Patient case: 46-year-old female with papillary thyroid carcinoma; genetic feature: NTRK1

Clinical trial: Phenylbutyrate/Genistein Duotherapy in Delta F508-Heterozygotes (for Cystic Fibrosis)

Summary: The purpose of this research study is to test a new combination of medicines, Phenylbutyrate and Genistein, to determine if they could be used to treat cystic fibrosis (CF). The most common genetic mutation found in patients with CF is called Delta F508. Due to this mutation, there is a lack of salt (chloride) movement in your nose, sinuses, lungs, intestines, pancreas and sweat glands. This lack of movement causes the clinical manifestations of the disease.
  Although Phenylbutyrate has been extensively used to treat patients with rare metabolic diseases, Phenylbutyrate is an investigational drug for the purpose of this study. Genistein is a naturally occurring substance that is found in food products such as soy and tofu, but is also an investigational drug for this study. When used together, both drugs may be able to restore normal chloride and salt (water) movements in body organs and glands in people with CF.
  We will be studying salt and water movement in the nose by a technique called nasal transepithelial potential difference (NPD).

Detailed description: This protocol is investigating novel pharmaceutical agents (Phenylbutyrate and Genistein), which are aimed at improving the physiologic function of mutant Cystic Fibrosis Transmembrane conductance Regulator (CFTR). CFTR is absent or dysfunctional in cystic fibrosis. Nasal epithelial CFTR function will be assessed by the NPD procedure.
  We will test the hypotheses that:
  1. Phenylbutyrate given orally for 4 days will be safe in adult Delta F508- heterozygous subjects with CF and will result in small improvements in nasal epithelial CFTR function.
  2. Topical administration of Genistein to the nasal epithelia of Phenylbutyrate treated Delta F508-heterozygous CF subjects will be safe and lead to augmentation of the improved nasal epithelial CFTR function observed during Phenylbutyrate treatment, but not during placebo treatment.
  Study Flow If eligibility is confirmed at the screening visit, there will be an additional 3 outpatient visits over a 1-2 week period, lasting 2-4 hours each.
  Visit 1, all study related safety evaluations will be completed. There will also be a Nasal Potential Difference (NPD) measurement performed. To measure nasal potentials, or voltages, a small butterfly needle will be placed in the skin of the forearm and connected by a thin plastic tube to a monitoring device. A very small soft plastic catheter or tube will be placed against the inner surface of the nose. This catheter will pump a very small amount of saltwater onto the nose and it will connect to the monitoring machine. This machine senses very small electrical voltages that are generated by the body. It does not and cannot send electricity or shocks to the subject. A measurement is made and then the fluid pumped into the nose is changed to one containing a drug called amiloride. Amiloride changes the makeup of salt transported in the nose and reduces the electrical voltage. Then the fluid is changed to saltwater that does not contain chloride. The fluid is then changed to one that has the drug isoproterenol. Isoproterenol causes the cells in subjects without CF to move chloride. The doses of amiloride and isoproterenol used in this study are much lower than those typically used in patients for other reasons. Finally, the fluid will be changed to one containing the experimental drug Genistein.
  Subject will then be randomized and given a 4-day supply of the study drug.
  Visit 2, subject will have safety evaluations and NPD performed in the same manner as previous visit. No more study drug after this visit.
  Visit 3, subject will have safety evaluations and NPD performed without the perfusion of Genistein.

Eligibility: Inclusion Criteria:
  1. Able to communicate with pertinent staff, able to understand and willing to comply with the requirements of the trial, and able and willing to give informed consent.
  2. Willing to practice a reliable and study-accepted method of contraception during the study.
  3. Diagnosis of cystic fibrosis consisting of both:
  1. clinical manifestations of cystic fibrosis and
  2. either cystic fibrosis genotype heterozygous for Delta F508 with a second identified CFTR mutation, or cystic fibrosis genotype with one Delta F508 allele and one unidentified allele and sweat sodium or chloride > 60 mEq/L
  4. Oxyhemoglobin saturation greater than or equal to 92% while breathing room air
  Exclusion Criteria:
  1. Underlying diseases likely to limit life span and/or increase risk of complications:
  1. Cancer requiring treatment in the past 5 years, with the exception of cancers that have been cured, or in the opinion of the investigator, carry a good prognosis such as non-melanoma skin cancer, papillary thyroid carcinoma, and cervical cancer in situ.
  2. GI disease
  i. Inflammatory bowel disease requiring treatment in the past year ii. elevations in ALT or AST levels to greater than 3 times the upper limit of normal
  2. Conditions or behaviors likely to affect the conduct of the study
  1. Current or anticipated participation in another intervention research project
  2. Recent (with 2 months) sinus surgery or nasal polypectomy
  3. Currently pregnant or less than 3 months post-partum
  4. Currently nursing or within 6 weeks of having completed nursing
  5. Unwilling to undergo pregnancy testing or to report possible or confirmed pregnancy promptly during the course of the study
  6. Unwilling to use a reliable contraceptive method for two months after the completion of the study.
  7. Major psychiatric disorder, which, in the opinion of the investigators, would impede conduct of the study, e.g., alcoholism
  8. Other condition, which, in the opinion of the investigators, would impede conduct of the study.
  3. Glucocorticoids other than topical, ophthalmic, and inhaled preparations.
  4. Conditions that would place the patient at an increased risk for complications:
  1. Pneumothorax within the last 12 months
  2. Uncontrolled diabetes
  3. Asthma or allergic bronchopulmonary aspergillosis requiring systemic glucocorticoid therapy within the last two months
  4. Sputum culture growing a pathogen that does not have in vitro sensitivity to at least two types of antibiotics which could be administered to the patient
  5. History of major hemoptysis: (Greater than 240 mL of blood within a 24-hour period within the last 12 months).
  5. Medication use or conditions not specifically mentioned above, including severe or end stage CF lung disease, that may serve as criteria for exclusion at the discretion of the investigators.
  6. History of significant cardiovascular disease, such as myocardial infarction, congestive heart failure, unstable arrhythmia, or uncontrolled hypertension.

Relevance to patient case: not relevant