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Scouting New Therapies

  • Early Trials Can Set the Stage for Later Success

    From Turning Point 2020
    By Eric Bender

    Geoffrey Shapiro, MD, PhD, shares expertise on the early clinical studies that open the gateways to better therapies.

    At any given moment, Dana-Farber is running more than 50 early phase/stage clinical trials, and it enrolls more than 300 patients annually for them, says Geoffrey Shapiro, MD, PhD, senior vice president of developmental therapeutics.


  • Geoffrey Shapiro, MD, PhD, in his lab

    Geoffrey Shapiro, MD, PhD


  • These trials take the giant step of moving candidate drugs out of the lab and putting them on the path toward clinical adoption, if all goes well. And they are built from scratch, which is no easy undertaking.

    The lead investigators must assemble mountains of electronic paperwork with everything from exhaustive sets of preclinical scientific data to the last tiny details of trial procedures. They must gather funding and regulatory approval, two tough challenges. Then the investigators must build trial teams, often across several institutions. They must enroll trial participants and painstakingly respond to their needs. And the investigators must supervise the almost endless gathering and interpreting of clinical data.

    Pulling this all together calls for deep and broad scientific knowledge, leadership and people skills, the energy to take on these intimidating challenges — and mastering the knowledge about how the whole process needs to unfold.

    Supplying, and sharing, that mastery has been a central role for Dr. Shapiro for 20 years.

    "We're doing difficult early work that just is not glamorous, trudging through, trying to make sure everything's safe and defining the right drug dose," says Dr. Shapiro. "It's arduous work, but it's critically important."

    The Role of Mentoring in Clinical Trials

    Soon after medical oncologist Panos Konstantinopoulos, MD, PhD, arrived at Dana-Farber in 2013, he joined with Dr. Shapiro to study treatment of women with ovarian cancer by combining a DNA-repair-inhibiting drug candidate called berzosertib with chemotherapy.

    Building on a promising phase 1 trial led by Dr. Shapiro, they launched a phase 2 trial, sponsored by the NCI's Experimental Therapeutic Clinical Trials Network (ETCTN). That trial did well enough to lay the groundwork for a much larger phase 3 study designed to get Food and Drug Administration approval.

    Dr. Konstantinopoulos, now director of translational research in gynecologic oncology, was the overall principal investigator on the phase 2 trial; Dr. Shapiro was his mentor.

    "Having a mentor for all these processes was very important," Dr. Konstantinopoulos says. "It's not easy. It requires a number of different set of skills. You need to know the science. You need to do well with your patients. You need to understand the clinical disease and the molecular pathways. You need to interact with the regulatory agencies. Geoff taught me a lot in terms of how to navigate this.

    "Geoff is extremely supportive and such a great approachable guy," he adds. "He's also one of the most hardworking people at Dana-Farber; you feel like he never sleeps."

    Dr. Konstantinopoulos is now mentoring medical oncologist Jennifer Veneris, MD, PhD, on another ETCTN project, again with Dr. Shapiro's oversight. It's a phase 1 study that combines DS8201, an antibody drug conjugate that targets the HER2 protein that is over-expressed in several types of women's cancers, with a PARP inhibitor to treat ovarian and endometrial cancer. The study will open this fall, beginning with about 20 patients.

    Developing the trial protocol, Dr. Veneris says, requires passing a series of tough evaluations by the NCI and the company sponsors. "Geoff has been a great advocate for Panos and me in navigating the logistics," she adds. "He always knows who to call and how to navigate these complicated processes. He is never discouraged by bumps in the road. He always has a solution to move things forward."

    Moreover, "he's let me take ownership of the project and the idea," Dr. Veneris adds. "And he has given me the experience of being able to develop this from the ground up."

    Doubling Down on Triple-Negative Breast Cancer

    Two current projects, on difficult-to-treat triple-negative breast cancer, highlight how discoveries in the lab are moved into Dana-Farber-led early trials, with Dr. Shapiro's guidance.

    One project builds on research on PARP inhibitors, a class of drugs designed to impair the ability of cancer cells to repair themselves. Several of these drugs are approved to treat women with mutations to BRCA genes that also may limit cell self-repair.

    Immunologist Jennifer Guerriero, PhD, is examining why some patients who are given this treatment later relapse, analyzing the roles played by the immune system. She and Dr. Shapiro, who runs his own basic science lab, are co-senior authors on a paper in Cancer Discovery about a recent discovery.


  • Jennifer Guerriero, PhD, in her lab

    Jennifer Guerriero, PhD


  • The Dana-Farber team showed that in patients with triple-negative breast cancer and BRCA alterations, PARP inhibitors heighten the activation of a biological pathway that boosts secretion of cell-signaling proteins called cytokines, which in turn recruit T cells and other types of immune cells.

    "Without T-cells, the PARP inhibitor does not work," Dr. Guerriero says. This was a major finding, and an important step in understanding how PARP inhibitors operate by modifying the microenvironment around the tumor.

    And it was fodder for a clinical trial, to be led by medical oncologist Erica Mayer, MD, MPH, that will provide an in-depth analysis of the effects of combining PARP inhibitors with immunotherapy. Meanwhile, Dr. Guerriero's lab will continue to examine how other immune cells play a role in PARP inhibitor resistance, under a Komen Career Catalyst award in which Dr. Shapiro is the lead mentor.

    Another upcoming trial will look at an emerging class of drugs called BET bromodomain inhibitors and how they may be best combined with other drugs to treat triple-negative breast cancer.

    BET inhibitors are designed to dampen the expression of genes, such as certain oncogenes, that are highly active in cancer cells, says geneticist Kornelia Polyak, MD, PhD. Her lab performed comprehensive molecular screening in cell lines to seek out the most lethal ways that BET inhibitors could be combined with other types of agents.

    "Dr. Polyak and her team have done very exciting preclinical work suggesting that there is potential synergy between chemotherapy, immunotherapy and BET bromodomain inhibitors in triple-negative breast cancer," says medical oncologist Ana Garrido-Castro, MD. She is leading the preparation for a phase one clinical trial that will triple-team drugs based on these lab results, with Dr. Shapiro acting officially as a mentor.

    Sharing the Art of Clinical Science

    "The clinical trial enterprise is very complex, staffing has to be very heavy, and there has to be a lot of institutional dedication to it," says Dr. Shapiro. He spearheads Dana-Farber's participation in the Experimental Therapeutic Clinical Trials Network (ETCTN), the National Cancer Institute (NCI) network of sites that do early-phase studies. Dana-Farber is one of very few institutions with an ETCTN grant.

    Securing funds for trials is always an issue. Drug companies typically cover the full costs for trials of their drug candidates. Not so the NCI. "You get a certain amount from the NCI, and then there's an expectation that the institution will take care of the rest," says Dr. Shapiro.

    Another tricky task is recruiting participants. "It takes a lot of time to enroll patients," he says. "The informed consent process is also dynamic and complicated, and you have to sit with patients and explain and make sure they understand what they're getting themselves into. Patients have to come to clinic a lot; participating can be very disruptive to people's lives."

    Managing the trial can become a seemingly endless effort.

    "The regulatory work for drugs that are not yet FDA approved is enormous, so we have regulatory staff," Dr. Shapiro says. "We have data managers who assemble the lab work, the EKGs, all of the assessments of the patients and put that into case report forms. There are lead investigators, either physicians or nurse practitioners, who see patients with research nurses, who write the research note. We have to account for the drugs. We document every side effect and grade it and decide whether that side effect was related to the drug or not. The follow-up is very intensive.

    "It takes a village to execute a trial, and everybody has to be invested," he says. "You need to make sure that everybody feels like they're an investigator, with a seat at the table."

    That's part of the knowledge he passes on to younger scientists. "Nearly every ETCTN trial is run by an early career investigator; they don't really like senior people like me walking in and running all the studies," Dr. Shapiro says cheerfully. "When we can assign projects to early career investigators, it is a way to get them trained and also get things done much faster. I've gotten a lot out of that type of interaction."

    "Geoff is extraordinary at promoting the work of younger investigators," says Dr. Garrido-Castro, his mentee on the proposed triple-agent trial for triple-negative breast cancer.

    Dr. Shapiro also can draw on expertise not just from clinical trials but from his work in his clinic and in his own basic science lab, she emphasizes. "When he talks, people listen. He just has incredible insights that help move the science forward."

    "In cancer therapeutics, Geoff is like an encyclopedia," says Dr. Guerriero. "He knows the molecular mechanism of every drug and knows every outcome for every clinical trial. His deep molecular knowledge and understanding of the way that cancer cells work is invaluable to the development of new strategies for cancer care."

    "Geoff is very responsive," says Dr. Polyak. "He has a great network of people everywhere. He's very motivated. He's really pushing things into the clinic to try to make progress."

    These early trials launch new drug candidates on a long, winding and challenging path that often ends up with better treatment options, Shapiro says.

    "I'm still in my clinical practice, and my entire practice is experimental drugs," Dr. Shapiro says. "I like it when we come up with novel approaches to try to help patients. I find that very exciting and rewarding."

Posted on November 23, 2020

  • Ovarian Cancer
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