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); Biological: Samalizumab (BAML-16-001-S1); Drug: Daunorubicin (BAML-16-001-S1); Drug: ZE46-0134 (BAML-16-001-S21); Drug: Venetoclax (BAML-16-001-S8 Group 2); Drug: Decitabine (BAML-16-001-S8 Group 2); Drug: Azacitidine (BAML-16-001-S16); Other: Laboratory Biomarker Analysis; Drug: Azacitidine (BAML-16-001-S18); Drug: AZD5991 (BAML-16-001-S18); 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: Gilteritinib (BAML-16-001-S8 Group 2); Drug: AG-221 (BAML-16-001-S3); Drug: SNDX-5613 (BAML-16-001-S17); 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: 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.

Enrollment: 2,000 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 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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2,000 participants in 16 patient groups

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)

Other: Laboratory Biomarker Analysis

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)

Other: Laboratory Biomarker Analysis

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)

Other: Laboratory Biomarker Analysis

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)

Other: Laboratory Biomarker Analysis

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)

Other: Laboratory Biomarker Analysis

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)

Other: Laboratory Biomarker Analysis

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

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)

Other: Laboratory Biomarker Analysis

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:

Other: Laboratory Biomarker Analysis

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

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

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)

Other: Laboratory Biomarker Analysis

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

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

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)

Other: Laboratory Biomarker Analysis

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)

Other: Laboratory Biomarker Analysis

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)

Other: Laboratory Biomarker Analysis

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

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

Other: Laboratory Biomarker Analysis

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)

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:

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

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

BAML-16-001-S21

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. 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)