Study of Biomarker-Based Treatment of Acute Myeloid Leukemia

Официальное название

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

Обзор

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.

Вмешательства

• Биопрепарат 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.
• Биопрепарат 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.
• Другое Laboratory Biomarker Analysis
  Molecular genomic assessment to assign patients to targeted therapy (sub-study) based on their specific subtype of acute myeloid leukemia
• Препарат Daunorubicin (BAML-16-001-S1)
  60 mg/m2, IV, on days 4, 5, and 6 of the induction cycle
• Препарат 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
• Препарат 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
• Препарат 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.
• Препарат 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
• Препарат 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.
• Препарат 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.

Первичные конечные точки

• Proportion of patients for whom molecular, immunophenotypic, and/or biochemical studies are completed in < 7 calendar days for assignment of treatment [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Up to 5 years]

Вторичные конечные точки (3)

• Proportion of patients enrolled on this trial that ultimately will be assigned and go onto an assigned therapy [Срок оценки: 7 days]
• Dynamic changes in clonal architecture over time in acute myeloid leukemia patients receiving targeted therapies [Срок оценки: 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) [Срок оценки: Up to 5 years]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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:

• 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.
• Patients must be able to understand and provide written informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.
• 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.
• Adequate renal function as defined by calculated creatinine clearance ≥ 60 mL/min for the local laboratory.
• 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
• 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.
• 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:

• Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML to enter the study).
• Acute promyelocytic leukemia (FAB M3).
• Favorable risk cytogenetics \[Core Binding Factor (CBF) AML\].
• Active central nervous system (CNS) involvement by AML.
• Signs of leukostasis requiring urgent therapy.
• 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).
• Patients willing and able to receive intensive induction chemotherapy.
• 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.
• Known active Human Immunodeficiency Virus (HIV), active hepatitis B or active hepatitis C infection.
• 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.
• 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.
• 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.
• 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:

• Written Informed Consent must be obtained from the patient prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
• Patient is ≥18 years of age at the time of obtaining informed consent.
• 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.
• 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.
• 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.
• Patients have a life expectancy of at least 3 months in the opinion of the Investigator.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
• Patient must meet the following criteria as indicated on the clinical laboratory tests:

• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN).
• 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.
• Estimated glomerular filtration rate (eGFR) of > >40 mL/min as calculated by the Modification of Diet in Renal Disease equation.
• 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 potential

BAML-16-001-S21 - Exclusion Criteria:

• Diagnosis of isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML).
• Acute promyelocytic leukemia (FAB M3).
• Active central nervous system (CNS) involvement by AML.
• Clinical signs/symptoms of leukostasis requiring urgent therapy.
• 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.
• Disseminated intravascular coagulopathy with active, unmanageable bleeding or signs of thrombosis.
• 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.
• 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.
• Female patients who are pregnant or lactating.
• Patients with QTcF > 470 msec that cannot be corrected with electrolyte replacement, hydration, or medication modifications.
• 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.
• 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.
• 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:

• ≥ 60 years at time of AML diagnosis
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
• 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.
• Adequate renal function as defined by calculated creatinine clearance > 40 mL/min per the local laboratory
• Patients must be able to understand and provide written informed consent.
• 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 potential
• No prior chemotherapy for leukemia, except hydroxyurea to control leukocytosis and ATRA for initially suspected APL, which is permitted. \[Prior therapy for myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) allowed except for hypomethylating agents\].
• 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:

• Patients able and willing to receive intensive induction chemotherapy for underlying AML.
• Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML to enter the study).
• Acute promyelocytic leukemia.
• Known active central nervous system (CNS) involvement by AML.
• Clinical signs/symptoms of leukostasis requiring urgent therapy.
• Known active Human Immunodeficiency Virus (HIV), active hepatitis B or active hepatitis C infection.
• Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis.
• 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.
• 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.
• 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.
• 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.
• 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.
• Patients who require treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 19 центров

• Mayo Clinic Arizona — Phoenix
• UCLA Ronald Reagan Medical Center — Los Angeles
• University of California, San Francisco — San Francisco
• University of Colorado — Denver
• University of Florida Health Shands Cancer Hospital — Gainesville
• Mayo Clinic Florida — Jacksonville
• Emory University — Atlanta
• University of Chicago — Chicago
• … и ещё 11 центров

Публикации

• Burd A, Levine RL, Ruppert AS, Mims AS, Borate U, Stein EM, Patel P, Baer MR, Stock W, Deininger M, Blum W, Schiller G, Olin R, Litzow M, Foran J, Lin TL, Ball B, Boyiadzis M, Traer E, Odenike O, Arellano M, Walker A, Duong VH, Kovacsovics T, Collins R, Shoben AB, Heerema NA, Foster MC, Vergilio JA, Brennan T, Vietz C, Severson E, Miller M, Rosenberg L, Marcus S, Yocum A, Chen T, Stefanos M, Druke PMID 33106665
• Borate U, Yang F, Press R, Ruppert AS, Jones D, Caruthers S, Zhao W, Vergilio JA, Pavlick DC, Juckett L, Norris B, Bucy T, Burd A, Stein EM, Patel P, Baer MR, Stock W, Schiller G, Blum W, Kovacsovics T, Litzow M, Foran J, Heerema NA, Rosenberg L, Marcus S, Yocum A, Stefanos M, Druker B, Byrd JC, Levine RL, Mims A. Samples from patients with AML show high concordance in detection of mutations by NG PMID 37459200
• Rosenberg L, Levaux H, Levine RL, Shah A, Denmark J, Hereema N, Owen M, Kalk S, Kenny N, Vinson G, Vergilio JA, Mims A, Borate U, Blum W, Stein E, Gana TJ, Stefanos M, Yocum A, Marcus S, Shoben A, Druker B, Byrd J, Burd A. Streamlined Operational Approaches and Use of e-Technologies in Clinical Trials: Beat Acute Myeloid Leukemia Master Trial. Ther Innov Regul Sci. 2021 Sep;55(5):926-935. doi: 10. PMID 33997942
• Cai SF, Huang Y, Lance JR, Mao HC, Dunbar AJ, McNulty SN, Druley T, Li Y, Baer MR, Stock W, Kovacsovics T, Blum WG, Schiller GJ, Olin RL, Foran JM, Litzow M, Lin T, Patel P, Foster MC, Boyiadzis M, Collins RH, Chervin J, Shoben A, Vergilio JA, Heerema NA, Rosenberg L, Chen TL, Yocum AO, Druggan F, Marcus S, Stefanos M, Druker BJ, Mims AS, Borate U, Burd A, Byrd JC, Levine RL, Stein EM. A study to PMID 37871309
• Duong VH, Ruppert AS, Mims AS, Borate U, Stein EM, Baer MR, Stock W, Kovacsovics T, Blum W, Arellano ML, Schiller GJ, Olin RL, Foran JM, Litzow MR, Lin TL, Patel PA, Foster MC, Redner RL, Al-Mansour Z, Cogle CR, Swords RT, Collins RH, Vergilio JA, Heerema NA, Rosenberg L, Yocum AO, Marcus S, Chen T, Druggan F, Stefanos M, Gana TJ, Shoben AB, Druker BJ, Burd A, Byrd JC, Levine RL, Boyiadzis MM. Ent PMID 37078412
• Saliba AN, Kaufmann SH, Stein EM, Patel PA, Baer MR, Stock W, Deininger M, Blum W, Schiller GJ, Olin RL, Litzow MR, Lin TL, Ball BJ, Boyiadzis MM, Traer E, Odenike O, Arellano ML, Walker A, Duong VH, Kovacsovics T, Collins RH, Shoben AB, Heerema NA, Foster MC, Peterson KL, Schneider PA, Martycz M, Gana TJ, Rosenberg L, Marcus S, Yocum AO, Chen T, Stefanos M, Mims AS, Borate U, Burd A, Druker BJ, L PMID 36315007
• Eisenmann ED, Swords R, Huang Y, Orwick S, Buelow D, Abbott N, Phelps M, Zeidner J, Foster MC, Lin TL, Baer MR, Madanat YF, Kovacsovics T, Redner R, Al-Mansour Z, Bhatnagar B, Stefanos M, Martycz M, Druggan F, Chen TL, Yocum AO, Borate U, Druker BJ, Burd A, Levine RL, Byrd JC, Baker SD, Mims AS. A Phase 1b/2 Study of TP-0903 and Decitabine Targeting Mutant TP53 and/or Complex Karyotype in Patients PMID 40557912
• Zeidner JF, Lin TL, Welkie RL, Curran E, Koenig K, Stock W, Madanat YF, Swords R, Baer MR, Blum W, Stein EM, Olin RL, Schiller G, Nichols A, Odenike O, Traer E, Lachowiez C, Duong VH, Hochman MJ, Cai SF, Smith C, Stefanos M, Martycz M, Huang Y, Rosenberg L, Marcus S, Chen TL, Yocum AO, Druker BJ, Levine RL, Borate U, Byrd JC, Mims AS. Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed NPM1 PMID 40504618

Идентификаторы

NCT: NCT03013998 · BAML-16-001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗