At the ASCO Annual Meeting in June, the Conquer Cancer Foundation presented the 2014 recipients of prestigious grants and awards, including the Young Investigator Award, Career Development Award, and the Advanced Clinical Research Award in Breast Cancer. In announcing the awards, Charles W. Penley, MD, FASCO, Chair of the Conquer Cancer Foundation Board of Directors, said, “These three awards support the development of cancer doctors during different phases of their careers; from the beginning of their research endeavor and faculty appointments through advanced clinical study. The Conquer Cancer Foundation is proud to support researchers at all stages, so they can focus on learning, innovating, and—most importantly—improving the care of patients worldwide.”

Those words are especially meaningful to Matthew S. Davids, MD, MMSc, Attending Physician in the CLL Center of the Lymphoma Program in the Division of Hematologic Malignancies at Dana-Farber Cancer Institute; Instructor in Medicine at Harvard Medical School; and one of the recipients of this year’s Career Development Award (CDA). Dr. Davids received a $200,000 3-year grant, which is helping fund his early-phase clinical study of the investigational agent IPI-145, a small-molecule PI3K inhibitor, given in combination with the standard chemoimmunotherapy regimen FCR (fludarabine, cyclophosphamide, and rituximab [­Rituxan]) in previously untreated, younger patients with chronic lymphocytic leukemia (CLL).¹ Launching the study, said Dr. Davids, most likely would not have been possible without the Career Development Award grant, because it is providing him with the financial support and dedicated research time necessary to write the study protocol, accrue patients, conduct laboratory studies, analyze the data, and eventually publish the study results.

Dr. Davids also credits the support of his mentor, Jennifer R. Brown, MD, PhD, Director of the CLL Center at Dana-Farber Cancer Institute, and Associate Professor in the Department of Medicine at Harvard Medical School, with helping to make his research possible. (See “The Value of Lifelong Mentorship in Career Development: A Conversation With Jennifer R. Brown, MD, PhD,” in sidebar).

The ASCO Post talked with Dr. ­Davids about his research, the importance of mentorship in a young investigator’s career development, and the outlook for more effective therapies in the treatment of CLL.

Clinical Study Goals

Please talk about the aim of your clinical study of IPI-145 plus FCR (iFCR) in patients 65 and younger with CLL.

Unfortunately, CLL is not a curable cancer. Although we have a lot of effective therapies that can put the disease in remission temporarily, inevitably it will recur. There are many new drugs recently approved and in development for patients with CLL, which hold great promise. Most of them are oral agents that are well tolerated, and there are a few different approaches researchers are taking to explore how best to incorporate them into treating CLL.

One idea is to rationally combine the new drugs together to get away from standard chemotherapy, and we believe that will likely be the best approach for older patients who do not tolerate chemotherapy very well. Although this may not cure the disease, it is likely to keep it in remission for years. On the other hand, younger, fit patients typically tolerate chemotherapy better, so our idea for the iFCR study was to add one of the most promising new drugs to our most powerful chemoimmunotherapy regimen to see if the combination regimen will lead to cure, at least in a subset of patients with CLL.

It is an ambitious goal because there is no precedence for curing CLL with conventional therapies. On the other hand, we now have an exciting opportunity to combine promising novel agents with chemoimmunotherapy, and this was the inspiration for our study.

There are a couple of main components to the trial. One is FCR, which is the gold standard chemoimmunotherapy regimen for treating younger patients with CLL, and the other is IPI-145, an oral drug that targets the delta/gamma isoforms of PI3 kinase. Based on preliminary data from early-phase clinical trials of IPI-145 showing that the drug is well tolerated and has promising efficacy data in CLL, we are hopeful that when we combine it with FCR we are going to see deep, durable responses with good tolerability.

 One of the aspects that we think is innovative about our trial approach is that we are using a surrogate endpoint of minimal-residual disease negative complete response after 8 months of treatment to evaluate the efficacy of this combination. Minimal residual disease is a well-validated predictor of progression-free and overall survival after FCR, so it will allow us to rapidly get an efficacy readout to compare to the historical experience with FCR alone, without having to wait several years to see differences in survival rates.

We see this trial as an initial step to evaluate whether this combination is safe, determine the appropriate dosing, and, hopefully, see a strong efficacy signal. If our study results are positive, there is potential for iFCR to quickly move to a more definitive randomized phase III study.

One of the exciting things about receiving a Career Development Award from the Conquer Cancer Foundation is that it is allowing me to conduct this trial and the laboratory correlative studies, which, if successful, could represent the first steps toward a major advance for patients with CLL. This is an amazing opportunity to have so early in my career.

Award Invaluable to Research

Would your study be possible without the Career Development Award?

I don’t believe so.  It takes so much time to get a clinical trial off the ground and the award has given me the salary support for dedicated research time. The grant allowed me to finish writing the study protocol and launch the study and is now helping me manage patient accrual, oversee management of the clinical study, and supervise the laboratory correlative studies.

Please talk about the importance of a mentor in career development for a young investigator such as yourself.

Having a mentor has been a tremendous help in so many ways. Dr. Brown has given me career advice and perspective on the field of CLL and helped me to recognize what the key issues are and why trials like this one are needed. She helped connect me to the key researchers developing IPI-145, which allowed me to get access to the drug. She has also provided much appreciated advice on the nitty-gritty details to include in the protocol document and continues to advise me as medical issues arise with patients on the trial.

Launching this and other clinical trials would not have been possible without mentorship from Dr. Brown. She has been a phenomenal source of support for me.

Has your experience as a mentee encouraged you to become a mentor to young investigators coming up behind you?

Yes, it definitely has, and I am already in the early stages of doing that. I have had a couple of residents and fellows who have approached me and I am starting to work with them informally. This is a critical juncture in my career, so I still need to be mentored, but I am gaining experience, perspective, and knowledge that I can share with people coming up, too, so it is a pretty exciting time for me in that respect as well.

‘Mentorship Mosaic’

You are actively involved in the translational research program in CLL at Dana-Farber. Please talk about some of those efforts.

This ties into the second aim of my Career Development Award. I am fortunate to have a true “mentorship mosaic.” While Dr. Brown provides outstanding mentorship on the clinical end of my translational research efforts, on the laboratory side I have benefited tremendously from the mentorship of Anthony Letai, MD, PhD, Associate Professor, Department of Medicine at Harvard Medical School and Associate Professor of Medicine, Hematologic Neoplasia/Malignancies at Dana-Farber Cancer Institute, with whom I did my postdoctoral laboratory research as a fellow. Dr. Letai is a leading expert in apoptosis biology and I have maintained strong ties to his laboratory since starting on faculty in order to incorporate novel laboratory correlative studies into my clinical trials.

Dr. Letai developed an assay in his lab is called BH3 profiling, which evaluates how close malignant cells are to undergoing apoptosis with the goal of using this information to predict who will respond best to chemotherapy. In my fellowship research, I looked at baseline blood samples from a small group of patients with CLL who were starting chemotherapy regimens such as FCR and was able to distinguish responders from nonresponders.

With my Career Development Award grant, I will be thoroughly characterizing all the patients in our iFCR study using the BH3 profiling method. I will test their blood at baseline to see if I can predict who will achieve a minimal residual disease–negative complete response. I will also evaluate the BH3 profile after patients have been on IPI-145 to determine what effects the drug has on the apoptotic state of their CLL cells in vivo.

On the Horizon

What progress has been made in CLL in terms of more effective therapies and overcoming treatment resistance?

I have been inspired over the last few years by the progress that has been made in CLL, and I am very optimistic about the future. In the past year, three new drugs have been U.S. Food and Drug Administration (FDA) approved for the treatment for CLL, including obinutuzumab ­(Gazyva), ibrutinib (Imbruvica), and idelalisib (Zydelig). Hopefully, there will be additional approvals in the near future.

IPI-145 is one of these promising new therapies that has not yet been FDA approved. Another exciting new drug I have worked with substantially is the Bcl-2 inhibitor ABT-199. This drug is particularly interesting to me since it relates directly to the laboratory research on apoptosis I have done with Dr. Letai.

I think the challenge over the next few years will be how to combine these drugs rationally and devise curative strategies for CLL, perhaps initially with chemotherapy and potentially eventually without the need for chemotherapy.

For a young clinical investigator in CLL research, this is a very exciting time. I feel very fortunate to be working in this field at this time. I am constantly humbled by my experiences with CLL patients, both the ones who have done well on new agents and have had their lives transformed and those who have not survived. They all inspire me to work harder to devise safer and more effective combination therapies to eventually cure CLL. ■

Disclosure: IPI-145 is being developed by Infinity Pharmaceuticals, which is providing study drug and support for the iFCR trial. Dr. Davids reported no potential conflicts of interest.

Reference

1. A Phase Ib/II Study of IPI-145 Plus FCR in Previously Untreated, Younger Patients With CLL. ClinicalTrials.gov identifier NCT02158091.