Clinical Trials

[Mary]

This message will give an overview of clinical trials and where to find them. The messages below highlight some of the clinical trials that are showing promise with bone sarcoma.

What is a clinical trial?

An Article Explaining Clinical Trials in Bone Sarcomas

Clinical Trial Database for all Sarcomas - START YOUR SEARCH FOR CLINICAL TRIALS HERE! This database is just for sarcomas and is much easier to go through than the national database of all clinical trials.

The National Institute of Health's Clinicial Trial Database

Cancer.gov breaks trials down by type of cancer, and gives you the phase of the trial, the primary location of the trial, and distant locations who are participating, if any.

Some advanced cases may not qualify for clinical trials. However, there are other ways to gain access to trial medications. Click here to learn more.

[Mary]

February 2008 - This drug is not currently in trial for sarcomas. Past research shows potential, so I will update this message if a new trial opens.

August 2006 - APO2L Clinical Trials continues to make news, this time in China. A recent report states:

"The preliminary results of the Phase I trials indicate that Rh-Apo2L is effective in reducing the size of tumors through a genetic process to the benefit of patients. Not only is tumor size reduced, but patients only experienced the nominal side-effects which are common in similar cancer fighting treatments. However, more severe side effects such as blood cell toxicity were not apparent. To date, our studies on Rh-Apo2L indicate that it may be one of the safest drugs for tumor therapy available.”

July 2006: Here is a personal message from someone with metastatic chondrosarcoma who is having the PRO 1762 trial:

I started the PRO 1762 trial last August and since then my lung mets have shrunk 74%. A lot of the tumors are no longer visible on x-ray or CAT scan. My results have been better than those of anyone else trying this drug for any type of cancer. While this has really been fantastic news for me and potentially for others in the group, my last two CAT scans have been somewhat disappointing. My prior scan showed no change in growth, but the latest showed a slight increase in size in two of the lung tumors. The increase was so small that it was measured in millimeters and it is possible that there might have been no growth at all. These last 2 tests were the first times that there was no reduction in the size of the tumors. There is also a possibility that I have hit a wall as far as the drugs effectiveness and the cancer has started to grow again. I will have another CAT scan in another 5 weeks and will know more then. Until the next test I am going to remain optimistic and a little nervous.

There were two other patients at MDA taking the drug. One patient was very advanced and had to stop because of health problems and the latest patient quit because of breathing difficulties and travel problems. The latest patient was only on the trial for a very short time.

At Genentech's website this drug is only mentioned as being used for lymphoma, but in the past it was used with sarcomas.

See the following links and click on Full Text or PDF to gain more understanding on the medical background of this trial drug:

http://tinyurl.com/zzgct
http://tinyurl.com/eqg5x
http://tinyurl.com/zrcpb

[Mary]

The Phase III trial of AP23573 started in September of 2007 and is currently open. The drugs has a LOT of promise in stopping/preventing the growth of sarcoma mets. It has done so in previous studies. Further information can be found here.

The problem with this Phase III trial is that it has very limiting inclusion criteria. Those with mets that have not responded to chemotherapy may be denied this trial. Still, it is worth investigating.

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Ariad today announced that the Company has received feedback from the U.S. Food and Drug Administration (FDA) regarding its Special Protocol Assessment on the design and endpoints for its Phase 3 pivotal trial of oral AP23573, its novel mTOR inhibitor, in metastatic sarcoma.

Based on the FDA's response, the Company intends to pursue its Phase 3 trial in the same treatment setting as originally proposed (patients with metastatic sarcoma following a favorable response to chemotherapy), with overall survival as the primary endpoint and progression-free survival as a key secondary endpoint.

As a result, the Company anticipates that initiation of patient enrollment may be delayed from the second to the third quarter of 2007. The Company expects to provide further details concerning the registration trial based on receipt of follow-up Protocol Assistance from the European Medicines Agency (EMEA) and ongoing interactions with the FDA.

Dr. Maki indicated that oral AP23573 would be compared to placebo in patients with metastatic sarcomas, who had a favorable response to first-line or second-line chemotherapy, a time frame when they normally would not receive other therapies. Approximately 500 patients at 50 to 75 sites worldwide will be randomized (1:1) to study drug or placebo. The trial is 99% powered to detect a 50% increase in median PFS comparing the AP23573-treated arm with the placebo arm. Two interim analyses are planned, and patient enrollment is expected to begin as soon as agreement on the SPA is reached with the FDA, which is anticipated by early second quarter 2007. Updated projections concerning the overall duration of the trial will be provided once patient enrollment is ongoing at multiple centers in the U.S. and Europe. The current target is to complete enrollment within approximately two years of entry of the first patient; the second interim analysis is planned to coincide with full patient enrollment.

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August 2007 - AP23573 going to phase III with new name

Deforolimus Approved as Nonproprietary Name for AP23573 - ARIAD's Novel mTOR Inhibitor

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Aug. 1, 2007--ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced that the United States Adopted Names (USAN) Council and the World Health Organization (WHO) have approved the name "deforolimus" for AP23573, ARIAD's proprietary mTOR inhibitor. ARIAD and Merck & Co., Inc. have a global collaboration to jointly develop and commercialize deforolimus for use in cancer. The Phase 3 trial of oral deforolimus in patients with metastatic sarcoma is expected to begin this quarter.

About Deforolimus (Previously Known As AP23573)

ARIAD's lead product candidate, deforolimus, is a novel small-molecule inhibitor of the protein mTOR, a "master switch" in cancer cells. Blocking mTOR creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism, and angiogenesis. Deforolimus is currently in Phase 1 and 2 clinical trials in patients with solid tumors and hematologic cancers. Deforolimus has been designated both as a fast-track product and an orphan drug by the U.S. Food and Drug Administration and as an orphan drug by the European Medicines Agency for the treatment of soft-tissue and bone sarcomas. ARIAD is collaborating with Merck to develop and commercialize deforolimus in oncology and with Medinol Ltd. to develop stents and other medical devices that deliver deforolimus to prevent reblockage at sites of vascular injury following stent-assisted angioplasty.


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AP23573 Has Well Tolerated and Efficacious in Advanced Sarcoma: Presented at ASCO

By Paula Moyer

ATLANTA, G.A. -- June 8, 2006 -- The investigative agent AP23573 has shown efficacy and tolerability in patients with advanced sarcomas, according to investigators who presented their findings here at the American Society of Clinical Oncology 2006 annual meeting (ASCO).

"There is a compelling single-agent efficacy of 25% in patients with a broad range of sarcomas," said principal investigator Sant P. Chawla, MD, adjunct member, bone and soft tumors division, John Wayne Cancer Institute, Santa Monica, California. "The progression-free survival rate was twice that of historical controls, and it was well tolerated with manageable side effects."

The mammalian target of rapamycin (mTOR) inhibitors have been shown to play a role in cell replication and angiogenesis, and several investigative teams are involved in the development of these agents against a variety of malignancies, Dr. Chawla said in a presentation on June 5th.

In their phase 2 study, Dr. Chawla and colleagues enrolled patients with advanced sarcoma regardless of whether or not the patients had received prior therapies. Subjects were divided into 4 cohorts based on histologic subtype. Treatment consisted of AP23573 at an intravenous dose of 12.5 mg for 5 days every 2 weeks.

The investigators used Response Evaluation Criteria in Solid Tumors (RECIST) guidelines to determine patient response to treatment and defined clinical benefit as complete or partial response or as stable disease for at least 16 weeks.

For each cohort, the investigators defined treatment as successful if the clinical benefit response rate was at least 25%. The team studied potential predictive markers of response by 18fluorodeoxyglucose-positron emission tomography (18FDG-PET) imaging, an analysis of mTOR pathway proteins in the tumoral tissue, and by measuring plasma cytokines and angiogenic factors.

The investigators treated 106 men and 107 women with AP23573, age range was 17 to 79 years (median 50 years).

The most frequent treatment-related adverse events included mucositis, rash, hyperlipidemia, fatigue, and thrombocytopenia.

Of the 212 patients for whom data were evaluable, 54 (26%) had a clinical benefit, including 5 partial responses among 3 patients with osteosarcoma, one with spindle cell sarcoma of the bone, and one with malignant fibrous histiocytoma.

Of the overall group, 76 patients (36%) were shown on 18FDG-PET to have rapid induction of partial metabolic responses following 3 to 5 days of study treatment.

Grade 3/4 toxicity events occurred in 6% of cases and consisted of mouth sores, fatigue, hypertriglyceridemia, anemia, and nausea.

The findings showed that AP23573 is well tolerated and efficacious. On the basis of these findings, the investigators are planning to conduct a phase III study, Dr. Chawla said.

The study was funded by ARIAD Pharmaceuticals, which is developing AP23573.

Read more here.

[Mary]

Cryotherapy in Treating Patients With Primary Lung Cancer or Lung Metastases That Cannot Be Removed By Surgery

This trial is being run by Dr.Littrup from Detroit - he is one of the rare interventional radiologist with much experience in sarcomas.

[Mary]

February 2008 - There are currently no Gemcitabine trials recruiting sarcoma patients. Patients can search the Clinical Trials database to see if any have opened up.

Here is a story where one patient's lung mets shrank by 86% and his life was extended by nearly a year with the use of Gemcitabine. The article states:

"Mr. Neiberg began that treatment August 2004, even though doctors had released him from the hospital and recommended hospice care. With perhaps a month to live, Mr. Neiberg began taking Gemcitabine and by June 2005, his tumors had shrunk 86 percent, according Patty Neiberg."

[Mary]

February 2008 - The study is titled A Phase 2 Study of AMG 479 in Relapsed or Refractory Ewing's Family Tumor and Desmoplastic Small Round Cell Tumors, and is being conducted in San Antonio, Texas. Read more here.

June 7, 2007: Article about this trial drug

April 16, 2007:  Ron is on this trial and has had success. Here is what he says: I had Ewings Sarcoma on my ribs back in 1999 with three recurrences since. They have spread to my lungs both times. I am currently on a clinical trial at CTRC in San Antonio with amazing results. I had 6 spots on my lungs in December, the biggest was 4.5cm. Currently they are all gone. They want more Ewing's patients. There are no side effects to this treatment either.

This trial does not work on all sarcomas. Ron's success may be rare. He has seen other patients with PNET and other sarcomas that did not have success.

[Mary]

February 2008 - A multi-center Phase 2 trial of low-dose perifosine in sarcomas that generally do not respond to chemotherapy, including chondrosarcoma and myxoid chondrosarcoma, is currently underway through the Sarcoma Alliance for Research through Collaboration (SARC) network. The trial locations are Santa Monica, Washington DC, Philadelphia, and Houston. Learn more about the trial here.

From a Press Release: Perifosine results showed an overall CBR (Clinical Benefit Response) of 52%

Perifosine is a novel, first-in-class, oral anti-cancer agent that modulates several key signal transduction pathways, including Akt, MAPK, and JNK that have been shown to be critical for the survival of cancer cells. Perifosine has demonstrated single agent anti-tumor activity in Phase 1 and Phase 2 studies and is currently being studied as a single agent and in combination with several forms of anti-cancer treatments for various forms of cancer.

145 patients with sarcoma were entered on studies prior to December 31, 2006 and were assessed for CBR (Clinical Benefit Response). Partial responses were seen, in one patient each, with chondrosarcoma, extra-skeletal myxoid chondrosarcoma, leiomyosarcoma and a desmoid tumor.

At lower doses with 52 patients fully evaluable for CBR (Clinical Benefit Response), the CBR was 52% with 4 partial responses and 23 stable disease at (greater than or equal to) 4 months. At higher doses with 30 patients fully evaluable for CBR, the CBR was 53% with 16 stable disease at (greater than or equal to) 4 months.

Toxicities were mainly gastrointestinal and/or fatigue.

[Mary]

February 2008 - SARC011: A Phase II Trial of R1507, a Recombinant Human Monoclonal Antibody to the Insulin-Like Growth Factor-1 Receptor for the treatment of patients with recurrent or refractory Ewing’s sarcoma, osteosarcoma, synovial sarcoma, rhabdomyosarcoma and other sarcomas

This Phase II trial is now open in multiple locations, including M.D. Anderson in Houston, Memorial Sloan-Kettering in New York City, and Fox Chase Cancer Center in Philadelphia.

There has been some confusion, as this trial has not been formerly announced as recruiting in some locations. There is information in the clinical trials database here. Locations that state "not yet recruiting" may actually be recruiting. As a proactive patient or caregiver, you may need to make some calls about this one.

More about the drug and previous trials is below:

R1507

R1507 (formerly called Roche 1) is a fully human antibody created by Genmab under a collaboration with Roche. R1507 was selected from a large panel of antibodies and targets the Insulin-like Growth factor-1 Receptor (IGF-1R).  The IGF-1R molecule has been shown to be important in tumor growth and protecting tumor cells from being killed.  IGF-1R is over-expressed on a variety of tumors including breast, colon, prostate, lung, skin and pancreatic cancers and is a well validated target for an antibody therapeutic approach.  Roche filed an Investigational New Drug application with the US FDA for the antibody in December 2005.

Ewing's Sarcoma
The Ewing's family of tumors (EFT) includes primary tumors of bone (classic Ewing's sarcoma, primitive neuroectodermal tumor and Askin tumor) and extrosseous primary tumors.  The estimated incidence of Ewing's sarcoma in the US is approximately 300 new cases per year.  More than 50 percent of patients are adolescents with a slight predominance in males.  Patients who present with metastatic disease at initial diagnosis have a survival rate of approximately 25 to 30 percent.

Previous Clinical Studies

Phase I Results
Positive results from a Phase I study of R1507 in patients with solid tumors conducted by Genmab's partner Roche were announced in October 2007.  Nine of 34 patients with solid tumors experienced disease stabilization when treated with R1507.  Four of the seven heavily pretreated patients with Ewing's sarcoma demonstrated clinical benefit with two of these patients achieving durable, objective partial responses.

Once a week administration of R1507 was well tolerated with few side effects.  The most frequently observed side effects were fatigue, anorexia and weight loss, symptoms that are commonly observed in patients with advanced cancer.  A similar side effect profile was seen in 26 patients who were treated with R1507 on a three week schedule.

Based on these initial results, Roche plans to conduct additional trials and work with a global consortium of sarcoma experts, including the Sarcoma Alliance for Research through Collaboration (SARC).

[Mary]

Some of you know that Kevin developed multiple Ewing's sarcoma bone mets about a year ago. He started taking Temozolomide and intravenous irinotecan, and these drugs have stopped disease progression and shrunk some of the tumors for nearly a year. They have been administered at Memorial Sloan-Kettering, and it looks like there may be a Phase II trial at some point. In the mean time, some doctors may be able to offer these drugs to patients with progressing Ewing's sarcoma even without an official trial.

More info here.

[Mary]

If you are thinking about becoming involved in a clinical trial or have been involved in one, please read this column in the Electronic Sarcoma Update Newsletter. In this column, you are invited to send questions and concerns about clinical trials to Denise Reinke, RN, who works with the The Sarcoma Alliance for Research through Collaboration. This team is hoping to receive input from patients and their families in order to serve us better.