A Phase III, Double Blind, Randomized, Placebo-Controlled Trial of Sorafenib in Desmoid Tumors or Aggressive Fibromatosis (DT/DF) (NSC# 091105, IND116279, 12/2/2013) Desmoid tumor (DT/DF) is a sarcoma of fibroblastic origin that afflicts children, adolescents and adults and has a median age of onset of 30 years1. Desmoid tumors can occur in any anatomic location and threatens vital organs and limbs which often results in significant morbidity from organ failure, mutilating surgeries (and amputations), loss of limb function, pain and death2,3. There is no standard of care for the treatment of DT/DF. Surgery is associated with high rates of recurrences (~40%)4,5. In advanced disease, systemic therapies range from anti-estrogens to cytotoxic chemotherapies with variable response rates however no systemic therapies have been demonstrated to improve survival or quality of life in this orphan disease6. DT/DF over express c-KIT and PDGFR and a Phase II study of imatinib showed a disappointing partial response (PR) rate of 6%14. Extrapolating this, the principal investigator of this application (Mrinal Gounder) treated an index patient: a 37 year old woman who presented with a large unresectable, intra- thoracic desmoids tumor with sorafenib. Sorafenib is a multi-target kinase inhibitor of BRAF, PDGFR and VEGFR and available through a compassionate use, expanded access program. Sorafenib has a current FDA orphan indication for renal, liver and thyroid cancers. At presentation the patient's desmoid tumor shifted her mediastinum and presented a high risk for cardiopulmonary collapse and sudden death (Figure 1). The patient was oxygen dependent and unable to ambulate more than 30 feet. Following administration of sorafenib, this young woman became independent of oxygen within 4 weeks, began to ambulate and within 3 months returned to work. She remains on sorafenib almost 4 years later. This partial response and dramatic clinical benefit prompted the applicant and colleagues at MSKCC to evaluate the single institution experience of sorafenib in 26 additional patients. We reported a 25% partial response (< 30% by size, durable for >4 yrs) and improvement of symptoms in 70% of patients. We reported that patients who had stable disease but reported subjective improvement in symptoms demonstrated decrease in the MRI T2 signal intensity. The central hypothesis of this proposal is that sorafenib will lead to improved progression free survival, objective responses and improvement in symptoms and function. This is a national, Phase III, randomized, double-blind, placebo-controlled trial of sorafenib in DT patients. Patients on placebo will cross over at progression. The study will enroll 75 patients to detect a PFS difference of 9 months between the sorafenib arm (15 months) and placebo arm (6 months) which represents a hazard ratio of 0.4. The sample size will have 90% power at a 1-sided significance level of 0.025 to detect this difference. Should the study meet this primary endpoint, it will be the first Phase III trial to identify an active agent in this orphan disease and will provide pivotal data needed for a new indication by FDA. Many questions remain unanswered regarding the use of sorafenib in DT. These include: 1) mechanism of action of sorafenib in DT, 2) the lack of a predictive biomarker of response, 3) the significance of decrease in MRI T2 signal and whether this represents a better imaging modality to assess drug efficacy and 4) to quantitate the magnitude of benefit in quality of life with sorafenib and if so, to develop a validated tool to compare effectiveness of this and future drugs. To answer biological questions, we will conduct genome-wide characterization (gene, methylation, microRNA and protein) of pre- and on-treatment tumor biopsies to validate targets we have recently identified as potential biomarkers of response. Once independently validated we hope to develop a companion diagnostic test to select appropriate patients for this drug. To improve upon current imaging modalities (i.e RECIST) in this disease, we are investigating MRI signal characteristics to quantitate and standardize changes in T2 signal as an accurate tool to measure efficacy of future drugs in this disease. Lastly, we are developing and validating new quality of life and patient reported outcome tools in this disease to capture clinical benefit that is not adequately reflected in tumor dimensional changes. By adhering to the highest regulatory standards (randomized, blinded, placebo), this new QOL/PRO tool sets the stage for an innovative endpoint to measure drug efficacy in this disease. This Phase III study attempts to answer important questions in a prospective and statistically robust manner. These correlative studies form the basis of the funding requested for this RFA-FD-13-001grant.

Public Health Relevance

/PUBLIC HEALTH RELEVANCE STATEMENT WRITTEN IN LAY LANGUAGE AND CAPABLE OF BEING UNDERSTOOD BY A GENERAL AUDIENCE Desmoid tumors are rare cancers that can arise in any part of our body. These are cancers that arise from cells that help in healing wounds and formation of scars. It is estimated that about 900 people are diagnosed with this cancer every year and about 40,000 people are living with this throughout the United States. Unlike other cancers, desmoid tumors do not spread to distant organs from where they first form. Instead these tumors keep growing and start pressing on nearby organs and cause a wide range of problems that affect everyday life and occasionally death. These tumors can develop at any age, but they often develop around 30 years of age. In children, adolescents and young men and women this becomes a lifetime of problems where they are constantly getting surgeries, radiation or toxic chemotherapies. Doctors recently discovered that a cancer pill called sorafenib when taken daily can shrink desmoid tumors and improve symptoms such as pain, breathing and function of limbs. In a small study of 26 patients, they found that in about 25% of patients, sorafenib shrunk the tumor and about 70% of patients the drug halted the growth of the cancer. While this is an encouraging result, oncologists realize that these are very few numbers of patients and the true benefit of sorafenib may have been overstated or subjected to bias. In order to truly understand the benefit of sorafenib, it must be compared to a placebo or ?sugar pill?. This is one way of getting approval for new drugs by the Food and Drug Administration or FDA. This new study is going to open in cancer centers throughout the country. In this trial, patients will be randomly assigned by a computer to get sorafenib or placebo (sugar pill). Neither the patient nor the doctors will know who is getting the drug and who is getting the placebo. At first this may sound discouraging as no one wants to be on a ?sugar pill?. However, if anyone on the trial has growth of their tumors and then found out to be taking placebo, they can then switch to sorafenib. Basically, everyone on the trial will get sorafenib at some point. Even in the 21st century, doctors don't understand what causes desmoids to occur and grow. The reasons on why chemotherapy or hormones work or don't work in desmoids is a mystery. In order to understand this, one needs to take a look inside the desmoid using microscopes and powerful research tools. Desmoids may be changing constantly and what was happening inside the tumor 2 years ago may not be relevant today. To crack this code, doctors will conduct a small biopsy of the desmoid tumor just before starting the trial and then a week later when sorafenib has had a chance to work. By comparing the tumor before and during treatment, researchers hope to learn how sorafenib works against the cancer. This sort of cutting edge research using some of the most advanced scientific tools is being conducted for the first time in desmoid tumors. Doctors are trying to come up with new tools for looking at the tumor and how the drug affects the cancer. Currently, a drug is considered a success if it shrinks a tumor. However, some drugs work by halting the cancer and causing the inside of the tumor to die or turn into a scar. In other words, all that remains is a shell. To see what is happening inside the tumor, doctors are using MRI (magnetic resonance imaging) to probe into the tumor without doing a biopsy or surgery. Similarly, questionnaires will be used to ask patients how they feel before they started sorafenib and after a few months. These questionnaires themselves may become tools to see whether someone is benefitting from sorafenib or other drugs in this disease. Overall, this study hopes to provide patients with a new and promising cancer pill that has few side effects and a hope for patients of all ages struggling with this rare cancer. This study hopes to not only provide a new drug in this disease but also understand how this drug works and develop new tools to help patients and doctors to eradicate this cancer.

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Sloan-Kettering Institute for Cancer Research
New York
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