The PANTHER Clinical Trial: Investigating a New Option for High-risk MDS Patients in the Upfront Setting

The Managing MDS Clinical Trials Spotlight published on July 2, 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 an interim analysis of pevonedistat plus azacitidine versus single-agent azacitidine as first-line treatment for patients with high-risk MDS, CMML, or low-blast AML (PANTHER).

Can you provide some background on clinical trials exploring new therapies for MDS?

Dr. Michael R. SavonaIt’s truly an exciting time for those of us who manage MDS, as many clinical trials are currently exploring the safety and efficacy of a variety of treatments for the disease. Given all the impressive early data, it is now critical for community oncologists to follow these trials so that they are prepared to use these agents appropriately upon FDA approval. One exciting agent that has been promising in clinical trials is pevonedistat, a first-in-class inhibitor of NAE (NEDD8 activating enzyme).

Recent research has shown that combining pevonedistat and azacitidine appears to be safe and effective for older patients with AML, resulting in response rates and durable remissions beyond what is typically expected for azacitidine alone and with limited additional toxicity.1 Based on data from the success of early studies that added pevonedistat to azacitidine in AML, clinical trials have been initiated to assess this combination in patients with AML and higher-risk MDS. The PANTHER trial is an ongoing phase 3 study, sponsored by Takeda, that is evaluating the safety and efficacy of pevonedistat plus azacitidine versus azacitidine monotherapy in participants with higher-risk MDS, as well as those with CMML and low-blast AML.2

Can you describe how pevonedistat works?

Pevonedistat is an NAE inhibitor. By inhibiting NAE, pevonedistat prevents activation of Cullin-RING E3 ubiquitin ligases. This family of E3 ubiquitin ligases is hijacked in cancers, such as AML, to process many proteins that normally protect the cell from clonal growth. In the presence of pevonedistat, these proteins accumulate and are ultimately toxic to cancer cells. Specifically, pevonedistat limits degradation (eg, p27, CDT1, and Nrf-2), leading to the accumulation of Cullin-RING E3 ubiquitin ligase substrates, and causes antiproliferative effects in AML. Pevonedistat is novel in that it is the first drug that affects this specific pathway. Simply put, the drug is believed to encourage apoptosis in rogue, clonal cells.

What will be assessed in PANTHER and what patient factors will determine eligibility for participation in the trial?

The multicenter, international PANTHER trial will compare overall survival (OS), event-free survival (EFS), and response to treatment with pevonedistat and azacitidine versus azacitidine alone in patients with higher-risk MDS, CMML, and low-blast AML. The trial will enroll approximately 450 participants who will be randomly assigned to receive pevonedistat 20 mg/m2 and azacitidine 75 mg/m2 in combination or single-agent azacitidine 75 mg/m2 over a 28-day treatment cycle. All participants will receive azacitidine via intravenous (IV) or subcutaneous route. Participants in the combination treatment arm will receive pevonedistat IV infusion.

To qualify for PANTHER, MDS patients must be age 18 or older; have intermediate-, high-, or very high-risk disease; have low-blast AML (defined as 20% to 30% myeloblasts in the bone marrow) and ≤30% myeloblasts in the peripheral blood; and be considered appropriate for azacytidine-based therapy. Participants with higher-risk MDS will have EFS follow-up study visits every month if their disease has not transformed to AML and they have not started subsequent therapy. All participants with higher-risk MDS at enrollment will enter OS follow-up (contacted every 3 months) when they have confirmed transformation to AML.

Can you provide more information on the rationale for the PANTHER trial to explore pevonedistat in MDS?

The PANTHER trial is building on a phase 1b study published in the March 2018 issue of Blood.1 In this trial, we assessed the safety and tolerability of pevonedistat plus azacytidine in patients age 60 and older with treatment-naive AML. Patients received IV pevonedistat 20 or 30 mg/m2 on Days 1, 3, and 5 combined with fixed-dose azacytidine (75 mg/m2 intravenously or subcutaneously) on Days 1 through 5, Day 8, and Day 9 over a period of 28 days. The overall response rate (ORR) based on an intent-to-treat analysis was 50%, and there was an 8.3-month median duration of remission. The observed ORR was extraordinary because we rarely see such high rates of response in elderly AML patients. To put this in perspective, we can expect a complete response rate of 10% to 15% in upfront AML and an ORR of 30% to 35%—at best—with azacitidine alone. Among patients receiving 6 or more cycles of therapy, the ORR was 83%. The most common treatment-emergent adverse events (AEs) in this trial were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). It was well-tolerated at the dose of 20 mg/m2.

The study published in Blood provided other important data that led to the consideration of using pevonedistat in higher-risk MDS.1 For example, the composite complete remission (CR)/partial remission (PR) rate was 80% for patients with TP53 mutations. This is for a small sample size, yet these results were unexpected and encouraging because TP53-mutated patients typically do not fare well after treatment. In addition, 60% of patients treated with pevonedistat plus azacytidine for at least one full cycle achieved CR when they received it in the upfront setting, which is an impressive number. Considering these findings and the data emerging from the PANTHER trial, there is optimism that pevonedistat may ultimately be approved.

For oncology practitioners treating a high-risk MDS patient who may be appropriate for participation in the PANTHER trial, what is the next step?

All practitioners who see MDS patients should evaluate them for clinical trial eligibility to optimize care and help researchers determine the role of investigational therapies. We are simply not doing a good enough job enrolling patients in clinical trials. If patients appear to meet the eligibility criteria for PANTHER, community oncologists can connect with the Takeda Study Registration Call Center (contact information provided below) or discuss their candidacy with participating sites or other MDS experts. If patients meet only some of the criteria, clinicians can review the MDS Foundation website for available clinical trials to see which studies are most appropriate.3 With so many trials being conducted in MDS, it is important to be vigilant about which studies are enrolling patients.

To Learn More About the PANTHER Trial

  • To learn more about PANTHER, contact the Takeda Study Registration Call Center at 1-844-662-8532.
  • Visit, identifier: NCT03268954.


  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.
  2. 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). Identifier: NCT03268954. May 21, 2018. Accessed May 21, 2018. 
  3. MDS Foundation. Clinical Trials. Accessed May 31, 2018.
Last modified: July 27, 2018