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ASH 2019: Dr. Pagel Discusses Intermittent Dosing of the PI3K Inhibitor ME401 in Chronic Lymphocytic Leukemia (CLL)

This content was current as of the date it was released. In science and medicine, information is constantly changing and may become out-of-date as new data emerge.

In this video, Dr. John Pagel, M.D., PhD, the Chief of Hematology at Swedish Cancer Center, in Seattle, Washington, is interviewed by CLL Society co-founder and Chief Medical Officer, Dr. Brian Koffman, M.D., a retired family physician and a CLL patient.  This video was recorded at the 61st Annual Meeting of the American Society of Hematology in 2019, in Orlando, Florida. Dr. Pagel serves on the CLL Society Medical Advisory Board and is a member of its Board of Directors.

Dr. Pagel discusses some interesting findings from a clinical trial that he is conducting entitled: A Study of ME-401 in Subjects With CLL/SLL, FL, and B-cell Non-Hodgkin’s Lymphoma. ME401 is a drug developed by MEI Pharma, a San Diego, CA based pharmaceutical company, focused on the development of oncology products.

The B-cell Receptor (BCR) signaling kinases or enzymes, play an important role as targets in the management of chronic lymphocytic leukemia (CLL) in patients today. These kinases become targets for the development of drugs to control B-cell malignancies including CLL. One of these kinases is Phosphoinositide 3-kinases (PI3Ks). They are part of a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking, which in turn are involved in cancer. By inhibiting these pathways, PI3K inhibitors can cause cell death, inhibit the proliferation of malignant cells, and interfere with several signaling pathways in CLL and other B-cell malignancies.

There are currently two PI3K inhibitor products available commercially. idelalisib (Zydelig®), which is marketed by, California-based Gilead Sciences and Duvelisib (Copiktra®), which is marketed by Verastem Oncology from Massachusetts. While these drugs are extremely effective in controlling CLL, their use has been largely limited because they are hard to tolerate.  They cause immune system dysregulation which results in diarrhea, rash and in the case of idelalisib, liver inflammation. While these adverse effects are usually reversible, they are bothersome to patients. More serious problems include colitis and lung inflammation that can present themselves  several weeks after starting the drugs.

Takeaways:

  • ME401, like the commercially available PI3K agents, is very active in relapsed/refractory CLL patients.
  • When this triple-armed open-label trial began (everyone knows who is getting what treatment), they initially orally dosed ME401 daily. Toxicities of diarrhea, rash, and liver inflammation were noted at levels similar with other PI3K drugs. Because toxicities generally occur later in treatment, a modification was made to the protocol, in which patients took their assigned dose daily for the first two twenty-eight (28) day cycles. Beginning with cycle three, patients received ME401 on days 1-7 and then were off the drug for three weeks.
  • What was found in this small group (approximately 35), was that this new dosing regimen resulted in early control of the disease with significantly reduced adverse reactions.
  • Two patients within the intermittent group relapsed and were put back on daily dosing resulting in them “re-responding” to ME401.
  • Approximately two-thirds of the intermittently dosed patients have now been followed for 18 months with the remaining third having been observed for 12-months. These patient’s CLL remain under control.

Conclusions:

As with other advances in CLL treatment, the growing number of targeted agents allows more options for physicians and patients to receive individualized care.  A major advantage of this intermittent dosing is that it reduces the known toxicities associated with PI3K inhibitors.

Dr. Pagel believes that this trial shows that in addition to assessing the safety, efficacy, and tolerability of cancer drugs, there needs to be innovative thinking and trials to address such considerations as to where drugs fit in sequencing, dosing schedules, which include, time of day or intermittent dosing to reduce side effects.

At this point, it is not known whether a similar intermittent dosing schedule for idelalisib or duvelisib may give similar benefits. Clinical trials would need to occur to assess this as a dosing option with these agents.

Dr. Pagel believes that the ideal treatment for each patient is one that is both easy and well tolerated.

This innovative dosing may allow us to maximize the benefits and minimize the risks of this potent, but at times, difficult to manage class of medications.

For more information about this clinical trial which is currently recruiting go to: https://clinicaltrials.gov/ct2/show/NCT02914938.

To learn more about clinical trials, in general, go to https://cllsociety.org/clinical-trials:

Thanks for reading this summary and viewing this interview.

Stay strong, we are all in this together!

Thomas. E. Henry III, MBA, RPh, CPh


Thomas Henry is a Registered Pharmacist and CLL Patient. He is President and Senior Consultant for Burlington Consulting Associates, a company that provides consulting services to health systems nationwide. Tom is a CLL Society Medical Advisory Board member and strives to educate other CLL patients through his blog https//www.cllpharmacist.com. He has a forty-two-year career in pharmacy and has served as Chief Pharmacy Officer at two Top-15 Comprehensive Cancer Centers, Moffitt (Tampa, FL) and Roswell Park (Buffalo, NY).