How Investigator-Initiated Clinical Trials Advance Medicine

The curiosity and tenacity of individual researchers can spark unforeseen advances and breakthroughs.

January 17, 2024

Gynecologic Cancer
Breast Cancer
Metastatic Breast Cancer
Endometrial Cancer

By Beth Dougherty

Investigators who run investigator-initiated trials (IITs) have two essential qualities. One is curiosity, which keeps them alert, aware of discoveries, and able to make connections that lead to new treatment ideas.

The second is determination.

"The burden of responsibility for what is typically a many-year-long study falls on that one investigator," says Ursula Matulonis, MD, chief of gynecologic oncology at Dana-Farber. "They need the drive and determination to improve outcomes for our patients by developing new and better therapies."

IITs arise when a clinician-scientist sees and seizes an opportunity to make a difference for patients. Other types of trials phase 3 registration trials, which aim for drug regulatory approval, for example, or large phase 1 clinical trials in which a drug might make a debut are typically initiated and funded by pharmaceutical companies. But IITs, which come in a range of shapes and sizes, are conceived, designed, and carried out by the investigator.

Not all institutions support IITs. They can be high-risk endeavors if they aren't executed with diligence. But Dana-Farber has the expertise, infrastructure, and resources needed to support these trials. For instance, Dana-Farber has teams of research personnel who specialize in different cancers and who support the principal investigator, as well as the conduct and management of IITs. Within the Susan F. Smith Center for Women's Cancers, about half of the breast and gynecologic trials underway are IITs because there are just so many ideas worthy of investigation.

"We're working as hard as we can to sort out which drugs are the right drugs for each person," says Erica Mayer, MD, MPH, director of clinical research in breast oncology at Dana-Farber. "Doing that work requires a whole spectrum of clinical trials and clinical trial design."

Adrienne Waks, MD (left), and Erica Mayer, MD, MPH.

Inspired by Insights From the Lab

As an example, Adrienne G. Waks, MD, associate director of clinical research in breast oncology at Dana-Farber, is leading an IIT testing a novel combination therapy involving three drugs in patients with hormone receptor (HR)-positive metastatic breast cancer. The trial aims to stave off drug resistance that occurs when patients take the standard two-drug therapy.

Dr. Waks and colleagues first had the idea for the trial in 2020, when a Dana-Farber lab scientist made a discovery. He found that in about 40% of patients with HR-positive metastatic breast cancer, tumors increased their signaling through a certain growth pathway, called the MAP kinase pathway, when they became resistant to a combination of anti-estrogen medication and CDK4/6 inhibitor medication.

CDK4/6 inhibitor medications have been a game changer for this patient group. These drugs, which members of Dana-Farber's division of breast oncology had previously helped shepherd to approval, have extended the lives of many patients when paired with anti-estrogen medicines.

"It was a really important advancement," says Dr. Waks. "But virtually all patients develop resistance to the combination eventually."

The discovery that resistance and relapse might be defeated by blocking that MAP kinase signal set Dr. Waks on a quest to design and run a trial to test the idea. Once the trial details were worked out, the next step was to execute the plan, which included securing supplies of medicines and funding.

IITs are often funded by a mix of philanthropic gifts, foundation support, and grants from organizations such as the National Cancer Institute (NCI). In this case, Dr. Waks saw an opportunity to collaborate with a pharmaceutical company, since several were developing agents, called RAF/MEK inhibitors, that block this pathway. It took many months of effort to identify a partner company interested in supporting the trial.

"With an IIT, you are the one carrying it forward, and this is just how it works," says Dr. Waks. "You keep going because you believe in the promise it might hold for patients."

Rebecca Porter, MD, PhD (left), and Ursula Matulonis, MD.

Responding to Patient Need

A different IIT, led by Rebecca Porter, MD, PhD, a physician in gynecologic oncology at Dana-Farber, focuses on patients with recurrent or advanced serous endometrial cancer. This patient group is relatively small, accounting for about 10% of endometrial cancer cases. Despite being uncommon, it accounts for about 40% of deaths from endometrial cancer.

Dr. Porter's IIT pairs an antibody-drug conjugate (ADC) called mirvetuximab soravtansine with an immune checkpoint inhibitor called pembrolizumab. The rationale for the treatment came from several angles, including the fact that about 50 to 60% of patients with this cancer express the target this ADC is designed to hit, a protein on the surface of the cancer cell called folate receptor alpha. In addition, laboratory work had suggested that the two medicines might be synergistic.

The trial not only makes scientific sense, but also addresses a strong need for new medicines for this patient group.

"It's important to run trials like this because it gives patients access to medicines that they could not get otherwise," says Dr. Porter.

Central to both Porter's and Waks' trials is that they will be collecting samples and data from patients as they go through treatment. Blood draws and tissue biopsies will enable the researchers to understand more about how the drugs are working and if they are, in fact, doing what the investigators predict.

"We're well suited for this kind of translational work here at Dana-Farber," says Dr. Porter. "We have such a rich environment, from basic science labs to testing facilities and clinical research expertise."

From Idea to Execution

After Dr. Waks found a company with a RAF/MEK inhibitor to collaborate in support of her trial, she then had to apply to the maker of a CDK4/6 inhibitor to supply that drug for patients who enroll in the trial. She and her scientific collaborators also have funding from an NCI Specialized Program of Research Excellence (SPORE) grant to fund the correlative science the blood tests, biopsies, and other work that would help them understand the biology.

This kind of experience running trials is priceless, particularly for Drs. Porter and Waks, who are not yet senior investigators.

"They work with the regulators, such as the U.S. Food and Drug Administration, and they manage the trial they secure the funding; they collaborate widely," says Dr. Matulonis. "It makes them more experienced clinical trialists and translational investigators. And our hope is that the work leads to new treatment strategies that help our patients."