NEW ORLEANS — Researchers at the University of Pennsylvania in collaboration with the drugmaker Inovio have launched a Phase I clinical trial assessing whether a cancer vaccine, dubbed INO 5401, can prevent high-risk breast cancer patients with BRCA1/2 germline mutations from relapsing and healthy individuals with these mutations from developing cancer at all.
Susan Domchek, executive director of the Basser Center for BRCA at the University of Pennsylvania, presented the trial details during the American Association for Cancer Research's annual meeting on Saturday. The study is enrolling participants to two groups: Cohort A includes 16 patients with BRCA1 or BRCA2 mutations who have had a prior diagnosis of invasive breast or ovarian cancer, pancreatic cancer, or prostate cancer and have completed adjuvant therapy with no clinical evidence of disease. Cohort B will include 28 healthy participants carrying BRCA1 or BRCA2 mutations.
The immuno-interception strategy that Domchek and her team are evaluating in the trial involves Plymouth Meeting, Pennsylvania-based Inovio's INO 5401, a DNA plasmid encoding hTERT, WT-1, and PSMA, alone or together with INO 9102, which encodes the gene for IL-12.
Following the vaccine, participants are given a small electric charge via an electroporation device called the Cellectra 2000 to increase the amount of vaccine taken up by muscle. Both cohort A and cohort B are separated into two treatment arms: One arm will receive INO 5401 followed by electroporation, and one arm will receive INO 5401 and INO 9102 together followed by electroporation.
Positive data from both the metastatic breast cancer setting and from a Phase I clinical trial of the strategy for solid tumor patients at a high risk of relapse offered the rationale for the Basser Center study to assess the feasibility for nonsurgical prevention.
That earlier study, dubbed TRT-001, was published recently in the Journal for Immunotherapy of Cancer. Among 93 patients with breast, ovarian, and pancreatic cancers, among others, an earlier iteration of the Inovio vaccine, INO 1400, was not only immunogenic, but also safe. Immune responses were observed across all tumor types, and the vaccine increased a CD8-positive phenotype associated with improved overall survival in pancreatic cancer patients. Patients experienced very few side effects, save local injection site reactions, which was a key consideration for moving the vaccine into trials of healthy individuals.
At Basser, Domchek and colleagues have already completed enrolling cohort A part one and are actively enrolling cohort B. "Soon, we will be vaccinating healthy BRCA1 and BRCA 2 carriers," she said, adding that there "seems to be great interest from healthy carriers who want to come on this study." Cancer vaccines typically have not been tested in early-stage or adjuvant trials, let alone intervention trials for germline mutation carriers who are at high risk of developing cancer, but who do not actually have a diagnosis.
Clinical trials evaluating drugs as a means to prevent or intercept, rather than treat, cancers are challenging and lengthy. Because the endpoints for these trials are often related to whether a patient goes on to develop malignancies far down the line, the trials can take decades or more. For this reason, prevention trials often lack adequate funding and drugmaker support. But researchers like those in Domchek's lab are increasingly determined to tackle them.
The Inovio-UPenn vaccination study is designed to evaluate the cancer vaccine's safety and dose-limiting toxicities as well as antigen-specific immune response over a period of two years, though it will take much longer to show the intervention's ability to prevent cancer development.
"We've considered cancer interception for years, but now I would argue that we actually have the tools to translate it," Domchek said during a plenary session at the meeting on Saturday. "There are multiple viable strategies for nonsurgical prevention in BRCA1 or BRCA2 carriers that are being tested or have a good opportunity to be tested."
Because BRCA1 and BRCA2 carriers are at high-risk for a number of the most common malignancies, including breast, ovarian, pancreatic, and prostate cancer, proving the success of an interception strategy could not only have sweeping implications but also be generalizable to future efforts in other high-risk populations and cancer types, Domchek suggested.
Moving PARPi into the prevention space
Other interventional possibilities could be on the horizon, too, when it comes to breast cancer prevention. For example, Merck and AstraZeneca's PARP inhibitor Lynparza (olaparib) has demonstrated efficacy in the adjuvant treatment setting for early-stage, high-risk breast cancer patients harboring BRCA1 or BRCA2 mutations. The drug recently secured US Food and Drug Administration approval for the adjuvant treatment of HER2-negative, high-risk BRCA1/2-positive breast cancer, based on an event-free survival benefit seen in the large, Phase III randomized OlympiA trial.
As Domchek suggested during her presentation, the fact that the PARP inhibitor has been effective for preventing recurrence following initial treatment for this high-risk, early-stage patient population raises the possibility that Lynparza might be an alternative to prophylactic surgery for healthy BRCA1/2 carriers.
As is the case across much of drug development, Merck and AstraZeneca began by evaluating Lynparza in the metastatic disease setting and then gradually moved the agent into earlier treatment lines from there. "We've gone from metastatic to adjuvant," Domchek said of PARP inhibitors. "Can we go to prevention? I don't know."
She pointed to several early "clues" that the strategy may be worth pursuing. For example, patients in the OlympiA trial who received Lynparza were less likely to develop second primary cancers than patients in the control arm. Indeed, 19 patients receiving Lynparza developed second primary cancers versus 32 patients who received a placebo. The numbers are not statistically significant, and it will take more time to see if the trend continues, but the signal is encouraging, Domchek said.
Within cancer prevention trials it is critical to balance potential benefit against the risk of toxicities. The fact that Lynparza in OlympiA did not appear to cause secondary cancers such as myelodysplastic syndromes or acute myeloid leukemia, as some other treatments do, and had a relatively manageable toxicity profile, is also encouraging for the potential of PARP inhibitors to be used for prevention.
"Compared to placebo [in OlympiA], there was no overall effect on quality of life with olaparib," Domchek added. "There are some differences with nausea and fatigue, but [managing that] is really a question of what should a schedule look like and what is considered tolerable for patients."
"We need to answer many of these questions," she continued. "There are a lot of people thinking about these issues and how we can move forward."
While drugmakers have not announced any concrete plans to evaluate Lynparza as a cancer interception strategy for healthy BRCA1/2 carriers, Domchek seemed to suggest that such a trial does not seem out of the realm of possibilities, especially in light of the high cost and quality-of-life implications of prophylactic mastectomies, oophorectomies, and other such invasive procedures too often presented as the sole option for high-risk BRCA1/2 carriers.
"I admit that large-scale interception studies are difficult, even in high-risk patients," she acknowledged. "They are large, they take a long time … but that does not mean we shouldn't do them. At the end of the day, this is what we want to do: intercept cancers and change people's lives."