After Yondelis, which drugs may get OK'ed next?

By Suzie Siegel

Many of us have waited years for the FDA to approve trabectedin (Yondelis) for soft-tissue sarcoma.

Dr. Gina D'Amato

“I was ready to march on Washington if it didn't get approved!” Dr. Gina D’Amato said Friday, after the FDA approved trabectedin for patients with liposarcoma and leiomyosarcoma who have already tried an anthracycline, such as doxorubicin, but have an inoperable tumor or one that has spread. Dr. D’Amato, a board member of the Sarcoma Alliance, treats patients at Georgia Cancer Specialists in Atlanta.

For metastatic leiomyosarcoma, Atara Weinstein had three surgeries and more than 35 rounds of chemotherapy with six different drugs before starting a clinical trial for trabectedin in February.

“I have been fortunate that with Yondelis I've had some stability these past few months. And it will be easier, all round, to get the drug without the hassles and red tape of a clinical trial protocol,” she said. “Spiritually, getting this approved is a big affirmation to never give up hope.

“Until a cure is discovered, chemo can be a good way to stay ahead of the rampage, and even though side effects are definitely a consideration, they can absolutely be managed for quality of life.”

Because sarcomas are rare, they get less money for research, companies have less interest in investing in them, and enrolling enough patients in clinical trials is difficult.

The FDA has approved only six other chemotherapy drugs for soft-tissue sarcoma: Dactinomycin in 1964 for rhabdomyosarcoma, doxorubicin (Adriamycin) in 1973, imatinib (Gleevec) for gastrointestinal stromal tumor (GIST) in 2001, sunitinib (Sutent) for GIST in 2006, pazopanib (Votrient) in 2012 and regorafenib (Stivarga) for GIST in 2013. Doxorubicin and pazopanib are the only ones commonly used in different types of sarcoma.

Some drugs approved for other cancers also help sarcoma patients. Because the FDA hasn’t approved them for sarcoma, however, doctors give them “off-label.” Examples are ifosfamide (Ifex), dacarbazine (DTIC), gemcitabine (Gemzar) and docetaxel (Taxotere).

Dr. Breelyn Wilky

Some doctors may try trabectedin off-label for sarcoma subtypes other than the two for which it got approval. One problem with this practice is that a person’s insurance may not pay for an off-label drug, noted Dr. Breelyn Wilky, assistant professor in the sarcoma program at the Sylvester Comprehensive Cancer Center in Miami.

Scientists and physicians have been working on trabectedin for more than 15 years, back when it was called ET-743. It was approved in Europe in 2007 and is widely used there. U.S. sarcoma doctors have grumbled over the length of time it has taken for FDA approval. This year, a phase III trial confirmed that the drug can keep leiomyosarcoma and liposarcoma from growing and spreading longer than can dacarbazine. The trial couldn’t prove patients live longer on trabectedin, perhaps because of the trial design.

Clinical trials are broken into three phases. The latest trabectedin trial may have succeeded because it focused on the two types of sarcoma that have gotten the most benefit. In the past, the FDA has hesitated to approve drugs that couldn’t be proven to significantly extend patients’ lives. In 2012, however, it didn’t require that proof for pazopanib. It approved the drug for keeping patients stable longer – just like trabectedin.

Dr. Jonathan Trent, co-director of the Musculoskeletal Center at the Sylvester cancer center, said he wants to stress how effective trabectedin is. “We have had metastatic patients in regression for more than two years.”

Trabectedin was synthesized from a sea squirt. The next sarcoma drug that may win approval also comes from the ocean. Eribulin (Halaven) was derived from sea sponges. This month, the FDA gave it Priority Review status, which means the FDA is expected to make a decision within six months. In a phase III clinical trial, eribulin helped patients with liposarcoma and leiomyosarcoma live longer, compared with dacarbazine. The FDA has already approved eribulin for breast cancer.

The FDA has granted Fast Track status to evofosfamide, formerly called TH-302. This designation speeds up the review process, but not as quickly as Priority Review does. Results from phase III studies are expected this year.

There is hope evofosfamide will be safer than its older cousin, ifosfamide. Dr. Trent said ifosfamide can be more dangerous than some drugs because patients have to be monitored more closely, and some oncologists weren’t trained in sarcoma centers that used it regularly. He said he uses higher doses of ifosfamide than some other doctors because he knows how to monitor it.

With some chemos, more is better, he said. For example, the higher the dose of doxorubicin and ifosfamide, the higher the percentage of patients who benefit.

Results of a phase IIb study of aldoxorubicin were published last month, saying it kept sarcoma stable longer than its cousin, doxorubicin. Because of the danger of damaging the heart, patients are limited on how much doxorubicin they can receive. So far, patients have been getting much more aldoxorubicin without hurting their hearts. A phase III clinical trial is underway.

Dr. Daniel Rushing

In the past, a common chemo combination was dacarbazine, doxorubicin and ifosfamide. Use of dacarbazine peaked in 1993, said Dr. Daniel Rushing, professor of clinical medicine at Indiana University in Indianapolis. It fell out of favor because of nausea and vomiting, he said, but it has made a comeback in recent years as new drugs have better controlled the side effects.

Regorafenib is in a phase II clinical trial for liposarcoma and bone sarcomas. But Dr. Trent said it’s unclear whether it will be approved – the FDA has issued a black-box warning for its potential to damage the liver.

A phase II study of masitinib found it superior to sunitinib for GIST. “I think masitinib could be the next super-Gleevec,” Dr. Wilky said. Another phase II study is looking at the addition of MORAb-004 to gemcitabine + docetaxel.

A phase Ib/II trial this year found olaratumab helped sarcoma patients (a third had leiomyosarcoma) live longer when the drug was added to doxorubicin, as opposed to doxorubicin only. The FDA gave it Breakthrough Therapy Designation.

In phase Ib/II trials, TRC105 + pazopanib got complete remission for two patients with angiosarcoma.

Dr. Jonathan Trent

It’s too early to tell whether AG-120, in a phase I clinical trial for chondrosarcoma, will prove effective, Dr. Trent said. But he describes a patient whose cancer was growing before the trial and now has been stable for nine months. “Is that success? I think so.”

The FDA has approved pembrolizumab (Keytruda) and nivolumab (Opdivo) for other cancers, and they are now in phase II trials for sarcoma. A clinical trial of avelumab may open in 2017. These drugs are anti-PD1 antibodies, a form of immunotherapy. Immunotherapy drugs help the body recognize and attack cancer cells. Immunotherapy has gotten great acclaim.

“Research is exploding,” Dr. Wilky said, adding that alveolar soft-part, synovial and clear cell sarcomas may respond well. In general, however, she sees sarcoma doctors becoming less enthusiastic.

“One issue is that the sarcoma may be growing quickly while the immunotherapy takes longer to work. Another issue is getting the drug into tumors that no longer have a big blood supply. Side effects also can be very dangerous.

“Single-agent anti-PD1 is not going to be enough to cure people.” Immunotherapy will probably need to be combined with other drugs, Dr. Wilky said. Next year, she hopes to open a trial with pembrolizumab + axitinib, which is similar to pazopanib.

PD1 is a checkpoint that keeps the immune system from eating cancers. Ipilimumab (Yervoy) targets another checkpoint, CTLA-4, while palbociclib (Ibrance) inhibits CDK4 and CDK6. The FDA has approved both for other cancers. A phase II trial of palbociclib in liposarcoma had promising results, Dr. Wilky said. She also is interested in the phase I/II clinical trial for ipilimumab + nivolumab.

She recalls how clinical trials were once the last resort for patients. That’s no longer the case, she said, because doctors can better predict which patients will benefit from an experimental drug. “You should consider going on a clinical trial early in your treatment.”

I got a chance to talk to Drs. Wilky and Trent at a patient education conference last month at the Sylvester cancer center, co-sponsored by the Sarcoma Foundation of America. Dr. Trent said it was the first conference for sarcoma patients in South Florida.

For more information, check out Dr. Wilky’s blog post on clinical trials: http://breelynwilkymd.com/2015/10/17/clinical-trials-what-you-should-know-to-make-an-informed-choice-about-your-therapy/ The Sarcoma Alliance has a page on clinical trials: http://sarcomaalliance.org/what-you-need-to-know/clinical-trials/ The Sarcoma Alliance for Research through Collaboration lists its trials: http://sarctrials.org/sarc-clinical-trials And the Sarcoma Foundation of America can help you find a trial: http://www.curesarcoma.org/patient-resources/sarcoma-clinical-trials/

Annual meeting of world sarcoma society

By Suzie Siegel

New research on sarcoma will draw hundreds of doctors and scientists from around the world to a conference in Salt Lake City next month.

The international Connective Tissue Oncology Society (CTOS) will celebrate its 20th anniversary Nov. 4-7 at its annual meeting. Executive Director Barbara Rapp expects 600-700 people will attend.

Dr. Lor Randall

“Treatment has evolved from trying to control the spread of sarcoma through surgery and radiation to standard chemotherapy to targeting the biology of different types of sarcoma as well as helping the natural biology of the individual patient,” said Dr. R. Lor Randall, director of sarcoma services at the Huntsman Cancer Institute in Salt Lake City. He is a former CTOS president and its current program cochair.

“We are looking at which patients face the greatest risk of developing sarcomas and having the sarcoma spread. We are trying to detect this spread microscopically before tumors become visible via searching for tumor DNA in the blood,” he said. “We also will examine the specific challenges facing adolescents and young adults with sarcomas.”

CTOS has dubbed 2015 the Year of Angiosarcoma and Hemangioendothelioma, two related vascular sarcomas. Angiosarcoma survivor Corrie Painter, cofounder of Angiosarcoma Awareness, said: "I'm excited about the progress we're making in this aggressive cancer."

A scientist who has studied biochemistry and cancer immunology, Painter is associate director of operations at the Broad Institute in Cambridge, Mass. Each year, about 300 people are diagnosed with angiosarcoma, she said, and almost a third of them will die within five years.

For the first time, the American Association for Cancer Research (AACR) will hold a special conference on the “Basic Science of Sarcomas” Nov. 3-4, in conjunction with the CTOS. Participants will discuss recent advances in genomics using new sarcoma models, immunotherapy, metabolism and signaling pathways.

Once again, the Sarcoma Alliance has planned a dinner for patient advocates Nov. 4. "It's a great forum for advocates to talk to one another in person and discuss ways we can work together," said Executive Director Alison Olig, a rhabdomyosarcoma survivor.

The next day, the Sarcoma Alliance for Research through Collaboration (SARC) will discuss its tissue bank, portal for genomic data and progress in its clinical trials. Another first will be a symposium Nov. 6 to strengthen international cooperation among sarcoma nurses, arranged by a group from Oslo University Hospital in Norway.

On Twitter, you can follow the news by searching for the hashtags #CTOS2015 and #AACRsar15.

Twitter Q&A on drug development next Thursday

By Suzie Siegel

Dr. Laurence Baker

While waiting for "the cure," many of us would settle for more effective drugs that have fewer side effects. Let's talk about this at 9 p.m. (EST) Thursday, Sept. 24, on Twitter.

Sarcoma medical oncologist Laurence H. Baker, DO, will answer your questions during the 45-minute chat. Use the hashtag #scmsm to tweet and find other people’s tweets.

Here are the basics on Twitter: https://media.twitter.com/
the-basics. Before the chat, you may want to learn about drug development here: http://www.cancer.net/research-and-advocacy/introduction-cancer-research/drug-discovery-and-development.

Dr. Baker, a professor of internal medicine and pharmacology at the University of Michigan Medical School in Ann Arbor, brings a wealth of knowledge to the subject. He has served as director for clinical research and hematology/oncology at UM’s Comprehensive Cancer Center; chairman of the Southwest Oncology Group, the largest clinical trials organization in the United States; executive director of the Sarcoma Alliance for Research through Collaboration, a national cooperative group that runs sarcoma clinical trials; and president of the Connective Tissue Oncology Society, an international group of sarcoma physicians and scientists.

Corrie Painter, PhD

He has treated sarcoma patients for more than 40 years, but instead of retiring, he helped establish UM’s sarcoma survivorship clinic last year.  He tweets @laurencebaker2. My Twitter co-hosts will be Bert E. Thomas IV, PhD, MBA, @SFA_Bert and Corrie Painter, PhD, @Corrie_Painter. Bert is CEO of the Sarcoma Foundation of America, the Alliance’s sister organization in Damascus, MD.  Corrie, an angiosarcoma survivor, is vice president of Angiosarcoma Awareness and associate director of operations and scientific outreach at the Broad Institute of MIT and Harvard in Boston.  I’m a leiomyosarcoma survivor who served on the Sarcoma Alliance board 2008-2013. I tweet @SuzieSiegel. The Alliance supports this chat.

I'll update this post as more people commit to the chat. 

This year has brought exciting news on trabectedin (Yondelis), eribulin (Halaven), aldoxorubicin and evofosfamide (TH-302). Some of you may be following the news on other experimental drugs, wondering why it takes so long for them to get FDA approval. Other possible questions include:
      -- How long does it take and how much does it cost to develop new drugs?
      -- Why does it take longer for some drugs to be approved in the U.S.? Yondelis, for example, is already approved in many countries. 
      -- What are the challenges of developing drugs for rare cancers like sarcoma?
      -- Are there initiatives to speed up the process without sacrificing safety? 
      -- In addition to raising money for research, how can people help speed up the process?

What would you like to ask?

A Brother's Story: Jeff Darling

ON DIAGNOSIS …

My sister Ali was diagnosed with either Stage 3 or 4 Alveolar Rhabdomyosarcoma when she was 13. She had been having pains for some time, but I don’t think we had a correct diagnosis for months. I think doctors assumed they were dealing with a benign cyst, and they performed a surgery to remove the “cyst” before performing a biopsy. The post-surgery biopsy came back with the cancer diagnosis - this is exactly the sort of “oops” surgery that Sarcoma Alliance tries to prevent through education.

 

I’d never heard of sarcoma before her diagnosis and cancer was one of those things that definitely happened to other families. It wasn’t until after word of her diagnosis spread through our school and friends that I started to hear from other people whose lives had been impacted by cancer.

I’m pretty sure we were all home when we got the official diagnosis. When you’re that young, you don’t have the understanding of what, “your sister has cancer,” really means. My reaction was along the lines of, “This isn’t a big deal, right? She’ll be fine, right?” 
 
Ali's diagnosis came just before my 16th birthday. Not having a birthday celebration was the first way that I really felt like the disease impacted me. Obviously, that was incredibly naive, and I never could have guessed how much cancer would impact our entire family.

ME, SCHOOL, AND SUPPORT …

At one point, I remember hearing that Ali had a 25% chance of survival. That was the first time it really sunk in that my sister could die. That I could actually lose my sister. I never heard this 25% number again, but that was the day it became real for me.

School definitely suffered. My dad was working in another city, and my mom and sister traveled far from home for treatment. There were long stretches of time where I was by myself. This was the first time in my life that I realized no one was watching. I didn’t have to go to school if I didn’t feel like it. My grades slipped for one semester and I probably missed 3-4 weeks of class while my parents were both out of town.
 
I mostly didn’t get support and didn’t know how to ask for what I needed, especially when Ali needed so much just to stay alive. I always tended to “go with the flow,” and at the time, I saw that as a positive trait, but I took that too far.
 
My friends definitely helped - they would come by the house when they hadn’t heard from me, and I had a holiday meal or two with their families. 

LONG-TERM IMPACT …

Problems with school were definitely the most glaring example. I’d always been a good student, but somewhat lazy about school. The lack of parental oversight (no matter how necessary) enabled me to take that laziness to its full extent. After high school, I went to college and simply stopped attending classes. Did skipping classes in high school set me up to do the same in college?

 
I later learned that it’s very common for siblings of cancer patients to have similar academic problems.

ADVICE FOR OTHERS …

I would tell other siblings that they deserve attention too. Most kids just aren’t capable of asking for attention directly and it’s natural (necessary) to focus entirely on the child with the disease. It’s literally a matter of life and death to make sure the child with cancer gets the best treatment possible.

 
The other siblings will survive, and so they may fall through the gaps. I don’t know if there’s a good answer - I don’t think our family found one, we just did what was necessary. Maybe it would have been different had there been extended family in the area - I could see a large family being able to share the weight of childhood cancer.
 
Sarcoma is a terrible thing, of course, but have there been any hidden blessings?

Ali and I were always pretty close as siblings, but I think there will always be a deeper bond from our family overcoming this life-threatening disease.  After many years of living in different states, we moved to within a mile of each other.  I don’t think there could have been a better close to this story than meeting my nephew the day of his birth.

 
Oh, and I’m still a fairly obsessive hand-washer more than 15 years later, so perhaps I’ve been spared some flu and cold seasons!

If we came to your house for dinner, what would we have?

 

Depends on who is cooking! If it’s on me to cook, my repertoire extends to spaghetti, lasagna, and grilling. Grilling was definitely a hidden talent - it’s all about getting the timing right. Put the food on, close the lid for a certain number of minutes, flip once, and then lid down until it’s done. I’d definitely grill if you were coming to dinner.

 

 

 

 

NCCN revises guidelines on uterine sarcoma

By Suzie Siegel

Guidelines on the treatment of uterine sarcoma have been “extensively revised” this year, according to the National Comprehensive Cancer Network® (NCCN®).

The nonprofit NCCN, an alliance of 26 leading cancer centers in the U.S., publishes separate guidelines for uterine cancers and soft-tissue sarcomas. Two separate panels of experts write them. In the past, some recommendations for uterine leiomyosarcoma (uLMS) differed from recommendations for LMS elsewhere in the body.

Dr. Suzanne George

In 2005, I urged sarcoma specialists to address this discrepancy. The next year, I wrote about the problem here and here. I stopped checking the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) until recently when I saw that Dr. Suzanne George, a renowned medical oncologist in sarcoma at Dana-Farber Cancer Institute in Boston, had been added to the uterine cancer panel in February 2013 as a liaison. I was thrilled, as were other LMS advocates.

“The NCCN Guidelines Panels for Soft Tissue Sarcoma and Cervical/Uterine Cancers have worked together since that time,” according to a statement from Drs. George, Wui-Jin Koh and Benjamin E. Greer. The latter two co-chair the NCCN Guidelines® panel for Cervical Cancer and Uterine Neoplasms. Dr. Koh is a radiation oncologist and Dr. Greer is a gynecologic oncologist, both at the Fred Hutchinson Cancer Research Center in Seattle.

“Uterine sarcomas are uncommon cancers, and women who are diagnosed with these tumors can be cared for by multiple disciplines, including gynecologic oncology, sarcoma-focused medical oncology, surgical oncology, radiation oncology and pathology,” Dr. George said in a separate statement. “It is our responsibility to work together across disciplines to help develop the best guidance possible for the care of women with uterine sarcomas.

"NCCN provides a unique opportunity to bring disciplines together to establish multidisciplinary clinical treatment guidelines with the aim to optimize patient care. It is an extension of the NCCN Mission to create the GYN/SARCOMA liaison position, which allows for collaboration between the Sarcoma panel and the Cervical/Uterine panel in the management of uterine sarcomas.”

The NCCN Guidelines for Uterine Neoplasms (v. 2.2015) primarily focus on the three most common forms of uterine sarcoma: uterine leiomyosarcoma (uLMS), which is the most common; low-grade endometrial stromal sarcoma (ESS); and high-grade undifferentiated endometrial sarcoma. This last category is treated similarly to uLMS. The Guidelines note that these categories are changing as we learn more. For example, some low-grade uLMS is being downgraded to tumors of unknown malignant potential, which are not considered cancers.

The NCCN Guidelines now separate three pathways toward diagnosis and treatment: total or supracervical hysterectomy; biopsy or myomectomy; and "any modality." The Guidelines state that sarcomas should be removed whole, not cut up (morcellated). However, some tumors fall apart on their own or become fragmented. According to the Guidelines, if a tumor was removed in pieces, doctors can consider a second surgery to remove any tumor fragments that may have been left behind.

Ovaries can be left in select patients with early-stage uLMS, but removing lymph nodes is controversial, the Guidelines say. Pelvic radiation remains controversial and isn't recommended routinely for stage I uLMS, the Guidelines say, adding that tumor-directed radiation therapy may be appropriate for people with higher-stage disease, depending on individual circumstances.

It's still not proven that chemo helps women with stage I uLMS if their tumor has been removed completely, but the Guidelines say some doctors may want to consider it because of the risk of relapse. More doctors will consider it for stages II and III. It is generally recommended for stage IV as well as for anyone with uLMS that wasn't completely removed in surgery.

If a uLMS patient is going to do chemo, the Guidelines recommend doctors try gemcitabine (Gemzar) + docetaxel (Taxotere) first. The Guidelines note a trend to use dacarbazine as a standard treatment for comparison in clinical trials, and say trabectedin (Yondelis) can be useful. However, according to the Guidelines, in the U.S. “trabectedin is currently not available outside of a clinical trial. Enrollment in clinical trials is strongly recommended."

For follow-up, the Guidelines propose a physical exam every 3 months for 2 years and then every 6-12 months. Also, doctors should consider CT imaging of the chest/abdomen/pelvis every 3-6 months for 2-3 years, with other imaging (MRI/PET) as clinically indicated. But they also caution: "Patients with bleeding (vaginal, bladder, or rectal), decreased appetite, weight loss, pain (in the pelvis, abdomen, hip, or back), cough, shortness of breath, and swelling (in the abdomen or legs) should seek prompt evaluation and not delay until the next scheduled appointment."

The Guidelines note that uLMS will return in 50 percent to 70 percent of patients. They urge doctors to educate patients on "symptoms of potential recurrence, lifestyle, obesity, exercise, and nutrition counseling" as well as "sexual health, vaginal dilator use, and vaginal lubricants/moisturizers." They recommend their Guidelines on Survivorship as well as the American Cancer Society's pages on survivorship as an additional resource.

People who are otherwise in good health are likely to get through surgery and other treatment more easily. But Drs. George, Koh and Greer clarified that: “There is no evidence that lifestyle choices impact risk of leiomyosarcoma.”

The Guidelines recommend hormone therapy for "ESS only," but add: "Aromatase inhibitors can be considered for ER/PR-expressing uLMS." They cite a study by Dr. George that says doctors are trying to determine whether suppressing estrogen helps patients with uLMS whose tumors express estrogen and/or progesterone receptors.

Observation without treatment is now an option for stage I ESS after surgery.

You can sign up for free to read this year’s NCCN Guidelines: http://www.nccn.org/professionals/default.aspx 

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Uterine Neoplasms V.2.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed Feb. 2, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Homework for July

By Suzie Siegel

We have until July 23 to collect signatures on our petition asking President Obama to proclaim July as Sarcoma Awareness Month. We are going to fall way short of the 100,000 we're supposed to get. But whatever we get will help the lobbyist who is working for free for the Sarcoma Foundation of America to catch the attention of the White House.

Click here to sign: http://wh.gov/i0o6U

We are grateful that the American Association of Clinical Oncology (ASCO), the American Association for Clinical Research (AACR) and the National Cancer Institute (NCI) have recognized July as Sarcoma Awareness Month. They have been tweeting lots of information on sarcoma.

Without government recognition, we can't get some organizations to participate. For example, the American Cancer Society has nearly 50 awareness efforts on its calendar, but nothing about sarcoma. I can't even get any of its PR people to call me back. The next time you donate to ACS or participate in Relay for Life, please ask why they don't do anything to raise awareness about sarcoma.

Another way you can help the sarcoma community is by nominating a doctor, nurse, social worker or other health-care worker for an Outstanding Care Award. Doctors and scientists can win grants and awards for their research. But we want to spotlight those who go beyond technical expertise to show real respect and compassion to patients. Don't worry if you're not the best writer in the world.  Just write from the heart. For more information, go to: http://sarcomaalliance.org/news/outstanding-care-awards/

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.

Treating Cancer with Viruses: What about Sarcoma?

Everyone is talking about the recent television reports on the use of viruses to treat cancer. The very general concept behind these treatments is that viruses can be adapted to kill cancerous cells while leaving healthy cells unaffected. This field of treatment is called Oncolytic Virotherapy. But if you've found your way to this article, you’re most likely thinking: “This is great… but what about sarcoma?”

The Sarcoma Alliance has put together this blog post as a way to provide a general overview of what oncolytic virotherapy is and how it is being studied in sarcoma. This is not a comprehensive look at all of the research that has been done pertaining to sarcoma, nor is it intended to reach conclusions about the future of oncolytic virotherapy as a sarcoma treatment. If you are interested in the studies listed below or want to learn more, we encourage you to speak with your or your loved one's treating sarcoma specialist.

While some research has been performed on sarcoma oncolytic virotherapy, there are still many challenges to developing these treatments. For example, viruses are attracted to cells with certain specific markers, so if a sarcoma cell does not have the marker for a specific virus, it won’t be attacked.  Additionally, many tumor cells mutate rapidly, which can lead to markers on only some of a tumor’s cells.  Conversely, if the sarcoma cells have the same type of cell markers that normal cells have, the virus might attack too many healthy cells. However, in spite of these potential complications, some preliminary studies on the efficacy of oncolytic virotherapy as a sarcoma treatment show promise. 

Several types of virotherapy have been studied in sarcomas, including:

• Using viruses to directly attack the sarcoma.  Since viruses kill cells, if they can be genetically “tweaked” to attack only a sarcoma, this may work well.
• Using vaccine viruses to attack the sarcoma. Vaccine viruses won’t cause disease, and since they have been used in vaccines they are known to be safe.  They may kill cancer cells directly, or have the immune system attack the cells.
• Using viruses to make the immune system do a better job of attacking the sarcoma cell.  In some cases, the immune system cells that attack cancer cells remain in the body only a short time, thus cancer can recur.  Tying the immune response to a viral infection seems to keep these immune cells around far longer, thus preventing tumor recurrence.
•  Developing drugs that attack cancer cells the same way that viruses attack cells.  These drugs mimic the ways that viruses kill cells, and thus may be able to be very specific for types of cancers, as well as “recognizing” mutated tumor cells.

Published studies using viruses in a laboratory setting, both in vitro and in vivo (in these cases, mouse models), show some positive results. Below is a brief overview of some of these most recent studies:

• The measles vaccine virus has been studied and shown some promise in treating various subtypes of sarcoma.[i][ii]
• The vaccina virus (similar to cowpox, used in the vaccine for smallpox) has also been studied in advanced extremity sarcoma, which reported some positive results.[iii]
• Vesicular stomatitis virus was studied in metastatic Ewing's sarcoma mouse models, and was shown to have “selectively infected and killed EWS" and delayed tumor growth.”[iv]

Due to the nature of drug development and the potential for differing results as studies continue, it’s impossible to say whether any of these studies will lead to treatments, but we will continue to monitor these and other early developments in oncolytic virotherapies.

In addition to laboratory studies, a few clinical trials using oncolytic virotherapies for sarcoma have been completed or are underway. Below is a brief overview of some of the most recent studies:

• A handful of clinical trials of Reovirus (Reolysin) have taken place, both for pediatric and adult sarcomas.[v][vi]While previous laboratory studies showed that Reolysin may be effective therapy in sarcomas,[vii] these clinical trials had mixed results. 
• A trial looking at varicella zoster virus (chicken pox) in combination with immunotherapy is currently open for osteosarcoma patients who meet certain criteria.  For more information about this trial visit: https://www.clinicaltrials.gov/ct2/show/NCT01953900?term=sarcoma+virus&recr=Open&rank=8
• A Phase II clinical trial that just opened in March testing pembrolizumab in both soft tissue sarcoma and bone sarcoma patients who meet certain criteria. While not a virotherapy, Pembrolizumab (Keytruda) is a promising drug that works similarly to virotherapies, and is already approved to treat melanoma.   For more information about this trial visit: https://clinicaltrials.gov/ct2/show/NCT02301039?term=pd1+and+sarcoma&rank=1

In summary, while some studies have shown promise, it is still unclear what the future holds for treating sarcomas with oncolytic virotherapies. We will continue to follow these and other potential treatments for this rare disease.

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[i]http://www.nature.com/cgt/journal/v21/n11/full/cgt201454a.html

[ii]http://jvi.asm.org/content/87/6/3484

[iii]http://onlinelibrary.wiley.com/doi/10.1002/ijc.29059/abstract

[iv]http://www.hindawi.com/journals/tswj/2014/171439/

[v]http://www.readcube.com/articles/10.1002%2Fpbc.25464?r3_referer=wol&tracking_action=preview_click&show_checkout=1&purchase_referrer=onlinelibrary.wiley.com

[vi]http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=6&ved=0CE0QFjAF&url=http%3A%2F%2Fwww.dovepress.com%2Fgetfile.php%3FfileID%3D20759&ei=Cz4cVbSEKcGhgwT35YGQCw&usg=AFQjCNEoIYpG1tEQQb2fI9FZEg9dPRlQtw&sig2=yVokHaMrHmtsd3phOfgF4g&bvm=bv.89744112,d.eXY

[vii]http://onlinelibrary.wiley.com/doi/10.1002/cncr.25741/full