Study of Biomarker-Based Treatment of Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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.

Official Title
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A Master Protocol for Biomarker-Based Treatment of AML (The Beat AML Trial)

Conditions
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Previously Untreated Acute Myeloid Leukemia

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


Participation Criteria
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Eligibility Criteria
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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 or B is allowed by the sub-study where age 18 and older is allowed. 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 Master Protocol and not considered screen fails. Subjects must be able to understand and provide written informed consent Cohort Inclusion Criteria - Group A: Subjects must have previously untreated acute myeloid leukemia (AML) according to the WHO classification with no prior treatment other than hydroxyurea. Subjects with blasts % in bone marrow of 10% to 19% or blasts in blood of 10% to 19% 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 but not with hypomethylating agents. Cohort Inclusion Criteria - Group B: Subjects must have relapsed or refractory AML according to the WHO classification. For study purposes, refractory AML is defined as failure to ever achieve 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 studies, patients ≥ 18 years of age may be allowed to enroll in this portion of the study. Exclusion Criteria: Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML or involved with 10% to 19% blasts to enter the study) Acute promyelocytic leukemia Symptomatic central nervous system (CNS) involvement by AML 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, 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAML-16-001-S1 (Closed)<br>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. | Biological: Samalizumab (BAML-16-001-S1)<br>* 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.<br>Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: Daunorubicin (BAML-16-001-S1)<br>* 60 mg/m2, IV, on days 4, 5, and 6 of the induction cycle<br>Drug: Cytarabine (BAML-16-001-S1)<br>* 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<br>|
| Experimental: BAML-16-001-S2 (Closed)<br>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. | Biological: BI 836858 (BAML-16-001-S2)<br>* 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.<br>Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: Azacitidine (BAML-16-001-S2)<br>* 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<br>|
| Experimental: BAML-16-001-S3 (Closed)<br>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. | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: AG-221 (BAML-16-001-S3)<br>* 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.<br>* Other names: Enasidenib;Drug: Azacitidine (BAML-16-001-S3)<br>* 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<br>|
| Experimental: BAML-16-001-S4 (Closed)<br>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. | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: Entospletinib (BAML-16-001-S4)<br>* 200 mg, oral, twice daily for 5 years until time of intolerance or disease progression. Dose may be escalated to 400 mg.<br>* Other names: GS-9973, ENTO;Drug: Azacitidine (BAML-16-001-S4)<br>* 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.<br>|
| Experimental: BAML-16-001-S5 (Closed)<br>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. | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: Entospletinib (BAML-16-001-S5)<br>* 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.<br>* Other names: GS-9973, ENTO;Drug: Decitabine (BAML-16-001-S5)<br>* 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.<br>|
| Experimental: BAML-16-001-S6 (Closed)<br>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). | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: Entospletinib (BAML-16-001-S6)<br>* 400 mg, oral, twice daily for 2 years until time of intolerance or disease progression.<br>* Other names: GS-9973, ENTO;Drug: Daunorubicin (BAML-16-001-S6)<br>* 60 mg/m2, IV, on days 1-3 or 1-2 of each 28-day cycle for the first and second induction cycle, respectively<br>Drug: Cytarabine (BAML-16-001-S6)<br>* 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<br>|
| Experimental: BAML-16-001-S9 (Closed)<br>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. | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: Pevonedistat (BAML-16-001-S9)<br>* 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<br>* Other names: TAK-924, MLN4924;Drug: Azacitidine (BAML-16-001-S9)<br>* 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<br>|
| Experimental: BAML-16-001-S16 (Closed)<br>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. | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: AG-120 (BAML-16-001-S16)<br>* 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.<br>Drug: Azacitidine (BAML-16-001-S16)<br>* 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<br>|
| Experimental: BAML-16-001-S8<br>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. | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: Gilteritinib (BAML-16-001-S8 Group 1)<br>* 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.<br>Drug: Decitabine (BAML-16-001-S8 Group 1)<br>* 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.<br>Drug: Decitabine (BAML-16-001-S8 Group 2)<br>* 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.<br>Drug: Venetoclax (BAML-16-001-S8 Group 2)<br>* 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.<br>Drug: Gilteritinib (BAML-16-001-S8 Group 2)<br>* 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.<br>|
| Experimental: BAML-16-001-S10 (Closed)<br>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. | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: AZD5153 (BAML-16-001-S10)<br>* 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.<br>Drug: Venetoclax (BAML-16-001-S10)<br>* 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).<br>|
| Experimental: BAML-16-001-S14 (Closed)<br>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. | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: TP-0903 (BAML-16-001-S14)<br>* 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.<br>Drug: Decitabine (BAML-16-001-S14)<br>* 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.<br>|
| Experimental: BAML-16-001-S18 (Closed)<br>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. | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: AZD5991 (BAML-16-001-S18)<br>* 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.<br>Drug: Azacitidine (BAML-16-001-S18)<br>* 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<br>|
| Experimental: BAML-16-001-S17<br>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. | Other: Laboratory Biomarker Analysis<br>* Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia<br>Drug: SNDX-5613 (BAML-16-001-S17)<br>* 113 mg, 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 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. 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 (days 1-21 or days 1-28).<br>Drug: Azacitidine (BAML-16-001-S17)<br>* 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.<br>Drug: Venetoclax (BAML-16-001-S17)<br>* 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 of each 28-day cycle until time of progression, unacceptable toxicity, or death (patients on moderate CYP3A4 inhibitor antifungals should receive 200 mg/day).<br>|
| Active Comparator: BAML-16-001-S12 (Arm A)<br>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. | Drug: Venetoclax (BAML-16-001-S12 Arm A)<br>* 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.)<br>Drug: Azacitidine (BAML-16-001-S12 Arm A)<br>* 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.<br>|
| Experimental: BAML-16-001-S12 (Arm B)<br>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. | Drug: Venetoclax (BAML-16-001-S12 Arm B)<br>* 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.)<br>Drug: Azacitidine (BAML-16-001-S12 Arm B)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients for whom molecular, immunophenotypic, and/or biochemical studies are completed in < 7 calendar days for assignment of treatment | The feasibility of completing molecular, genetic, immunophenotypic, and biochemical testing for assignment of therapy will be assessed based on the proportion of patients for whom testing is completed within 7 days of the registration sample arriving at the laboratory | 7 days | 
| 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 | The feasibility of assigning patients to a treatment group will be assessed based on the proportion who are eligible for screening in this study who are assigned to treatment either on this study or an industry study relevant to the specific marker group and not unassignable due to insufficient material, laboratory error, or any other factors | 7 days | 
| Clinical response rate (rate of complete and partial responses) according to International Working Group criteria for treatment outcomes in therapeutic trials in acute myeloid leukemia |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients enrolled on this trial that ultimately will be assigned and go onto an assigned therapy |  | 7 days | 
| Dynamic changes in clonal architecture over time in acute myeloid leukemia patients receiving targeted therapies |  | time of diagnosis, remission (complete response or complete response with incomplete blood count recovery), 1 year of treatment, and relapse | 
| Relationships between baseline functional status and response rate or progression-free survival based on graphical comparison (eg, side-by-side boxplots or Kaplan-Meier plots) | Assessments of functional status will include Eastern Cooperative Oncology Group Performance Status. Assessment of clinical response will be made according to International Working Group criteria. Relationships will be explored graphically (eg, side-by-side boxplots or Kaplan-Meier plots), where estimates with confidence intervals will be presented as the primary method of analysis due to the limited number of patients. | Up to 5 years |