Study of Biomarker-Based Treatment of Acute Myeloid Leukemia

Beat AML, LLC

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Previously Untreated Relapsed Refractory Acute Myeloid Leukemia

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

Study type: Interventional

Funder types: Other

Identifiers

NCT03013998

BAML-16-001

Details and patient eligibility

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)." 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 a marker negative sub-study 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 criteria

• Adults, age 60 years or older at the time of diagnosis unless in a specific known cytogenetic and genomic group for which treatment in Group A, B, or C is allowed by the sub-study where age 18 and older is allowed. In such case, waiting for Foundation Medicine test results would not be required to proceed with sub-study treatment. Patients < 60 years old who are screened but do not fall within the cytogenetic and genomic open sub-studies would still be followed on the M1 Master Protocol and not considered screen fails.
• Patients must be able to understand and provide written informed consent
• Cohort Inclusion Criteria - Group A: Patients must have previously untreated acute myeloid leukemia (AML) according to the WHO classification with no prior treatment other than hydroxyurea. Patients with myeloid malignancies [e.g. myelodysplastic syndrome (MDS) or other disease], will be allowed to enroll to this group. For previously untreated subjects with ≥ 20% blasts in bone marrow or blood only: Prior therapy for myelodysplastic syndrome (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 as specified in this protocol, will be allowed to enroll to select sub-studies that allow enrollment and treatment of all patients regardless of their genomic mutations or cytogenetics. For this group, patients will proceed to enroll to that select sub-study without waiting for results of genomic testing and genomic samples will be collected to be analyzed retrospectively after patients' enrollment.
• Cohort Inclusion Criteria - Group B: Patients must have relapsed or refractory AML according to the WHO classification. For study purposes, refractory AML is defined as failure to ever achieve a complete response (CR) or recurrence of AML within 6 months of achieving CR; relapsed AML is defined as all others with disease after prior remission. For select genomic aberrations specified in the sub-studies, patients ≥ 18 years of age may be allowed to enroll in this portion of the study. Patients with relapsed or refractory myeloid malignancies (e.g., MDS or other diseases) will be allowed to enroll to this group.
• Cohort Inclusion Criteria - Group C: For select sites which are not part of the Beat AML core sites. These sites will only participate in select sub-studies. Patients in this group will enroll under the Beat AML M1 Master protocol with the intent to enroll into these select sub-studies and following screening on Beat M1 Master protocol, they will come off M1 Master protocol.

Exclusion criteria

• Acute promyelocytic leukemia
• Clinically active central nervous system (CNS) involvement by AML. A patient may be considered eligible if CNS leukemia is showing response to treatment at study entry and should continue to receive intrathecal therapy as clinical indicated. Patients who require or are undergoing craniospinal irradiation of disease control would not be eligible for participation.
• Signs of leukostasis requiring urgent therapy
• Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis
• Patients with 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 potentially hamper compliance with study treatment and follow-up
• Any other significant medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient participating in the trial or would confound the interpretation of the results of the trial.

BAML-16-001-S17 - Inclusion Criteria:

1. Patients, age 60 years or older at the time of diagnosis with untreated AML according to the International Consensus Classification (ICC) 2022 guidelines, that have NPM1 mutated or MLL rearranged disease and who are not candidates for or do not wish to pursue intensive induction chemotherapy.
2. Patients must be able to understand and provide written informed consent.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.
4. Aspartate aminotransferase (AST) < 5 x upper limit of normal (ULN), alanine aminotransferase (ALT) < 5 x ULN, and total bilirubin < 2 x ULN (except for patients with known or suspected Gilbert's syndrome and with direct bilirubin within normal range) for the local laboratory.
5. Adequate renal function as defined by calculated creatinine clearance ≥ 60 mL/min for the local laboratory.
6. Females must be non-child bearing, postmenopausal, surgically sterile or meet certain criteria if of childbearing potential. Males must adhere to criteria if with females of child bearing potentia
7. Patients must have previously untreated AML with 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 one dose of intrathecal chemotherapy for suspected CNS involvement (that is ruled out) is allowed. Prior therapy for myelodysplastic syndrome is (MDS) allowed except for hypomethylating agents.
8. If the patient has co-morbid illness or malignancy, life expectancy attributed to this must be greater than 2 years.

BAML-16-001-S17 - Exclusion Criteria:

1. Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML to enter the study).
2. Acute promyelocytic leukemia (FAB M3).
3. Favorable risk cytogenetics [Core Binding Factor (CBF) AML].
4. Active central nervous system (CNS) involvement by AML.
5. Signs of leukostasis requiring urgent therapy.
6. Patients with WBC ≥ 25,000/μl. (Patients must have WBC < 25,000/μl to begin therapy and Hydroxyurea may be used to obtain this level).
7. Patients willing and able to receive intensive induction chemotherapy.
8. Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis.
9. Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up.
10. Any other significant medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient participating in the trial or would confound the interpretation of the results of the trial.
11. Known active Human Immunodeficiency Virus (HIV), active hepatitis B or active hepatitis C infection.
12. Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction 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 with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
13. As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control.
14. Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent and until toxicity from this has resolved to grade 1 or less; if the half-life of the agent is unknown, patients must wait 4 weeks prior to first dose of study treatment. An investigational agent is one for which there is no approved indication by the United States (US) FDA.
15. Patients with QTcF (Fridericia) > 450 ms for male patients and > 468 for female patients; patients with right, left, or partial bundle branch blocks or pacemaker that may confound interpretation of this reading are excluded from this provided they lack history of primary arrhythmic events and are cleared by cardiology for enrollment in the trial. Any factors that increase the risk of QTc prolongation or risk of arrhythmic event such as congenital long QT syndrome or family history of long QT syndrome.

BAML-16-001-S21 - Inclusion Criteria:

1. Written Informed Consent must be obtained from the patient prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).

2. Patient is ≥18 years of age at the time of obtaining informed consent.

3. Patient is refractory to or relapsed after multiple AML therapies (with or without HSCT). and have exhausted all reasonable therapies expected to produce benefit unless the patient declines or is ineligible for these.

4. Group 1: Patient must have a confirmed FLT3-ITD or FLT3-TKD mutation by central laboratory testing. Group 2: Patient must have a documented SF3B1, SRSF2, U2AF1, or ZRSR2 pathogenic mutation by local lab sequencing.

5. For Group 1 only: Patients must have previously been treated with Gilteritinib with failure to stop disease progression, or not met the criteria for treatment with Gilteritinib in the opinion of the Investigator or chosen not to have treatment with Gilteritinib.

6. Patients have a life expectancy of at least 3 months in the opinion of the Investigator.

7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

8. Patient must meet the following criteria as indicated on the clinical laboratory tests:

   1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN).
   2. Serum total bilirubin ≤1.5 × ULN unless due to Gilbert's disease where a maximum total bilirubin level of 4.0 mg/dL is acceptable.
   3. Estimated glomerular filtration rate (eGFR) of > >40 mL/min as calculated by the Modification of Diet in Renal Disease equation.

9. Females must be non-child bearing, postmenopausal, surgically sterile or meet certain criteria if of childbearing potential.

10. Males must adhere to criteria if with females of child bearing potential

BAML-16-001-S21 - Exclusion Criteria:

1. Diagnosis of isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML).
2. Acute promyelocytic leukemia (FAB M3).
3. Active central nervous system (CNS) involvement by AML.
4. Clinical signs/symptoms of leukostasis requiring urgent therapy.
5. Known active infection with Human Immunodeficiency Virus (HIV), hepatitis B or hepatitis C. Patients with a history of positive serology for hepatitis B or C require a negative Polymerase chain reaction (PCR) test for virus to go onto therapy.
6. Disseminated intravascular coagulopathy with active, unmanageable bleeding or signs of thrombosis.
7. Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent; if the half-life of the agent is unknown, patients must wait 1 week prior to first dose of study treatment. An investigational agent is one for which there is no approved indication by the local regulatory authority.
8. Systemic chemotherapy or radiation therapy within 1 week prior to starting protocol with the exception of hydroxyurea, which is allowed to control white blood cell counts.
9. Female patients who are pregnant or lactating.
10. Patients with QTcF > 470 msec that cannot be corrected with electrolyte replacement, hydration, or medication modifications.
11. Patients with psychological, familial, social, or geographic factors, other significant medical condition, laboratory abnormality that otherwise preclude them from giving informed consent, following the protocol, potentially hamper compliance with study treatment and follow-up or would confound the interpretation of the results of the study.
12. Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction with evidence of residual abnormalities within 6 months prior to enrollment (Troponin (regular or high sensitivity) leak alone not included if no residual dysfunction), 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 with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
13. Infection is a common feature of AML, as such patients with active infection are permitted to enroll provided that the infection is under control in the opinion of the Investigator. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control.

BAML-16-001-S24 - Inclusion Criteria:

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

BAML-16-001-S24 - Exclusion Criteria:

1. Patients able and willing to receive intensive induction chemotherapy for underlying AML.
2. Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML to enter the study).
3. Acute promyelocytic leukemia.
4. Known active central nervous system (CNS) involvement by AML.
5. Clinical signs/symptoms of leukostasis requiring urgent therapy.
6. Known active Human Immunodeficiency Virus (HIV), active hepatitis B or active hepatitis C infection.
7. Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis.
8. Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent; if the half-life of the agent is unknown, patients must wait 1 week prior to first dose of study treatment. An investigational agent is one for which there is no approved indication by the United States (US) FDA.
9. Systemic antineoplastic therapy (for any indication) within 5 half-lives or radiation therapy within 1 week prior to starting protocol except for hydroxyurea, which is allowed to control white blood cell counts.
10. Patients with psychological, familial, social, or geographic factors, other significant medical condition, laboratory abnormality that otherwise preclude them from giving informed consent, following the protocol, potentially hamper compliance with study treatment and follow-up or would confound the interpretation of the results of the trial.
11. Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction within 6 months prior to enrollment (Troponin leak alone not included if no residual dysfunction) 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 with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
12. As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control.
13. Patients who require treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A.
14. Patients who require treatment with concomitant drugs that are strong inhibitors or inducers of P-glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the care of the patient.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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3,000 participants in 18 patient groups

BAML-16-001-S17

Experimental group

Description:

This is an open-label Phase 1b dose escalation and 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 MLL-rearranged disease. After determination of the recommended dose of SNDX-5613, the study will have an expansion cohort to be treated at the recommended dose in combination with azacitidine and venetoclax in the same patient population.

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)

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)

Other: Laboratory Biomarker Analysis

BAML-16-001-S12 (Arm B)

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:

Other: Laboratory Biomarker Analysis

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

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

BAML-16-001-S21 (Group 1)

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)

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:

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

Other: Laboratory Biomarker Analysis

BAML-16-001-S24

Experimental group

Description:

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)