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Friday, November 06, 2015

With MALCOLM A. SMITH, MD, PHD, NCI’s Pediatric Preclinical Testing Consortium Program Director



Earlier this year the National Cancer Institute launched the Pediatric Preclinical Testing Consortium (PPTC)—a program to develop high quality preclinical data to help identify which novel agents will be most effective in treating pediatric cancers.


In some ways it continues the work of the NCI’s previous Pediatric Preclinical Testing Program—a collaboration with more than 50 pharmaceutical companies to test novel agents, said the Consortium’s Program Director, Malcolm A. Smith, MD, PhD. But, he added: “The new effort focuses on a systemic approach to in vivo testing using large panels of genomically characterized models.”


The new PPTC includes the PPTC Coordinating Center at Research Triangle Institute (RTI) International and five research programs responsible for the evaluation of agents against pediatric cancer preclinical models, which are funded through NCI cooperative agreement research grants. The five research programs were chosen based on their preclinical testing capabilities and experience using genomically characterized models in cancer drug evaluation, Smith said.


In a phone interview, Smith explained some of the challenges of developing pediatric cancer drugs and why the Consortium offers a better pipeline.


1. What makes childhood cancer drugs so difficult to develop in the first place?

“One key challenge is the distinctive biology of many childhood cancers compared to adult cancers, meaning that research findings for many adult cancers may have limited relevance to childhood cancers.  Another major challenge is the relatively small number of children with cancer, which means that compared to adult cancers only a limited number of clinical trials can be conducted to identify more effective treatments.


2. How does the new Consortium improve the work of the previous NCI program for pediatric cancer research?

“[The new program] focuses on a systematic approach to in vivo preclinical testing using relatively large panels of genomically characterized models. There are preclinical testing activities—certainly outstanding preclinical testing activities—across the country and the world. But, they more typically focus on in vitro testing, which is less expensive and on a smaller scale than in vivo testing.


“Our program, by focusing on a larger more systematic approach to in vivo testing, is distinctive. It is relatively resource intensive—so it’s not the kind of thing that most companies or most academic centers would really be able to do.


“A key point about the PPTC, in the era of precision medicine, is being able to take a range of genomically characterized models and do high-quality in vivo testing to look for whether there’s likely utility from using the agents—to learn how to better apply precision medicine principles for childhood cancer clinical trials.”


3. What makes in vivo testing better than in vitro testing in this pediatric cancer drug research setting—and how will improving it improve pediatric cancer drug development?

“In vitro testing certainly provides important insights about any cancer agents, but they provide very little limited information about whether an agent is going to have a therapeutic window when it is transferred into the clinic. Most chemicals will kill at high enough concentrations—even something like Clorox—within plastic plates.


“In vivo testing provides a better assessment for a therapeutic window—and especially when we’re able to compare the relative tolerability of agents in mice and humans in terms of the drug levels that the mice tolerate compared to the drug levels that humans tolerate. And instead of perhaps using only one or two models of a particular cancer type, with in vivo testing we would typically use six or more models of that type of cancer to try to better interrogate the heterogeneity that exists in the clinic. We get a better idea of the likelihood for activity through testing a larger spectrum of models of each disease.


“A key contribution of the Consortium will be developing data to use in prioritizing agents for clinical evaluation against specific childhood cancers. Unlike the situation for more common adult cancers in which many clinical trials evaluating experimental agents can be conducted in the hopes of finding an active agent, for any given childhood cancer a much smaller number of clinical trials of novel agents can be performed. Hence, the data from the Consortium is important for more rationally selecting agents [that can be tested in a] clinical study—and for increasing the likelihood that truly active agents will be moved forward.


“If we bring ineffective agents into clinical testing for children, then our clinical trials are destined for failure. If we bring truly effective agents into testing, then we have a much better chance of success in the clinical trials that we conduct.”


The PPTC’s Five Research Programs

The five programs within the new PPTC are:

  • The Sarcoma and Renal Tumor Research Program at the Greehey Children’s Cancer Research Institute at University of Texas Health Science Center in San Antonio;
  • The Neuroblastoma Research Program at The Children’s Hospital of Philadelphia;
  • The Osteosarcoma Research Program at The Children’s Hospital at Montefiore;
  • The Leukemia Research Program at Children’s Cancer Institute (Sydney, Australia); and
  • The Brain Tumor Research Program at Baylor College of Medicine.

Tuesday, October 20, 2015

SAN ANTONIO—“In general, this type of response is unheard of in this patient population,” Arul M. Chinnaiyan, MD, PhD, Director of the Michigan Center for Translational Pathology at University of Michigan and a Howard Hughes Medical Institute Investigator, said during a keynote lecture here at the American Society for Radiation Oncology sharing some of the first analyses from the Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team work. The study includes 500 men with metastatic castration-resistant prostate cancer from eight different clinical sites, whose tumors have undergone DNA and RNA sequencing.


The “unheard of response” was that of a man on the study who was found to have homozygous deletion in BRCA2 and amplification of androgen receptor, who was treated with a PARP inhibitor (to target the BRCA aberration) and abiraterone (to target the androgen receptor amplification), Chinnaiyan explained during the talk. The patient has had massive tumor regression with PSA levels now essentially undetectable (from 127 at time of treatment)—and has had a durable response now for two years since starting this combination of treatment, he said.


It bears repeating Chinnaiyan’s remark: “This type of response is unheard of in this patient population.”


Though findings like these are promising, there is still a lot of work to do before they become “heard of” on a greater scale for these patients. The information Chinnaiyan shared during the talk was based on analyses of the first 100 men in this study, he said.


In a follow up email interview, Chinnaiyan answered these questions about the goals of the research and when it could be scalable for patients beyond this study.


1. Could you explain what the study is and its goals?

“The study uses whole exome and transcriptome sequencing for metastatic prostate cancers. The goal of the research is to determine the mutational landscape of castration resistant prostate cancer and identify clinically actionable subsets of patients.


“We have been able to show that we can carry out comprehensive clinical sequencing in a multi-institutional fashion in real-time.”


2. What would you say are some of the key and significant findings about the genomic landscape of these patients that you’ve found so far in the work? And what do the findings mean for radiation oncologists—your audience for this talk here at ASTRO?

“The most clinically relevant results were the somatic and germline aberrations in the DNA repair genes BRCA2, BRCA1, and ATM found in 23 percent of patients. This [finding] suggests that this subset of metastatic prostate cancer patients may benefit from PARP inhibitors or platinum therapy.


“It will be important to understand the mutational and gene expression blueprint of cancer in order to potentially predict higher sensitivity to radiotherapy. Also when combining other therapies with radiation, it will important to consider this with the molecular profile in mind.”


3. You touched on this briefly during the talk—is this type of sequencing feasible on a bigger scale across multiple types of cancer centers?

“It would still be challenging to scale the approaches I presented across cancer centers, but I do believe that intermediate sized panels targeting DNA and RNA may be possible.


“Challenges that remain will be reimbursement for the sequencing assays, as well as the targeted agents that they may suggest. We also need to develop more drugs against cancer targets that have been traditionally considered undruggable.” 

Sunday, September 27, 2015


With SUPARNA B. WEDAM, MD, Medical Officer at the FDA



SAN FRANCISCO—“We’ve seen kind of an explosion of requests—and I don’t think anybody really expected that,” Suparna B. Wedam, MD, Medical Officer at the U.S. Food and Drug Administration, said about the FDA’s four expedited programs, which she discussed here at the 2015 Breast Cancer Symposium in her talk “FDA Drug Approvals: Getting Drugs to Patients Sooner.” Those four programs include three designations (breakthrough therapy, priority review, and fast track designations) and one approval pathway (accelerated approval).


In an interview after the talk, she summed up these key points and elaborated on what these approval programs mean for the future of oncology drugs.


1. You spent a lot of time during the talk on breakthrough therapy designation, which is the newest program of the four—what should oncologists know about the designation?

“With breakthrough therapy designation, you have to have clinical evidence that this [drug] is substantially better than a significant endpoint, and for fast track designation, non-clinical data can be used. Having said that, we do not accept non-clinical data usually for oncology—typically we require at least some clinical data. Especially in oncology, we feel that [non-clinical] data that comes from cell lines or animals does not always translate well into humans.


“And the other part is the level of senior level involvement. Once a drug has the breakthrough therapy designation, it really is an all-hands-on-board situation from the top down, where the senior manager is helping with the whole process—so, it’s the intensity of involvement that differentiates it.”


2. You mentioned a New York Times article in your talk with the headline “Speedy Drug Approvals Have Become the Rule, Not the Exception”—is that true for oncology drugs? Should these programs be the norm for oncology drugs?

“I think it is true. All of the molecular entities in the last two years that we’ve approved in hematology and oncology, every one of those drugs had taken advantage of at least one of the programs. And many have taken advantage of more than one of those four programs.


“Everything we deal with in oncology is a serious disease [so all of the drugs fit that requirement]. But still, we are approving drugs when we think they’re safe—when we feel the benefit justifies the risk.


3. What are the risks of using these programs?

“There’s caution that needs to be said. We don’t have the same number of patients treated, and we don’t always know that the complete picture that’s not known when we approve a drug. There’s a lot more that we learn post-marketing. And in some of the accelerated approvals we have even a smaller safety base. We need to be very vigilant and follow those safety signals after [the approval] to make sure that this is indeed a safe drug and if there are any safety signals, we need to deal with those.


“And we need to be engaging patients in this process to make sure they understand when a drug was approved through an expedited program. It’s important to explain that the drug was approved in this way and the safety data might not be as complete—and then it’s up to the patient and the physician to make that decision. We [FDA] always feel that it is safe enough to approve the drug—and that’s why it’s out there—but that discussion still needs to happen in the office between the patient and the physician.”

Saturday, September 26, 2015

With experts at the 2015 Breast Cancer Symposium



SAN FRANCISCO—Four oncology thought leaders spoke about ongoing clinical trials in breast cancer and the new directions research needs to go in a session here at the 2015 Breast Cancer Symposium. The trials were too numerous to discuss them all—in the session today or in a single news article—as there are more than 2,400 trials in metastatic breast cancer alone, 131 of which are active, according to, which was noted by speaker Lori J. Goldstein, MD, FASCO, Professor and Director of the Breast Evaluation Center at Fox Chase Cancer Center. Goldstein, who covered clinical trials in systemic therapy for metastatic disease, summed up some of the most notable research in her allotted 18 minutes.


Most exciting though, according to the session’s co-chair Norman Wolmark, MD, Chair of the National Surgical Adjuvant Breast and Bowel Project and Chairman of the Department of Human Oncology at Allegheny General Hospital Cancer Center in Pittsburgh, Pennsylvania, about the current and potentially upcoming clinical trials was the new direction of research, he said in an interview after the session. “We’re seeing a transformation in the way we are perceiving the biology of the disease.


“The clinical trials where we randomized 5,000 patients to answer one question—I think are going to become extinct. We’re seeing targeted therapies with some very exciting results. The results of PALOMA3 for example, with palbociclib; and now putting palbociclib, a CDK 4/6 inhibitor, into the neoadjuvant setting and the adjuvant setting—clearly an example of how things have changed dramatically based on the understanding of the biology of the disease. By the same token, I think we’re seeing the basket trials evolving where we’re targeting a mutation, for example, that might have a 3 percent prevalence.


“Things are moving very rapidly and we’re moving very quickly and we don’t know we’re going to end up, which has always been the challenge, as well as provided the stimulus to move the state of the art forward.”


Basket trials, checkpoint inhibitors, and immunotherapies all come with a lot of questions, Wolmark continued. “And we just don’t know. We really don’t know how to use them properly—in combinations? Sequentially? It’s going to take time, but certainly the environment is a very exciting one.”


The 15 (or so) minutes at the session’s end left for audience questions (asked by the session co-chairs) brought up a few of those unknowns. Here’s what the speakers said.


The session was co-chaired by Wolmark and Kelly Hunt, MD, FACS, Professor in the Department of Surgical Oncology in the Division of Surgery at the University of Texas MD Anderson Cancer Center. The speakers were: Carol Lee, MD, a radiologist specializing in breast cancer at Memorial Sloan Kettering Cancer Center, who spoke about trials in breast imaging; Judy Caroline Boughey, MD, Professor of Surgery at Mayo Clinic, who spoke about trials in locoregional therapy; Debu Tripathy, MD, Professor and Chairman in the Department of Breast Medical Oncology in the Division of Cancer Medicine at MD Anderson, who spoke about trials in systemic therapy for early-stage disease; and Goldstein.


1. WOLMARK asks GOLDSTEIN: “In terms of basket trials—clearly that’s the next horizon and the next challenge—what’s the appropriate control? We saw an example from the Lung-MAP, which took a long time to get started, but now nivolumab’s approved. How does one deal with these challenges?”

“These basket trials are living programs. They have to evolve as the data evolves. They rewrote the [Lung-MAP] study—they changed the study to change the control arm based on the nivolumab data; so we will need to do the same thing.


“One schema I showed was [the investigational] agent plus chemotherapy with chemotherapy as the control. That’s the standard now, but it may not be the standard by the time we open the trial. It may be an Hsp inhibitor; it may be an immunotherapy as a control—depending on where we are at the time of the trial.”


2. WOLMARK asks LEE: “This question was asked—and I shudder to ask because of our commitment to clinical trials—in your heart of hearts, what do you believe the best screening modality to be for women with dense breasts?”



“And perhaps for women in general?”

“Mammography. I say that with no hesitation at all. It’s not perfect, but as I said earlier, it’s the only imaging tool that’s been proven to decrease mortality from breast cancer. So, what we’re doing now in trying to refine and improve on our ability to pick up early breast cancer—that’s all well and good, but we have a tool that’s been proven, and it’s underutilized.”


3. HUNT asks TRIPATHY: “Is triple negative disease really breast cancer?”

“That’s actually a very good question. Yes—triple negative disease is breast cancer, but it has a lot more genetically in common with high-grade serous ovarian cancer, but it is an adenocarcinoma. It expresses cytokines. And as best we know, our paradigms for treatment are similar, with the exception that chemotherapy probably does offer a benefit.


“But we do need to think of these as biologically distinct. So, as an example, the platinum trial that is ongoing is going to see if there is a subset of these patients that may behave differently.


“So, I think the final word on that is still out. There’s basal type; there’s DNA repair deficient; there’s luminal androgen receptor—so it’s really a heterogeneous group of diseases.”

Friday, September 18, 2015

With Jon Retzlaff, MBA, MPA, of AACR’s Office of Science Policy and Government Affairs



Why did 300 doctors, researchers, caregivers, patients, and patient advocates flood Capitol Hill Thursday? Their trek to Washington—for the third annual Rally for Medical Research Hill Day—was to remind Congress that medical research funding needs to be a national priority when it comes to the 2016 federal budget.


“At NIH and NCI, we’ve seen a 25 percent reduction in funding over the past decade (taking inflation into account),” explained Jon Retzlaff, MBA, MPA, Managing Director of the Office of Science Policy and Government Affairs at the American Association for Cancer Research, who was in Washington Thursday. “You’re talking about going from one in three grants that were being funded back in 2003 to about one in six today. That’s leaving a lot of great ideas on the cutting room floor.


“The goal of our effort is to inspire the support of Congress to provide the National Institutes of Health with robust, sustained, predictable budget increases for the 2016 fiscal year.”


AACR was the founding organizer of the first rally that took place in 2013, which included 10,000 people representing 205 organizations (OT 5/25/13)—and AACR has continued to play a key role in organizing the event. In between Thursday’s events on Capitol Hill, Retzlaff answered these questions in a phone interview about how the situation has changed since the first rally—and what still needs to change.


1. What has changed since this effort began in 2013—in terms of the message, the participants, and the response?

“The message is starting to get traction. There’s a convergence of support for medical research that we really haven’t seen in many many years. And there are all kinds of reasons for that. The medical research community has been doing a great job of educating and informing members of Congress as to why NIH needs to be a national priority; and I think we’ve really gotten to a point collectively where the messaging battle is understood and, to some degree, has been won. Members of Congress really are talking about NIH needing robust, predictable, and sustained budget increases—and it needing to be a national priority.


“We had four influential Senators speak last night [at the Rally for Medical Research evening reception] in support of this effort: Senator Patty Murray (D-WA), Ranking Member on the Subcommittee on Labor, Health, and Human Services within the Appropriations Committee; Senator Dick Durbin (D-IL), number two in the Senate in the leadership; Senator Amy Klobuchar (D-MN), who actually requested to speak this year—she said this was one of the most important causes out there; and Senator Jerry Moran (R-KS), a member on the Subcommittee on Labor, Health, and Human Services with the Appropriations Committee. And this morning we heard from House Chairman Tom Cole (R-OK) [at a breakfast to kick off the rally’s Hill Day], who showed immense leadership this year. He proposed a $1.1 billion increase for NIH.


“Now I think the message has really resonated. And we are on Capitol Hill today to push to get over the finish line in terms of having these increases provided.”


2. What’s the finish line? Despite the changed momentum, what challenges still need to be overcome to actually get more NIH funding?

“We have to have these budget caps raised; and we have to have sequestration eliminated at some point. It’s a macro-economics issue right now. Without those changes, there’s no room—even though there’s the interest—to provide those increases. There are not enough resources available to provide NIH with these necessary increases unless we do that.”


3. So what’s actually happening in Congress today for Hill Day?

“We have 300 individuals going to Capitol Hill to advocate on behalf of NIH. Those 300 individuals all have schedules. We will be meeting with 80 Senators (40 states are represented). And they will be meeting with more than 200 Representatives in the House. We’re going to be blanketing Capitol Hill today with information, with passion, with stories of hope, and with stories of success about why NIH funding needs to be a national priority.


“Our advocates here in D.C. today are survivors, advocates, family members, representatives of the supporting organizations, doctors, researchers, and young investigators. That’s really been the value—having every sector really represented here and participating in this—the entire medical research eco-system.


“I think anyone on Capitol Hill today—if they don’t know what the rally medical research is going into today, they’ll know what it is after being on Capitol Hill today.”

About this Blog

Sarah DiGiulio

SARAH DIGIULIO, Associate Editor of Oncology Times, asks oncology’s thought leaders for their perspectives and takes on the field’s current news and controversies.

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