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AML World Awareness Day 2020 | Clinical trials involving novel agents in AML

Apr 20, 2020

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On April 21, 2020, communities will unite on Acute Myeloid Leukemia (AML) World Awareness Day (WAD) to raise awareness of AML. Both scientific and patient communities will achieve this collective goal by sharing knowledge and advances in the prevention, management, and treatment of AML, worldwide. The AML Hub is proud to support AML WAD and has written a series of articles on key themes in AML to be shared in the lead-up to April 21. This article discusses clinical trials involving novel agents in AML.1


An increased understanding of the epigenome has allowed the identification and development of new targeted agents that transcend the conventional 7 + 3 induction chemotherapy regimen. These agents target a range of cellular processes, including signaling pathways, epigenetic regulation of DNA and chromatin, nuclear export of proteins, and antigens that are expressed on leukemia cells via antibody-based therapies. Many clinical trials involving these new, targeted agents are underway.

Novel targeted agents

Vascular disrupting agents

A phase I/II trial, NCT02576301, is investigating the use of OXi4503, a vascular disrupting agent, in patients with relapsed/refractory (R/R) AML. The study will investigate OXi4503 monotherapy as well as in combination with intermediate-dose cytarabine. OXi4503 has been granted fast track designation by the United States Food & Drug Administration (FDA).

BCL-2 inhibitors

Venetoclax is a BCL-2 inhibitor that is being studied extensively in hematological malignancies. One study, NCT03236857, is investigating venetoclax monotherapy in pediatric and young adult patients with R/R AML — an area of unmet medical need.

Watch Gert Ossenkoppele discuss venetoclax in AML below.

Venetoclax in AML

Selective inhibitors of nuclear export (SINE)

The SAIL study (NCT02249091) is evaluating cytarabine and idarubicin in combination with selinexor, a SINE, in patients with R/R AML. Read the results of the phase II study here.

Cyclin dependent kinase (CDK) 9 inhibitors

Alvocidib is a CDK9 inhibitor being investigated in a biomarker-driven phase II study (NCT02520011) in patients with R/R AML with MCL-1 dependence of > 40%. In this study, the combination of alvocidib, cytarabine, and mitoxantrone is being compared to cytarabine and mitoxantrone alone. Watch Joshua Zeidner discuss this trial below.

Biomarker-guided phase II study in MCL-1 dependent R/R AML patients

Cereblon E3 ligase modulators

CC-90009 is a cereblon E3 ligase modulator being investigated as monotherapy in patients with R/R AML (NCT02848001).

Watch Jordi Esteve discuss the phase I results below.

Results of single agent CC-90009 in R/R AML

AKT inhibitors

Triciribine (PTX-200) is an AKT inhibitor that is being tested in patients with R/R AML in combination with cytarabine. The FDA granted PTX-200 orphan drug designation in 2017. Learn more here.

TRAIL-receptor agonists

ABBV-621 is a first-in-class, second-generation TRAIL-receptor agonist that is enrolling patients with R/R AML in the dose optimization cohort. This cohort will investigate ABBV-621 as monotherapy and in combination with venetoclax (NCT03082209).

Fms-like tyrosine kinase 3 (FLT3) inhibitors

The phase III ADMIRAL study is comparing gilteritinib (ASP2215) to salvage chemotherapy in patients with R/R AML with FLT3 mutations — read the full results here. A phase I/IIa study, NCT03194685, is investigating FF-10101-01, another FLT3 inhibitor, in patients with R/R AML. Meanwhile, the QUANTUM-R study (NCT02039736) is comparing quizartinib monotherapy to salvage chemotherapy in patients with FLT3 internal tandem duplication mutated AML.

Isocitrate dehydrogenase (IDH) 1 and IDH2 inhibitors

Ivosidenib (AG-120) is an IDH1 inhibitor, approved by the FDA as monotherapy for patients with R/R AML with IDH1 mutations. Results in patients with newly diagnosed (ND) AML are available here and results in patients with R/R disease are available here. Enasidenib is also being extensively studied in patients with IDH2 mutations.

Proviral integration site of Moloney murine leukemia virus (PIM) kinase inhibitors

PIM inhibitors, such as INCB053914, are being investigated as treatments for patients with advanced malignancies like AML. One trial (NCT02587598) is investigating INCB053914 as monotherapy and in combination with standard of care (SOC) regimens: Parts 1 and 2 (monotherapy) are enrolling patients with AML that is unresponsive to current options with no SOC or curative treatment, while Parts 3 and 4 (combination cohorts) are enrolling patients with R/R AML or patients with ND AML who are aged 65 or older or who are unfit for intensive chemotherapy.

Nucleophosphomin (NPM1)-mutated AML

The AMLSG 09-09 study (NCT00893399) is investigating chemotherapy with all-trans retinoic acid with or without gemtuzumab ozogamicin in patients with NPM1-mutated AML.

EZH1 and EZH2 inhibitors

Valemetostat (DS-3201b) is an EZH1 and EZH2 inhibitor being investigated in a phase I trial (NCT03110354) in patients who have failed induction therapy or relapsed following prior therapy.

Poly ADP ribose polymerase (PARP) inhibitors

An example of a PARP inhibitor is talazoparib, which is being investigated in combination with decitabine in patients with both ND and R/R AML (NCT02878785).

TET-2 mutated AML

The combination of azacitidine (a hypomethylating agent [HMA]) with ascorbic acid (vitamin C) is being investigated in patients with TET2-mutated ND or R/R AML (NCT03397173). Results from a similar study investigating the potential synergistic effects of ascorbic acid with decitabine (another HMA) are available here.

Curaxin-targeting agents

CBL0137 is a FACT complex-targeting curaxin under investigation as monotherapy (NCT02931110). Patients with AML are being enrolled in the expansion cohort if they have > 5% blasts in the bone marrow and > 1 × 109/L blasts in peripheral blood.


Included within the category of new agents are immunotherapies, which utilize aspects of the body’s own immune system to recognize and attack leukemic cells.

Monoclonal antibodies (mAbs)

Hu5F9-G4 is an anti-CD47 mAb being investigated as monotherapy and in combination with azacitidine in patients with R/R AML (NCT03248479). Watch David Sallman discuss whether HU5F9-G4 is a promising treatment strategy in AML below.

Could the first-in-class anti-CD47 antibody HU5F9-G4 be a promising treatment strategy?

Pembrolizumab, an anti-PD-1 mAb, is also being tested in patients with R/R AML following allogeneic hematopoietic stem cell transplant (allo-HSCT; NCT03286114).

mAbs are also being investigated with other targeted agents: for example, spartalizumab (PDF001), an anti-PD-1 mAb, is being investigated in combination with MGB453, a TIM-3 inhibitor, with or without decitabine in 5 study arms. Arms 1–3 are enrolling patients with R/R AML or de novo AML suitable for treatment with decitabine, whilst arms 4 and 5 are enrolling patients with R/R AML following one or more prior therapy (NCT03066648).

  • Arm 1: decitabine + PDR001
  • Arm 2: decitabine + MBG453
  • Arm 3: decitabine + PDR001 + MGB453
  • Arm 4: MGB453
  • Arm 5: PDR001 + MBG453

Bispecific antibodies (bsAbs)

XmAb14045 is a bsAb, targeting CD123 and CD3, being investigated in patients with R/R or secondary AML (NCT02730312). AMV564 is another bsAb, targeting CD33 and CD3, being tested in the AMV564-101 trial in patients with R/R AML; updated results from the phase I trial (NCT03144245) were recently reported. Read more about other chemotherapy-free treatments for R/R AML here and more about bsAbs here.

Bispecific T-cell engagers (BiTE®)

AMG 330 is a BiTE®, targeting CD33 and CD3, under investigation in a phase I study as monotherapy, administered by continuous intravenous infusion in patients with R/R AML (NCT02520427). Read the results from the phase I study here.

Antibody–drug conjugates

Iomab-B, a radio-immunoconjugate of a murine anti-CD45 mAb, is being investigated in the SIERRA study in combination with reduced-intensity conditioning prior to allo-HSCT in patients with active or R/R AML (NCT02665065). The European Medicines Agency previously provided positive scientific advice for a trial of iomab-B in R/R AML.

Another antibody–drug conjugate is IMGN632, which targets CD123. It is under investigation in patients with R/R AML (NCT03386513). Read more from the phase I dose-escalation study here. Watch Eunice Wang discuss IMGN632 below.

Why could IMGN632 be an important treatment option for AML?

Recombinant viruses

VSV-hIFNbeta-NIS is a recombinant virus being used in a clinical trial of patients with R/R AML with or without ruxolitinib phosphate (NCT03017820).

Donor-derived multiple tumor-associated antigen (TAA)-specific T cells

Another approach under investigation is the use of donor-derived multiple-TAA specific T cells, which are T cells that have been ‘trained’ to recognize tumor proteins like WT1, NY-ESO-1, PRAME, and Survivin. Five dose levels of the experimental product are being investigated in AML (NCT02494167), with Group A receiving the therapy as adjuvant therapy post-HSCT and Group B receiving the therapy for R/R disease post-HSCT.

Chimeric antigen receptor (CAR) T-cell therapy

Whilst CAR T-cell therapy has proven successful in treating aggressive lymphomas, with promising activity in multiple myeloma, its role in AML is less clear. Learn more about CAR T-cell therapy in AML here. Watch Arnon Nagler discuss whether CAR T-cell treatment is advanced enough to be used in AML below.

Is CAR T-cell therapy advanced enough to be used for the treatment of AML?

The challenges of using CAR-T in AML are also summarized by Mohamad Mohty below.

What are the main challenges of CAR T in AML compared to lymphoma and multiple myeloma?

Clinical trials determining how to decide the optimal treatment strategy 

Some clinical trials in AML are also trying to elucidate how to identify the best treatment for a patient, for example by precision medicine. The BEAT AML master trial is an umbrella study of 11 substudies, covering the most prominent subtypes of AML. The study aims to assess whether molecular, immunophenotypic, and/or biochemical studies can profile patients within seven calendar days and assign them to molecularly-defined, subtype-specific therapy based on the results. Read more about this study here.

Another study, NCT02551718, is underway to determine whether choosing treatment based on high throughput ex vivo drug sensitivity assay and mutational analysis is feasible in patients with R/R AML. The AML1310 study (NCT01452646) is using risk-adapted, minimal residual disease-directed therapy in young adults with ND AML.


There are many trials underway in the field of AML, which are only possible based on the determination of researchers worldwide who are working extensively to identify optimal therapeutic strategies for individual patients, as well as develop novel agents. The new era of personalized medicine will likely lead to individualized treatments based on patient characteristics and specific disease, which is only possible due to the continued enrollment of patients in investigatory clinical trials.

Expert Opinion

Clinical trials are an essential part of the development of new interventions and tests in AML that can help our patients and may alleviate the symptoms of their disease or condition. One of the principal challenges of recruiting clinical trial participants is a lack of awareness, both amongst healthcare professionals and participants, about clinical trials, their availability, and how to participate. As with all aspects of healthcare, AML patients look to members of the healthcare profession for trusted medical advice and guidance. Thus, healthcare providers, including general practitioners, specialists, other health professionals and nurses, play an important role in raising awareness about clinical trials in AML. In many cases, being part of a clinical trial helps patients play an active role in their healthcare and learn more about treating and managing their condition. They will work with doctors and researchers who are experts in their disease or condition. There is also evidence that patients taking part in clinical trials do better than others with the same disease or condition.

  1. National Cancer Institute. Treatment Clinical Trials for Adult Acute Myeloid Leukemia. Accessed Apr 9, 2020.


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