Clinical trial will use mice to guide treatment choices in soft-tissue sarcoma

Mice in Champions lab.

By Suzie Siegel

Cancer treatments have been tested on mice for years. Now a new technology uses mice to determine which treatments may best fight an individual patient’s sarcoma.

The TumorGraft technology “provides options for patients in difficult situations when, often as doctors, we are not sure how to treat people,” said medical oncologist Justin Stebbing, a professor of cancer medicine and oncology at London’s Imperial College. “In doing so, it advances the frontiers of science and medicine, but in a practical way, giving clinicians information on treatment choices – what is likely to work, and as importantly, what is likely to not work.”

Champions Oncology soon hopes to open a phase II clinical trial of its TumorGrafts for patients with soft-tissue sarcoma, Chief Medical Officer Angela Davies said. About 200 people whose sarcoma has recurred or metastasized will be enrolled at sarcoma centers across the United States and Canada.

“We have plans for clinical trials in many different tumor types,” she said. “We currently are partnering with academic centers conducting a clinical trial in breast cancer and advanced non-small-cell lung cancer, with plans for a trial in head-and-neck cancer and colorectal cancer to start within the next 12 months.”

In the sarcoma trial, she said, patients will start standard treatments while waiting for results from the TumorGraft process, which can take 4-6 months. The trial will accept only patients who are expected to survive at least six months and who are healthy enough to undergo systemic therapy, such as chemo. If the initial treatment fails, the TumorGrafts may help a doctor choose which treatments to try next.

Until a clinical trial validates the process, a U.S. doctor can’t use it to justify delaying or changing treatment in a patient with advanced sarcoma, said Sujana Movva, a sarcoma medical oncologist at Fox Chase Cancer Center in Philadelphia.

Dr. Sujana Movva

Dr. Movva helped design the trial, which was discussed last fall at the annual meeting of the Connective Tissue Oncology Society in Berlin. Other physicians involved in the research were from Massachusetts General Hospital in Boston; University of Michigan, Ann Arbor; Oregon Health & Science University, Portland; Mount Sinai Hospital, New York; Rutgers Cancer Institute of New Jersey, New Brunswick; Johns Hopkins University, Baltimore; M.D. Anderson Cancer Center, Houston; Sarcoma Oncology Center, Santa Monica, Calif.; University of California, Los Angeles; and University of Pennsylvania, Philadelphia.  

Dr. Stebbing serves on Champions’ Scientific Advisory Committee, as does medical oncologist George Demetri, director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute in Boston.

Before surgery, patients can ask for a piece of their tumor and its surroundings to be saved for Champions. The fresh tissue will be implanted into one or more immunodeficient mice. If the graft grows, it will be divided again and implanted in more mice. Grafts also will be preserved for future testing.

These grafts are called patient-derived xenografts (PDX) or patient-derived tumor xenografts (PDTX).

“Champions can test chemotherapy, targeted agents, monoclonal antibodies and antiangiogenics as single agents or in combination,” said Dr. Davies, a medical oncologist. Immunotherapies cannot be tested now, but scientists are working on a mouse model with a humanized immune system engrafted.

“No model system is perfect,” Dr. Movva said, “but it is the best ‘in-vivo’ testing available so far.”

The Hackensack, N.J., company began testing different cancers in 2007, with the greatest number of tests in sarcoma, Dr. Davies said. “The rare and heterogeneous nature of sarcomas and the lack of well-defined treatment strategies make sarcoma well-suited to a personalized approach.”

More than 150 sarcoma patients have tried TumorGrafts, she said. “We managed to grow approximately 100 tumors. Currently, we have 60 successful mice models for sarcoma patients.” That translates into a 65-percent success rate for growing sarcomas in mice, she said, “and 67 percent of patients for whom a model was successfully developed decided to proceed with drug sensitivity testing in the model.”

Implantation costs about $2,000, she said. Testing one therapy costs an additional $2,500-$3,000, and the cost mounts as more therapies are tested. The upcoming clinical trial would be free to patients, however. A successful phase III trial could lead to insurance coverage for TumorGrafts.

Some sarcoma patients choose to do chemosensitivity or chemoresistance tests in which their cancer cells are grown in a Petri dish. TumorGrafts have an advantage because they preserve the biological characteristics of the original human tumor, Dr. Davies said.

“Previous work has shown that implanted tumors are able to spontaneously metastasize,” Dr. Movva said. “This suggests that there is interaction between the tumor and its microenvironment, which may therefore mimic the patient response better.”

Genetic testing can help people with certain cancers, but researchers have found few targeted therapies for people with sarcoma, she said. There are more than 70 subtypes of sarcoma, and chemo is less effective in many of them than in more common cancers.

“A recent paper by Stebbing et al. summarizes the clinical experience of 29 patients,” she said. “A few of these patients did have DNA sequencing of their tumors, which guided the physician in selection of drugs for the sensitivity testing.”

In 13 cases, treatments that worked in the mice also helped the patients. “A few patients derived benefit from drugs not normally prescribed for patients with soft-tissue sarcoma,” Dr. Movva said. Grafts failed for seven patients. Six died before data from the mice became available. In three cases, there was no correlation between the mice and the patients.

“It is unclear, therefore, if this approach (using a PDX model to direct care) is better than participating in a phase I trial, for example,” Dr. Movva said. Nevertheless, “patients should definitely consider participating in the TumorGraft clinical trial when it becomes available. This will help determine how well the PDX model predicts patient response and also help sort out some of the issues related to engraftment rates and feasibility.”

Other companies have developed PDX models for research. But Champions is the only one that sells them to individual patients, Dr. Davies said.

Phase 3 trial on aldoxorubicin raises hopes

By Suzie Siegel

Imagine a drug that would be just as effective as Adriamycin (doxorubicin) but could be taken longer, without damaging your heart. That's the dream of aldoxorubicin, which is in a Phase 3 clinical trial for soft-tissue sarcoma in the U.S. and Europe.

Stephanie Zimmerman, MSN

Stephanie Zimmerman of Atlanta shares this dream. At age 8, she was given doxorubicin and underwent chest radiation to cure her of Ewing's sarcoma. Three decades later, her heart failed and she had to have a transplant.

"I look forward to the day that a less cardiotoxic chemotherapeutic agent such as aldoxorubicin is made widely available to adults and children alike," said Zimmerman, president and co-founder of myHeart, yourHands, a nonprofit that raises awareness about late effects of cancer treatment, raises money for research and supports survivors. She has a master's degree in nursing and worked in pediatric oncology before her heart problems.

"No one should be cured of cancer only to lose their hearts, their lives, to a life-threatening late effect such as heart failure. The preliminary findings on aldoxorubicin are encouraging, and oh, how I hope, the clinical trial continues to be promising."

CytRx Corp. of Los Angeles is developing the drug, which is designed to deliver doxorubicin directly into a tumor, leaving healthy tissue unharmed.

Sant Chawla, MD

"We are excited about the potential for aldoxorubicin to safely treat patients with relapsed or refractory soft-tissues sarcomas, many of whom have received and failed to respond to prior doxorubicin therapy," said Sant Chawla, MD, the principal investigator of the trial. "Because of the cardiac safety profile of aldoxorubicin, the FDA is allowing us to treat patients who have received up to 375 mg/m2 of prior doxorubicin, and we can treat until tumor progression is observed." 

Dr. Chawla, director of the Sarcoma Oncology Center in Santa Monica, Calif., has much experience running clinical trials.

"This 100-center, international trial is the first that allows the use of the investigator’s choice of standard soft-tissue sarcoma drugs in the control arm, a situation that should allow rapid recruitment to the study.” In the randomized trial, doctors can choose to compare the drug to doxorubicin, dacarbazine, pazopanib, gemcitabine + docetaxel, or ifosfamide. For more information, go to ClinicalTrials.gov.

Chondrosarcoma trial opens nationwide

By Suzie Siegel

An exciting trial for patients with chondrosarcoma is opening at hospitals across the country.

Dr. Jon Trent

"This trial is very important to me as a sarcoma medical oncologist because I see patients with chondrosarcoma for which there are no treatment options," said Jon Trent, MD, PhD, director of the Sarcoma Medical Oncology Research Program at the University of Miami's Sylvester Comprehensive Cancer Center. "I pray every day that this new therapy is as effective as imatinib is in GIST or CML."

Imatinib, a k a Gleevec, is a landmark in the targeted treatment of sarcoma, helping keep people with gastrointestinal stromal tumors (GISTs) alive for years. It was originally developed for chronic myelogenous leukemia (CML).

Sarcoma researchers are looking at drugs used to treat leukemia because both cancers arise from mesenchymal cells. At the annual meeting of the Connective Tissue Oncology Society last fall, physicians joked that “leukemia is just sarcoma of the blood.”

Miriam Zimms in therapy.

"Since chondrosarcoma doesn't respond to chemotherapy and rarely radiation, trials like these are important for patients dealing with local recurrence or metastasis. It also gives those of us who are cancer-free a sense of security to know drugs are being tested," said Miriam Zimms of Tampa, who has survived both triple-negative breast cancer and chondrosarcoma in her left pelvis. "I'm the Bionic Guatemalan since I've had my breasts, ovaries/tubes and left pelvis amputated and rebuilt."

Agios Pharmaceuticals is sponsoring the new trial, called the "Study of Orally Administered AG-120 in Subjects With Advanced Solid Tumors, Including Glioma, With an IDH1 Mutation."

"Our bone sarcoma pathologist, Andrew Rosenberg, was part of a team who recently identified IDH mutation in 70 percent of patients with conventional and dedifferentiated chondrosarcoma," Dr. Trent said. "I found a pharmaceutical company manufacturing an IDH-1 inhibitor for leukemia. I presented the data on IDH-1 mutation in chondrosarcoma, and we have reached an agreement to do a Phase I clinical trial for patients with IDH-1 mutant chondrosarcoma.

"If effective, this drug will bind to the mutant IDH-1 and turn it off, just like turning off a light switch. This would result in the cancer cells turning back into normal cells. I think this stands a very good chance at helping a lot of people affected by chondrosarcoma.

"I am happy to see any patient with chondrosarcoma at our Sarcoma Center. The patient's tumor must have an IDH-1 mutation, which we test for routinely at our institution."

Read the details of the clinical trial here to see if you may be eligible. Patients can call (305) 243-1287 or (305) 243-1000 for an appointment with Dr. Trent.