Adding Years with Experimental Therapies
words by mary ann littell /
photographs by john emerson and pete byron
Deborah L. Toppmeyer, md, associate professor of medicine, UMDNJ-Robert Wood Johnson Medical school (RWJMS); director, NJ Comprehensive Breast Cancer Center, the cancer institute of new jersey (CINJ)
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hysicians at The Cancer Institute of New Jersey (CINJ) are pursuing cutting-edge research targeted to diagnosing, treating and preventing cancer and managing its symptoms. The center has enrolled more than 1,000 patients in clinical trials, including approximately 15 percent of new adult cancer patients and 70 percent of new pediatric cancer patients. Here is a look at the work of three CINJ physicians involved in clinical research.
‘Astounding’ Therapies Target Breast Cancer
When a powerful cocktail of chemotherapy drugs caused the tumor in Jennie Collucci’s breast to shrink from 8 centimeters to 7 millimeters, her doctors had one word to describe it: “Astounding.”
Collucci first noticed a small bruise and swelling in her breast in April 2008. Since she has a strong family history of breast cancer on her father’s side, she was “shocked, but not surprised. I thought, ‘I guess it’s my turn now,’” says the 40-year-old mother of two. She met with Deborah Toppmeyer, MD, who suggested she enter a clinical trial combining standard chemotherapy and Herceptin with Avastin, the study drug. Avastin interferes with the growth of cancer cells by cutting off the flow of blood to the tumor and potentially works synergistically with Herceptin and improves chemotherapy delivery to the tumor. “This is an exciting trial, as we are taking combinations of drugs that have been effective in advanced disease and now testing them in earlier-stage disease to determine if we can further reduce the risk of breast cancer recurrence,” says Toppmeyer.
“Entering this study was a no-brainer,” says Collucci. “When you have cancer, why wouldn’t you use every available tool to get rid of it?”
Collucci began her chemotherapy regimen in May. She initially had eight cycles of chemotherapy, each 21 days apart, to shrink the tumor prior to surgery. Avastin was administered with the other drugs in the fourth through seventh cycles. Following the first cycle of chemotherapy, the patient had a dramatic response evidenced by a marked improvement in the bruising and swelling of the breast.
When Collucci underwent a mastectomy in November, only a small focus of residual cancer was detected. She resumed treatment with the study medications in December, and will receive a total of one year of Avastin in combination with Herceptin. “Preliminary results from a similar trial showed that patients with previously untreated, metastatic breast cancer who received Avastin along with standard chemotherapy had an improvement in progression-free survival, meaning they were able to remain on the current treatment for a longer period of time before there was evidence that the disease was progressing,” says Toppmeyer.
Toppmeyer is also the lead researcher in another clinical trial investigating a new combination of chemotherapy drugs and Avastin targeted at patients who have been diagnosed with previously untreated triple-negative metastatic breast cancer. This type of cancer does not express estrogen or progesterone receptors or HER2 protein, so standard treatments with hormone-blocking agents such as tamoxifen and herceptin are not effective.
“I’m thankful that I came here,” says Collucci. “If I hadn’t, I may not have had access to this clinical trial, which I believe saved my life.”
Treating Blood-Borne Malignancies
Mecide Gharibo, MD, assistant professor, medicine, UMDNJ-Robert Wood Johnson Medical School (RWJMS) and the Cancer Institute of New Jersey (CINJ)
Mecide Gharibo wrote her first clinical trial protocol as a second-year hematologic oncology fellow, and was hooked. “Academic medicine is a perfect fit for me,” she says. “It combines my love of research and taking care of patients.”
The physician, a Turkish native, grew up in Sweden and came to the U.S. as a high school foreign exchange student. She stayed here because of the wealth of opportunities in medicine. After completing a fellowship at RWJMS, she joined the faculty as an assistant professor in 2004. “I came to RWJMS because I wanted to be part of the hematological malignancy group at CINJ,” she says. “We see a large population of leukemia patients, probably comparable to Memorial Sloan-Kettering, and between six and nine new patients a month. They are referred from community physicians, who don’t treat these patients because their care is so complex. This work is challenging, but rewarding.”
Gharibo is principal investigator for eight clinical trials for leukemia, Hodgkin’s disease, lymphoma and myeloma. “We’ve made progress, but these are tough cancers to cure,” she says. “Our objective is to try and find not only new treatments, but those that are less toxic as well.”
She cites one promising trial evaluating the drug Busulfan to treat elderly patients with leukemia. “Older patients with leukemia have a life expectancy of only 6 to 12 months and don’t tolerate a lot of intensive treatment,” she says. “The goal of this trial is to lengthen their lives, and we are seeing patients survive beyond a year on this drug.” Initially the medicine was given orally, which required patients to take between 50 and 60 pills a day, “which was hard for patients. Now it’s available as an intravenous formulation, which has greatly improved patients’ quality of life. They get one IV dose and they’re done. We follow them carefully to monitor for side effects.”
Another trial she’s working on is a Phase I, multi-institutional study using a novel MDM2 inhibitor for leukemia. The drug targets a protein in malignant cells that protects the cells from dying off. The idea is that if you inhibit this protein, you can promote death in the malignancy. Describing a leukemia patient who’s on this trial, Gharibo says: “Unfortunately, she has limited treatment options, but wants to participate in this trial even though we don’t know if she’ll benefit from it. It’s an extraordinary thing to do — for herself and for others.”
Combating The Most Lethal Cancer
There’s a philosophical question underlying the best clinical trials,” says Joseph Aisner, MD: “That question is, ‘What can we do better than we did?’”
Aisner, a professor of medicine at RWJMS, is currently principal investigator for four clinical trials for lung cancer, the number one cause of cancer deaths each year for both men and women. He also participates in trials for other thoracic cancers. “Perhaps our greatest excitement is the basic discoveries about the biology of cancers and the translation of these laboratory discoveries into new treatments, and in particular, those treatments that derive from our own laboratories,” he says.
“For example, our portfolio in thoracic oncology includes a Phase II trial that is directly derived from some of these findings at CINJ,” says Aisner. “This trial evaluates whether hydroxychloroquine (HC), an earlier-generation anti-malaria drug, can be combined with conventional chemotherapy to enhance its effectiveness in killing cancer cells. Initially this trial will first calibrate the dose of HC when added to established doses of the chemotherapy and then evaluate the combination’s effectiveness.” Another nationwide trial he is leading combines chemotherapy with vandetinib, a new oral medicine that inhibits the development of blood vessels.
Administration of chemotherapy in general and when using new treatments demands vigilance on patient safety and a focus on goals for treatment. “In our three-step safety program, our faculty physicians write the chemotherapy orders, our oncology specialty pharmacists then verify the orders, eligibility, and safety issues and then our chemotherapy certified nurses re-check and administer the agents,” says Aisner. “We follow these steps for all chemotherapy, not just investigational drugs.”
Patient recruitment is also an important component of clinical trial success. “We believe that these trials offer the best opportunity for improving outcome and the best of care. How can we therefore make these trials more available to the people in New Jersey?” he asks. CINJ is a partner in New Jersey Cancer Trials Connect (www.njctc.org), a Web site that matches patients with the cancer treatment trials available in the state. This site offers patients and physicians a personal and private place to enter disease and other information and match trial opportunities. It also gives contact information for trials. The NJCTC Web site is overseen by Susan Goodin, PharmD, professor of medicine at RWJMS and associate director of clinical trials and therapeutics at CINJ. “This site is a terrific tool and uses the electronic age to enhance trial opportunities for patients. As such, NJCTC is a national model,” adds Aisner.
Aisner also oversees the CINJ Phase I group and mentors junior faculty to develop and run protocols. Phase I trials in cancer have the specific purpose of developing the best dose for the newer agents. These new drugs usually have years of background science and pre-clinical testing warranting their application to cancer. “Phase I trials in cancer patients clearly have therapeutic intent, and patients eligible for these studies generally have no better options. All of our currently active anti-cancer drugs were first studied in Phase I trials.”
Several of the CINJ Phase I trials are investigating new molecular targeted drugs alone or in combination with other treatments. “Studying cancers in the laboratory has led to the identification of molecular disturbances that make these cells cancerous,” explains Aisner. “Targeting these disturbances offers the opportunity to treat these cancers very specifically, and there are already several outstanding examples of this approach. The ever-expanding technology enables us to screen large numbers of chemical compounds against these targets, identify potentially active agents, and test them against the cancers. Understanding the targets also allows the scientists to custom-build agents against these targets. Better accrual into clinical trials will help us sort out which of these agents can really make a difference. The delivery of care and the application of research in cancer has truly become a team effort. By working together we are gaining ground in the struggle against lung and other pernicious cancers.”