieve CR/CRi after 3 cycles of combination therapy will discontinue study treatment. If CR or CRi is obtained with combination therapy after 3 cycles, decitabine will be administered on days 1-5 of each subsequent 28-day cycle until progression, intolerance, or patient desire to discontinue therapy.
DRUG
AZD5153 (BAML-16-001-S10)
20 mg, oral, once daily during 7-day lead-in and then on days 1 through 21 of each 28-day cycle for up to 2 years or until allogeneic stem cell transplantation, time of intolerance, or disease progression \[if the continuous administration AZD5153 on Days 1-21 of a 28-day cycle is not tolerated, an alternative schedule of 2 weeks on and 2 weeks off (i.e. AZD5153 will be administered on Days 1-14 of a 28-day cycle) will be explored\]. Dose may be de-escalated to 10 mg or escalated to 30 mg based on occurrence of dose-limiting toxicity during phase 1 dose escalation. Starting with Cycle 2, patients may receive concomitant fluconazole, isavuconazole, or posaconazole and doses adjusted to 2, 5, or 8 mg daily. The Phase 1b expansion pharmacokinetics cohort will allow for posaconazole starting at Cycle 1 with AZD5153 dose adjusted from 10, 20, or 30 mg daily to 2, 5, or 8 mg daily. Phase 2 dose will be based on Phase 1 results.
DRUG
Venetoclax (BAML-16-001-S10)
400 mg, oral, on days 1 through 21 of each 28-day cycle and continuing for up to 12 cycles (for Cycle 1, day 1 dose will be 100 mg, day 2 dose 200 mg, and days 3 onward 400 mg). Starting with Cycle 2, patients may receive concomitant fluconazole or isavuconazole and daily doses adjusted to 200 mg, or posaconazole and daily doses adjusted to 70 mg. The Phase 1b expansion pharmacokinetics cohort will allow for posaconazole starting at Cycle 1 with Venetoclax dose adjusted to 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, and 70 mg on day 4 onward).
DRUG
TP-0903 (BAML-16-001-S14)
37 mg, oral, once daily on days 1 through 21 of each 28-day cycle for up to 2 years to time of intolerance or disease progression. Dose may be de-escalated to as low as 12 mg or escalated to 50 mg based on occurrence of dose-limiting toxicity during Phase 1 dose escalation. Phase 2 dose will be based on Phase 1 results.
DRUG
Decitabine (BAML-16-001-S14)
20 mg/m2, IV, on days 1 through 5 or 10 of each 28-day cycle and continuing for up to 2 years to time of intolerance or disease progression. During the first induction cycle, and the 2nd and 3rd induction cycles if they are needed, administration occurs on days 1 through 10 of each 28-day cycle. During maintenance, decitabine is administered on days 1 through 5 of each 28-day cycle. Patients may switch to TP-0903 monotherapy maintenance if they develop toxicity or are unwilling to continue decitabine during maintenance therapy.
DRUG
Decitabine (BAML-16-001-S8 Group 2)
20 mg/m2, IV, on days 8 through 12 of the first 35-day induction cycle, then on days 1 through 5 of subsequent 28-day cycles and continuing for up to 60 cycles, disease progression, intolerance, or patient desire to discontinue therapy.
DRUG
Venetoclax (BAML-16-001-S8 Group 2)
Oral dosing based on concurrent antifungal use. Dose without use of concomitant antifungal is 400mg, dose if on posaconazole is 70mg, dose if on voriconazole is 100mg, and dose if on moderate CYP3A inhibitors (ie fluconazole, isavuconazole) is 200mg continuing for up to 12 total cycles. For the 35-day induction cycle 1, dosing is days 2 through 28. For the 28-day induction cycle 2, if needed, dosing is days 1 through 21. For the 28-day consolidation cycles, dosing is days 1-15.
DRUG
AZD5991 (BAML-16-001-S18)
150 mg, IV, on days 1, 4, 8, 11, 15, and 18 of three 28-day cycles; followed by 150 mg/m2, IV, on days 1, 4, 8, and 11 of twenty-one 28-day cycles; followed by 150 mg/m2 on days 1 and 4 of each 28-day cycle until time of progression, unacceptable toxicity, death, or 57 total cycles of treatment. Dose may be escalated to a maximum dose of 400 mg or de-escalated to 100 mg based on occurrence of dose-limiting toxicity.
DRUG
Azacitidine (BAML-16-001-S18)
75 mg/m2, IV or SC, on days 1-7 or days 1-5 and 8 and 9 or days 1-2 and 5-9 (based on institutional guidelines) of each 28-day cycle until time of progression, unacceptable toxicity, death, or 57 total cycles of treatment
DRUG
SNDX-5613 (BAML-16-001-S17)
Patients starting induction with CYP3A4 inhibitors will be dosed at 113 mg capsule or 110 mg tablet, oral, every 12 hours on Day 1-28 of each 28-day cycle, until time of progression, unacceptable toxicity, or death. Dose may be escalated to a maximum dose of 163 mg capsule or 220 mg tablet on days 1-28 or de-escalated to 113 mg on days 1-21 based on occurrence of dose-limiting toxicity. Other possible dose escalation and de-escalation would be 163 mg on days 1-21, 75 mg on days 1-21 and 75 mg on days 1-28. Patients starting treatment without CYP3A4 inhibitors will be dosed at 276 mg capsule (270 mg tablet) or 226 mg capsule (220 mg tablet) oral, every 12 hours on Day 1-28 of each 28-day cycle. Following completion of induction, patients who do not require strong CYP3A4 inhibitor antifungals will have daily doses increased for doses in range of 113-226 mg capsules or 110-220 mg tablets (days 1-21 or days 1-28).
DRUG
Azacitidine (BAML-16-001-S17)
75 mg/m2, IV or SC, on days 1-7 (during induction cycle/cycles) or can use alternative scheduled on days 1-5 and 8 and 9 or days 1-2 and 5-9 (based on institutional guidelines) during continued therapy cycles of each 28-day cycle until time of progression, unacceptable toxicity, or death.
DRUG
Venetoclax (BAML-16-001-S17)
For Cycle 1 induction, day 1 dose is 10 mg, day 2 dose 20 mg, day 3 dose is 50 mg, and day 4 onward dose is 100 mg or 70 mg depending on concomitant antifungal treatment. For Cycles 2 and 3 inductions, daily doses are 100 or 70 mg depending on concomitant antifungal treatment. During continued therapy cycles, if not on concomitant strong CYP3A4 inhibitor antifungals, 400 mg, oral, on days 1 through 28 or days 1 through 14 of each 28-day cycle until time of progression, unacceptable toxicity, or death (patients on moderate CYP3A4 inhibitor antifungals should receive 200 mg/day).
DRUG
Gilteritinib (BAML-16-001-S8 Group 2)
Phase 1b induction: 80-120 mg, oral, daily for day 1 up to day 28 of the 35-day induction cycle 1; then 80-120 mg, oral, daily for day 1 up to day 28 of the 28-day induction cycle 2 (induction cycle 2 administered if needed after cycle 1 based on results bone marrow evaluation). Phase 1b consolidation: 80-120 mg, oral, daily for day 1 up to day 21 of the 28-day cycles, for a total of 12 total induction and consolidation cycles. Phase 1b induction and consolidation dose and duration may be escalated or de-escalated based on occurrence of dose-limiting toxicity. Phase 2 induction and consolidation dosage to be based on results of Phase 1b. Phase 1b and 2 maintenance: 120 mg, oral, daily for 28 days of the 28-day cycles until patient is minimal residual disease negative for FLT3 based on scheduled bone marrow biopsy, progression of disease, unacceptable toxicities, or desire to discontinue therapy.
DRUG
Venetoclax (BAML-16-001-S12 Arm A)
400 mg, oral, on days 1 through 28 of each 28-day cycle for up to 2 cycles or until unacceptable toxicity or death. For Cycle 1, day 1 dose is 100 mg, day 2 dose 200 mg, and day 3 onward dose is 400 mg. (Dose adjusted by anti-fungal agent use per the package insert.)
DRUG
Azacitidine (BAML-16-001-S12 Arm A)
75 mg/m2, IV or SC, on days 1-7 or days 1-5 and 8 and 9 or days 1-2 and 5-9 (based on institutional guidelines) of each 28-day cycle for up to 2 cycles or until unacceptable toxicity or death.
DRUG
Venetoclax (BAML-16-001-S12 Arm B)
400 mg, oral, on days 1 through 14 of each 14-day cycle for up to 2 cycles or until unacceptable toxicity or death. For Cycle 1, day 1 dose is 100 mg, day 2 dose 200 mg, and day 3 onward dose is 400 mg. (Dose adjusted by anti-fungal agent use per the package insert.)
DRUG
Azacitidine (BAML-16-001-S12 Arm B)
75 mg/m2, IV or SC, on days 1-7 or days 1-5 and 8 and 9 or days 1-2 and 5-9 (based on institutional guidelines) of each 14-day cycle for up to 2 cycles or until unacceptable toxicity or death.
DRUG
ZE46-0134 (BAML-16-001-S21 Group 1)
10 mg to 100 mg oral on Days 1-28 of each 28-day cycle for up to 24 cycles. On the first day of Cycle 1, a loading dose of 30 mg to 200 mg will be administered, after which the daily maintenance dose of 10 mg to 100 mg will be administered on days 2-28 of Cycle 1. Maintenance dose continues in subsequence cycles, for up to 24 cycles total.
DRUG
ficlatuzumab (BAML-16-001-S24)
10, 15 or 20 mg/kg IV on days 1 and 15.
DRUG
Azacitidine (BAML-16-001-S24)
75 mg/m2, IV or SC, on days 3-9 (during induction cycle 1) or can use alternative scheduled on days 3-7 and 10 and 11 or days 3-4 and 7-11 (based on institutional guidelines) for 30 days of Induction Cycle 1. All other induction cycle or continued therapy cycles of each 28-day cycle will be days 1-7, days 1-5 and 8-9 or days 1-2 and 5-9 (based on institutional guidelines) until time of progression, unacceptable toxicity, or death.
DRUG
Venetoclax (BAML-16-001-S24)
For Cycle 1 induction, day 3 dose is 100 mg, day 4 dose 200 mg, day 5 onward dose is 400 mg, depending on concomitant antifungal treatment. For Cycles 2 and 3 inductions, daily doses are 400mg or lower depending on concomitant antifungal treatment. During continued therapy cycles, if not on concomitant strong CYP3A4 inhibitor antifungals, 400 mg, oral, on days 1 through 14 of each 28-day cycle until time of progression, unacceptable toxicity, or death (patients on moderate CYP3A4 inhibitor antifungals should receive 200 mg/day).
DRUG
ZE46-0134 (BAML-16-001-S21 Group 2)
60 mg to 200 mg oral on Days 1-28 of each 28-day cycle for up to 24 cycles, for up to 24 cycles total.
DRUG
Bleximenib (BAML-16-001-S25/HO181)
Participants will receive bleximenib
DRUG
Cytarabine (BAML-16-001-S25/HO181)
Participants will receive Cytarabine
DRUG
Daunorubicin or Idarubicin (BAML-16-001-S25/HO181)
Participants will receive Daunorubicin or Idarubicin
DRUG
Placebo (BAML-16-001-S25/HO181)
Participants will receive Placebo
DRUG
Revumenib (BAML-16-001-S26/HO177)
day 1- 28 per cycle
DRUG
Placebo (BAML-16-001-S26/HO177)
day 1-28 per cycle
Primary outcome measures
BAML-16-001-M1: Proportion of patients for whom molecular, immunophenotypic, and/or biochemical studies are completed in < 7 calendar days for assignment of treatment
Time frame: 7 days
BAML-16-001-M1: Proportion of patients assigned to a novel therapeutic treatment group in 1 of several sub-studies in this Master Protocol, based on the result of the molecular, immunophenotypic, and/or biochemical studies
Time frame: 7 days
BAML-16-001-M1: Clinical response rate (rate of complete and partial responses) according to European Leukemianet (ELN) criteria for treatment outcomes in substudies in acute myeloid leukemia.
Time frame: Up to 5 years
BAML-16-001-S25/HO181: Event-Free Survival (EFS) in adult patients with newly diagnosed NPM1m or KMT2Ar AML eligible for intensive chemotherapy
Time frame: Up to 4 years and 5 months
To assess if treatment with bleximenib, as compared with placebo, in combination with remission induction chemotherapy, prolongs event-free survival (EFS) measured from the time from randomization to failure to achieve CR after remission induction, hematologic relapse after achieving CR, or death, whichever occurs first.
BAML-16-001-S26/HO177: Overall survival (OS) in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy.
Time frame: 58 months after last patient inclusion
To assess if treatment with revumenib, in combination with azacitidine and venetoclax, prolongs overall survival (OS) measured from the date of randomization to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive.
BAML-16-001-S26/HO177: Rate of CR in adult patients with newly diagnosed NPM1-mutated AML ineligible for intensive chemotherapy
Time frame: 58 months after the first randomized NPM1-mutated AML patient
Defined as the proportion of NPM1-mutated AML patients who achieve CR at any time-point during protocol therapy.
Who can participate
This study lists these criteria on ClinicalTrials.gov. A study coordinator reviews eligibility during screening — this page does not determine whether you qualify.
Inclusion criteria
- 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
- 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
- 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
- Patients must be able to understand \& provide written informed consent
- Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
- 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
- Adequate renal function as defined by calculated creatinine clearance ≥60 mL/min for the local lab
- 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
- 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
- If patient has co-morbid illness or malignancy, life expectancy attributed to this must be \>2 yrs S17 - EC
- Isolated myeloid sarcoma (must have blood or marrow involvement w/ AML)
- APL (FAB M3)
- Favorable risk cytogenetics (Core Binding Factor AML)
- Active CNS involvement by AML
- Signs of leukostasis requiring urgent therapy
- WBC ≥25,000/μl (WBC \<25,000/μl to begin therapy, Hydroxyurea may be used to obtain this level)
- Willing \& able to receive intensive chemotherapy
- 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, or complying w/ study treatment \& follow-up
- 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
- Known active HIV, active hepatitis B or C infections
- 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
- Patients w/ uncontrolled infection shall not be enrolled until infection is treated \& brought under control
- 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.
- 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
- ≥60 yrs at AML diagnosis
- ECOG score of 0, 1, or 2
- 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
- Adequate renal function as defined by calculated creatinine clearance \>40 mL/min per the local lab
- Patients must be able to understand \& provide written informed consent
- 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
- 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)
- If patient has co-morbid illness or malignancy, life expectancy attributed to this must be \>2 yrs S24 - EC
- Patients able \& willing to receive intensive chemotherapy for underlying AML
- Isolated myeloid sarcoma (must have blood or marrow involvement w/ AML)
- Known active CNS involvement by AML
- Clinical signs/symptoms of leukostasis requiring urgent therapy
- Known active HIV, active hepatitis B or C infections
- DIC w/ active bleeding or signs of thrombosis
- 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
- 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
- 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
- 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
- Patients w/ uncontrolled infection shall not be enrolled until infection is treated \& brought under control
- Patients who require treatment w/ concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A
- 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
- ≥18 yrs (or legal age of majority in jurisdiction where study is taking place, whichever is greater) at time of informed consent
- 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
- Considered eligible for intensive chemotherapy
- WHO/ECOG score ≤2
- Adequate renal \& hepatic functions prior to randomization S25/HO181 EC
- Prior (chemo-)therapy for AML, including prior treatment w/ hypomethylating agents
- Known active leukemic involvement of CNS
- Recipient of solid organ transplant
- Cardiac disease:
- 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
- QTcF ≥470 ms. Prolonged QTc interval associated w/ BBB or pacemaking is permitted
- Left ventricular ejection fraction (LVEF) \<40% by ECHO or MUGA scan obtained w/in 28 days prior to start of study treatment
- Previously received cumulative dose of any combination of anthracyclines or anthracenediones of ≥500 mg/m2
- Chronic respiratory disease requiring supplemental oxygen S26/HO177 - IC
- 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
- Central confirmation of NPM1 mutation or KMT2A rearrangement in 1 of the dedicated central genetic labs
- Age ≥18 yrs, no upper age limit
- 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
- Patient must have a projected life expectancy of at least 12 wks (as assessed by treating physician)
- 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
- 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)
- 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
- 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:
- 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
- Established intrauterine device (IUD) or intrauterine system (IUS)
- Bilateral tubal occlusion
- 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
- 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
- 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
- Male patient must not donate sperm starting at screening \& throughout the study period \& for 6 months after the final study drug administration
- Able to understand \& willing to sign an informed consent form (ICF)
- 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
- 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
- APL w/ t(15;17)(q24.1;q21.2); PML-RARA; or other pathognomonic variant chromosomal translocation/fusion gene
- AML w/ BCR-ABL1; or myeloid blast crisis of CML
- Significant active cardiac disease w/in 3 months prior to start of study treatment, including:
- NYHA class III or IV CHF
- 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)
- Severe obstructive or restrictive ventilation disorder
- History of stroke or intracranial hemorrhage w/in 6 months prior to randomization
- 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
- 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
- Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or DIC
- Conditions that limit ingestion or gastrointestinal absorption of orally administered drugs
- 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
- 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)
- Severe neurological or psychiatric disorder interfering w/ ability to give informed consent
- Contraindication to AZA or VEN (as per Summary of Product Characteristics)
- Weighing \<40 kg at registration
- Participation in other prospective studies w/ anti-leukemic and/or investigational agents
- 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
- Taking known strong cytochrome P450 (CYP) 3A4 inducers, unless patient can be transferred to other medications w/in ≥5 half-lives prior to dosing
- Pregnant or lactating woman or plans to become pregnant during the study
- Patient screened \& randomized into this S26/HO177 trial but considered ineligible cannot re-enter this trial at later date
Where
- Phoenix, Arizona
- Scottsdale, Arizona
- Los Angeles, California
- San Francisco, California
- Denver, Colorado
- Gainesville, Florida
- Jacksonville, Florida
- Orlando, Florida
- Atlanta, Georgia
- Augusta, Georgia
- Chicago, Illinois
- Fairway, Kansas
And 17 more locations — see the full list below.
Collaborators
Syndax Pharmaceuticals, Stichting Hemato-Oncologie voor Volwassenen Nederland, AVEO Pharmaceuticals, Inc.
Related conditions & keywords
Frequently asked questions
What is a clinical trial?
A clinical trial is a research study that tests new medical treatments, drugs, devices, or procedures to determine their safety and effectiveness. Trials are carefully designed and monitored to protect participants while advancing medical knowledge.
Is it safe to participate?
Clinical trials follow strict safety guidelines and ethical standards. Trials must be reviewed and approved, and participants are closely monitored by medical professionals throughout the study. You can withdraw at any time if you choose.
Will I be compensated?
Many clinical trials offer compensation for your time, travel expenses, and inconvenience. The specific compensation varies by study and will be discussed during the screening process. All study-related medical care is typically provided at no cost to participants.
Will I receive a placebo instead of treatment?
When effective treatment exists, participants typically receive either the standard treatment plus the study intervention, or the standard treatment plus placebo. You would not be denied effective care. Placebos are primarily used when no proven treatment is available, or in addition to standard care. Your trial consent form will clearly explain what treatments you may receive.
Can I leave a trial if I change my mind?
Absolutely. Participation in clinical trials is completely voluntary. You have the right to withdraw from the study at any time, for any reason, without penalty or loss of benefits to which you are otherwise entitled.
How long does a clinical trial last?
Trial duration varies widely depending on the study design and purpose. Some trials last just a few weeks, while others may continue for months or years. The study coordinator will provide specific timeline information during your screening call.
Data: ClinicalTrials.gov · synced Sep 3, 2026 · Source of record for eligibility and locations