A Look at Pevonedistat and Other Ongoing Clinical Trials in MDS

The Managing MDS Clinical Trials Spotlight published on August 13, 2018
Michael R. Savona, MD
Associate Professor of Medicine
Director, Hematology Research
Vanderbilt University School of Medicine
Nashville, Tennessee

In this installment of the Clinical Trials Spotlight, Managing MDS interviews Dr. Michael R. Savona, Director of Hematology Research and Associate Professor of Medicine at Vanderbilt University Medical Center, about ongoing clinical trials being conducted in patients with MDS.

Can you give us some background on current clinical trials investigating pevonedistat in patients with MDS?

Dr. Michael R. SavonaToday, there is a great deal of excitement surrounding the management of myelodysplastic syndromes (MDS) because many clinical trials are exploring the safety and efficacy of several different therapies, including pevonedistat. Pevonedistat is a first-in-class inhibitor of NAE (NEDD8 activating enzyme). A recent study suggested that combining pevonedistat with azacitidine appears to be a safe and effective treatment strategy for older patients with acute myeloid leukemia (AML).1 The role of combination pevonedistat/azacitidine is also being assessed in the phase 3 PANTHER trial. In this study, the safety and efficacy of pevonedistat/azacitidine is being compared with azacitidine alone in participants with higher-risk MDS as well as those with chronic myelomonocytic leukemia (CMML) and low-blast AML.2

In addition to the PANTHER study, a phase 2 clinical trial was recently launched to explore combination pevonedistat/azacitidine in patients with MDS or MDS/myeloproliferative neoplasms (MPN) who have failed primary therapy with DNA methyltransferase inhibitors (DNMTi) and who are refractory to treatment or have relapsed.3 This study’s primary objective is to compare survival rates of combination pevonedistat/azacitidine with the historical survival of patients with relapsed/refractory MDS or MDS/MPN who are ineligible for hematopoietic stem cell transplant.

Secondary objectives are to determine hematologic improvement, complete remission (CR) and marrow CR rates, and the reduction of bone marrow blasts in patients receiving treatment with pevonedistat and azacitidine after DNMTi failure. During each 28-day cycle, participants will receive azacitidine 75 mg/m2 on Days 1 through 5 and pevonedistat 20 mg/m2 on Days 1, 3, and 5. The study also has several exploratory objectives, which includes: correlating specific genetic mutations/aberrations with treatment responses, overall responses, and survival in patients treated with combination pevonedistat/azacytidine; measuring the effect of the combination treatment on quality of life; and defining epigenetic biomarkers for pevonedistat use in this patient population.

Another aim of this trial is to re-sensitize patients who are clearly not responding to azacitidine. In this study, azacitidine failure is clearly defined as receipt of 4 cycles of the drug with no improvement or 2 cycles with a clear evolution in blasts (greater than 50% growth). For example, if a patient has 5% blasts and receives azacitidine for two months but their blasts increase to 10% while receiving azacitidine, then they are deemed a candidate to be enrolled into the study. In patients who meet these criteria, azacitidine is clearly not working.

What other ongoing clinical trials in MDS should oncology practitioners be aware of and what is the purpose of these investigations?

For many years, research into new treatments for MDS was limited, but that has changed in recent years with an influx of new clinical trials. Studies are now assessing different types of therapies that may be beneficial when treating patients with MDS. One trial (NCT02966782) is currently recruiting higher-risk MDS patients who have failed previous treatment with hypomethylating agents (HMAs) and is exploring venetoclax in combination with azacitidine.3 This phase 1b open-label, multicenter study will evaluate the safety and pharmacokinetics of venetoclax as a single-agent and in combination with azacitidine. The rationale for testing venetoclax in MDS is based on its success in clinical trials for AML. To be included in this trial, patients must have failed prior therapy with HMAs as first-line MDS treatment. Other inclusion criteria include a presence of ≥5% and <0% bone marrow blasts per bone marrow biopsy/aspirate at screening; an ECOG performance score of ≤2; and adequate hematologic, renal, and hepatic function. There are many good reasons for optimism with venetoclax in combination with azacitidine in higher-risk MDS, but its efficacy in lower- and intermediate-risk MDS has yet to be determined.

Several immunotherapies are also being examined in clinical trials as potential treatment options in MDS, including dual-affinity re-targeting (DART®) agents and bi-specific T cell engager (BiTE®) therapies. DARTs are bispecific, antibody-based molecules that can bind two distinct cell-surface molecules simultaneously.4 One experimental DART therapy is MGD006 (generic name: flotetuzumab). The drug recognizes both CD3, a molecule produced in T cells, and CD123, a protein that is overproduced by certain types of cancer cells, including those in AML and MDS. In this way, MGD006 redirects T cells to recognize and kill CD123-producing cancer cells. A phase 1 study is currently underway to assess the maximum tolerated dose level of MGD006 in patients with AML and MDS whose disease is not expected to benefit from cytotoxic chemotherapy. Studies will also be performed to see how this DART therapy acts in the body via pharmacokinetic and pharmacodynamic analyses and to evaluate its potential anti-tumor activity.5

BiTEs are recombinant proteins consisting of two separate antibodies held together by a flexible peptide linker or bands of amino acids. The antibodies are designed to function as a link between T cells and cancer cells. One antibody or protein domain binds to the surface of cancer cells while the other binds to CD3 on T cells, resulting in death of malignant cells. BiTE antibody constructs are being engineered to target a range of tumors and have demonstrated impressive clinical activity in relapsed non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL). Investigators are just now beginning to explore the efficacy and safety of BiTEs in MDS. The hope is that ongoing clinical trials will provide more insights and a better understanding of the role of DARTs, BiTEs, and other bispecific antibodies as potential treatments for MDS.6

When should community oncologists consider referring MDS patients to a clinical trial, and what eligibility factors should be considered?

Considering the large number of clinical trials assessing a variety of agents in MDS, it’s important for physicians to follow results from these investigations. We also need to be vigilant in assessing patient candidacy for investigational treatments. When hematologists/oncologists stay abreast of the ongoing trials in MDS, they can proactively refer patients to trials for which they are most appropriate, based on their responses to previous therapy.

If MDS patients have received azacitidine but have not benefited from it, they should be referred to a specialist to see if they can or should enroll in a clinical trial. Fortunately, several trials are being conducted at multiple centers, meaning there is increased accessibility. For example, the trial assessing combination pevonedistat/azacitidine in relapsed/refractory MDS is offered at several US sites, including the University of Kansas, University of Rochester, Memorial Sloan Kettering, University of Miami, and Vanderbilt University Medical Center.

To Learn More About the Pevonedistat/Azacitidine Trial in MDS

  • For more information on the trial assessing combination pevonedistat and azacitidine in patients with MDS or MDS/MPN, contact Vanderbilt-Ingram Cancer Center by phone at 1-800-811-8480 or email at This email address is being protected from spambots. You need JavaScript enabled to view it..
  • Visit www.clinicaltrials.gov, identifier: NCT03238248.


  1. Swords RT, Coutre S, Maris MB, et al. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018;131(13):1415-1424. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909884/
  2. ClinicalTrials.gov. Pevonedistat plus azacitidine versus single-agent azacitidine as first-line treatment for participants with higher-risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (AML) (PANTHER). ClinicalTrials.gov Identifier: NCT03268954. May 21, 2018. https://clinicaltrials.gov/ct2/show/NCT03268954. Accessed May 21, 2018.
  3. ClinicalTrials.gov. A phase II trial of pevonedistat and azacitidine in MDS or MDS/MPN patients who fail primary therapy with DNA methyl transferase inhibitors. NCT Identifier: NCT03238248. May 1, 2018. https://clinicaltrials.gov/ct2/show/NCT03238248. Accessed May 22, 2018.
  4. Moore PA, Zhang W, Rainey GJ, et al. Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma. Blood. 2011;117:4542-4551. http://www.bloodjournal.org/content/117/17/4542
  5. ClinicalTrials.gov. A phase 1, first in human, dose escalation study of MGD006, a CD123 x CD3 dual affinity re-targeting (DART®) bi-specific antibody based molecule, in patients with relapsed or refractory AML or intermediate-2/high risk MDS. NCT Identifier: NCT02152956. September 13, 2017. https://clinicaltrials.gov/ct2/show/NCT02152956. Accessed May 22, 2018. 
  6. Marin-Acevedo JA, Soyano AE, Dholaria B, Knutson KL, Lou Y. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol. 2018;11:8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767051/
Last modified: August 2, 2018

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