An Open Label Study to Assess the Safety and Efficacy of COR-003 (2S, 4R ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome

Posted on July 1, 2015 by MaryO
RESEARCH STUDY SUMMARY

An Open Label Study to Assess the Safety and Efficacy of COR-003 (2S, 4R ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome

PURPOSE

The primary objectives of this study are to evaluate the efficacy of ascending doses of COR-003 in subjects with elevated levels of cortisol due to endogenous Cushing’s Syndrome by assessment of reduction in Urinary Free Cortisol (UFC) concentrations and to identify the range of safe and effective doses of COR-003 that reduce mean UFC concentrations ≤ULN (upper limit of normal) of the assay at month 6 of the maintenance phase of dosing without a prior dose increase in that phase.

TO LEARN MORE

CW ID: 208654
Date Last Changed: June 25, 2015

Inclusion Criteria:

Subjects eligible for enrollment in the study must meet all the following criteria:

  • Male or female, ≥18 year of age
  • Confirmed diagnosis of persistent or recurrent CS (with or without therapy) or newly diagnosed disease, if they are not candidates for surgery. Subjects in whom surgery will be delayed beyond 5 months will be permitted to participate. CS will be defined according to the criteria in the guidelines for diagnosis of CS (Nieman 2008). Previous medical records will be collected and used to support the diagnosis. The diagnostic criteria for appropriateness of inclusion of each subject into the study will be reviewed by the Medical Monitor. Diagnosis of the disease will be based on the association of clinical features of endogenous CS (see Appendix G in clinical protocol), review of past medication history, excluding exogenous sources of glucocorticoids, and abnormal values from two of the three following tests:
    • Elevated 24-hour UFC levels ≥1.5X ULN of assay based on a minimum of 4 measurements from adequately collected urine. Urine may be collected on sequential days.
    • Abnormal DST: Elevated 8 AM serum cortisol ≥1.8 ug/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior (if not conducted already in the diagnostic workup of the subject within the previous 6 months; previous test results and details of conduct will need to be available; normal serum cortisol ≤ 1.4 ug/dL)
    • Elevated late night salivary cortisol concentrations (at least 2 measurements) >ULN at screening
    • [NOTE: For subjects with estimated glomerular filtration rate (eGFR as determined by MDRD equation >40 and <60 mL/min) a late night salivary cortisol test (≥2 measurements) MUST be conducted in addition to measuring UFC levels to demonstrate evidence of CS.]
  • Previously irradiated subjects will be allowed as long as the radiation treatment occurred ≥2 years ago and they do have stable UFC levels based on 24-hour urine collections for at least 6 months. The total number of previously irradiated subjects will not exceed 10.
    • In the vast majority of subjects treated with radiation, efficacy is observed in <2 years.
  • Confirmed diagnosis of persistent or recurrent endogenous hypercortisolemia as defined by UFC concentrations on repeated determinations (described in Inclusion #2) caused by either ACTH-dependent or ACTH-independent etiologies.
  • Subjects on treatment for CS for whom treatment has been inadequate or not well tolerated must agree to the following minimum washout periods as determined by the nature of their treatment before baseline assessments are performed for participation in this study:
    • Inhibitors of steroidogenesis: 2weeks; subjects on ketoconazole will be considered inadequately treated if they had failed to normalize UFC with a dose lower than or equal to 600 mg/day (also see Exclusion 7 below).
    • Dopamine agonists: bromocriptine (2 week), cabergoline (8 weeks)
    • Octreotide acetate LAR and lanreotide Autogel®: 12 weeks
    • Lanreotide SR/long-acting pasireotide: 8 weeks
    • Octreotide acetate (immediate release formulation) or short-acting pasireotide: 1 week
    • Mifepristone (RU 486): 4 weeks
  • Subjects on megasterol acetate (medroxyprogesterone acetate) must agree to a wash out of ≥6 weeks prior to receiving the first dose of the study medication.
  • Female subjects should be either post-menopausal, surgically sterile, or women of child-bearing potential (WOCP) with a negative serum beta human chorionic gonadotropin (ßhCG) pregnancy test prior to entering the study and who agree to use an acceptable method of contraception, for the duration of the study. Condoms will be considered an acceptable form of contraceptive.
  • 12-lead ECGs show no acute ischemia or clinically significant abnormality needing medical intervention
  • Ability to comprehend and comply with procedures
  • Agree to commit to participate in the current protocol
  • Subjects provide written informed consent prior to any study procedures being performed (all subjects should be able to understand the informed consent form and any other documents that subjects are required to read)

Exclusion Criteria:

Subjects will be excluded from the study if any of the following criteria are met:

  • De novo Cushing´s disease AND a candidate for pituitary surgery
    • If surgery is to be delayed for >5 months, subjects may be allowed to participate in the trial while awaiting surgery, but must agree to complete this study prior to surgery.
  • Subjects treated with radiation within the previous 2 years.
    • In the vast majority of subjects treated with radiation, efficacy is observed in <2 years.
  • Characteristics of pseudo-CS (see Appendix H in clinical protocol)
  • Subjects with adrenal carcinoma
  • Body Mass Index (BMI) exceeding 50 kg/m2
  • Body habitus preventing repeated venipuncture as required by protocol
  • Subject is currently in another study or has received any investigational treatment (drug, biological agent or device) within 30 days or 5 half lives of screening, whichever is longer
  • History of significant abnormalities in liver function tests on ketoconazole; history of therapeutic response failure to ketoconazole as defined by lack of normalization of UFC at a dose greater than 800 mg/day; lack of therapeutic response failure at maximum dose of mitotane
  • Male and female subjects with QTc interval of >470 msec
  • History of Torsades des Pointes or ventricular tachycardia or ventricular fibrillation
  • Subjects with a non-endogenous source of hypercortisolemia such as exogenous source of glucocorticoids or therapeutic use of ACTH
  • History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to the initial dose of the study medication. Subjects with history of carcinoma must have a life expectancy of >1 year and must be on stable doses of their specific therapies. Subjects with early stage prostate cancer undergoing no treatment due to low grade potential may be enrolled.
  • Diagnosis of HIV
  • History of persistent uncontrolled hypertension (>210/110 mmHg) despite medical intervention
  • Subjects with hypercholesterolemia who are on current atorvastatin or simvistatin and not willing or unable to change to alternative therapies as noted (pravastatin, fluvastatin, and rosuvastatin) with 2 weeks of study screening
  • Subjects with T2DM or with a history of hyperglycemic episodes requiring repeated, frequent hospitalizations
  • Subjects with decreased renal function as defined by eGFR ≤40 mL/min, using Modified Diet in Renal Disease (MDRD) equation for estimating renal function (eGFR).
  • Any other clinically significant medical condition, as determined by the Investigator that precludes enrollment and participation in the study through completion (for example, New York Heart Association (NYHA) class III or IV congestive heart failure).
  • Known hepatic disease, other than mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic steatohepatitis [NASH]), with ongoing sustained biochemical activity (subjects with CS would be at risk for NASH)
  • History of recurrent gall stone attacks or pancreatitis
  • Positive for hepatitis B surface antigen (HbsAg) or positive hepatitis C test
  • Liver function tests (LFT) must not be above the following cut-offs at screening: ALT and/or AST >3.0X ULN, alkaline phosphatase (AP) >1.5X ULN and total bilirubin >ULN. If all LFTs are within normal limits (WNL) and total bilirubin is elevated, examination of direct and indirect bilirubin may be conducted. Subjects with indirect total bilirubin up to 3X ULN are presumed to have Gilbert’s syndrome and may be enrolled if all other LFTs are WNL.
  • Presence of any other clinically significant medical condition, as determined by the Investigator that would preclude the subject from being able to follow instructions or to perform the necessary procedures (for example, psychiatric instability or severe disability)
  • Compression of the optic chiasm
  • Abnormal free T4. Subjects with TSH
  • Excessive alcohol intake (>20 g per day for females (1.5 standard alcohol drinks) or >30 g per day for males (2.0 standard alcohol drinks) (a standard drink contains 14 g of alcohol: 12 oz of beer, 5 oz of wine or 1.5 oz of spirits) or drug abuse. (1.0 fluid oz (US) = 29.57 ml)
  • The subject is currently taking any H2 receptor antagonists or proton-pump inhibitors (which inhibit absorption of COR-003). Only over-the- counter liquid and tablet antacids are allowed which should be used in moderation and taken a minimum of 2 hours after dosing of COR-003.
  • The subject is receiving the following concomitant therapies:
    • Weight loss medications (prescription or over the counter)
    • Coadministration of COR-003 and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both therapeutic and/or adverse effects. Therefore, appropriate dosage adjustments may be necessary.
    • Medications with metabolism largely mediated by CYP3A4 and a narrow therapeutic margin include: cyclosporine, midazolam, triazolam, alprazolam, digoxin, coumarin-derivatives, phenytoin, rifampin, erythromycin, clarithromycin, loratadine, astemizole, terfenadine, nicotinic acids, resins, orlistat, sibutramine, HIV protease inhibitors, thiazolidinodiones, aliskiren, and spironolactone.
    • A complete list of medications metabolized by or with an effect on cytochrome P450 3A4 is provided in Appendix K. Also see Section 10.2.
    • Coadministration of strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with COR-003 and cannot be discontinued prior to the start of the study (see Appendix K for the list)
    • Statins other than pravastatin, fluvastatin and rosuvastatin
    • Following herbal medicines should be avoided: St John’s Wort, yohimbe and red rice yeast
    • Potent topical steroids, containing urea or salicylic acid, which are applied over 20% of the body
    • Inhaled steroid medications that exceed minimal to moderate use
    • Carbamazipine, fenofibrate, carbenoxolone
    • Excessive ingestion of genuine licorice
  • Pregnant or lactating women
  • Any other condition which would increase the risk of participation in the trial in the opinion of the Investigator

Contact

Adrine Gdakian
UCLA School of Medicine
700 Tiverton Avenue, Factor Building Rm 9-240
Los Angeles, CA 90095
Phone: 310-825-5874
Fax: 310-206-5553

Jessica Rios-Santiago
Coastal Metabolic Research Center University Medical Center, Dept. of Endocrinology
3454 Loma Vista Rd.
Ventura, CA 93003
Phone: 805-658-8460
Fax: 805-658-8462

Betsy Parrott, RN, CCRC
Rhode Island Hospital, Hallett Center for Diabetes and Endocrinology
900 Warren Avenue, Suite 300
East Providence, RI 02914
Phone: 401-444-2091
Fax: 401-444-4921

Becky Wood, CCRP
Swedish Neuroscience Research
500 17th Ave
Professional Bldg 303
Seattle, WA 98122
Phone: 206-320-7115

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“My feet are killing me!” An unusual presentation of Cushing’s syndrome

Posted on June 19, 2015 by MaryO

Adverse effects of steroid excess on bone metabolism are well established but presentation of Cushing’s syndrome with metabolic bone disease is reported to be uncommon. We describe a case of Cushing’s syndrome presenting with pathological fractures probably present for 8 years before diagnosis.

A 33 year old nurse first sustained spontaneous stress fractures of her metatarsals in 1994, with repeated fractures occurring up to 2002. In 2001 she developed hypertension, acute lumbar back pain and gained weight.

In 2002 she was admitted to hospital with chest/back pain. Lumbar spine X-ray showed new fracture of L3,old fractures of L4/5,with fractured ribs on CXR. Isotope bone scan revealed multiple hot spots. MRI showed collapse of T8 with features consistent with malignant disease. The primary malignancy was sought and a left-sided 1.5 centimetre thyroid nodule detected.

Suspicious cytology prompted thyroid lobectomy revealing follicular variant of papillary carcinoma. T8 biopsy revealed chronic infection with Propionobacteria rather than metastatic carcinoma. Despite antibiotic therapy further spontaneous vertebral fractures developed. Bone densitometry revealed Z scores of minus 2.4 at L2-4, minus 2.5 and 2.9 at the hips.

Referral to our centre prompted investigations for Cushing’s syndrome. Serum potassium was 4.1 millimols per litre, androgens, calcitonin and urinary catecholamines all normal. TSH was suppressed by T4 therapy. Urinary free cortisol values were raised,(563-959 nanomols per 24hours) with loss of diurnal rhythm in cortisol secretion (9am 429-586,midnight 397-431 nanomols per litre)and no suppression on low or high dose dexamethasone. Abdominal CT showed a 3.5 centimetre adrenal mass. These findings were consistent with adrenal dependent Cushing’s syndrome. Risedronate and metyrapone were commenced before adrenalectomy, completion thyroidectomy and ablative radioiodine.
Comment: Cushing’s syndrome may present with spontaneous fractures in both axial and appendicular skeleton in the absence of marked clinical features. This case demonstrates the importance of thorough investigation of unexplained fractures.

LM Albon, JD Rippin & JA Franklyn

From http://www.endocrine-abstracts.org/ea/0005/ea0005p26.htm

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Interview May 13 with Michelle B (MichelleB), Cyclic Cushing’s Patient

Posted on May 13, 2015 by MaryO

Hello all, I’m Michelle mother of 3 beautiful children, I work part-time, 33yrs young, non-smoker, non-drinker, overall health is good for the most part…..Where do I even begin.

I just recently received the diagnosis of cyclic Cushing’s. I’m not really sure how long I have actually had Cushing’s because I have had a diagnosis of PCOS since I was 17 yrs. old ( I’m now the ripe young age of 33). However looking back through labs with my endocrinologist who I see every 6 months, my ACTH levels have been elevated for a bit over 1 yr. It was not until recently January of 2015- things were going terribly wrong.

Starting in January I started to feel genuinely unwell, on a regular basis. I cant really explain all my symptoms there were so many different sensations and feelings that were seemingly different daily. However the red flag was I was having blood pressure spikes from really high, to very low back to back. I never had any blood pressure issues so this was a concern that led me to see a cardiologist. Upon tons of testing the cardio MD felt that something was telling my otherwise very healthy heart to do this and I should see a endocrinologist. (thank goodness for him) I contacted my endo and let him know…. the testing began.

I did every test: the midnightcortisol saliva test, dex suppression, 24 hr urine test, CRH stimulation testing. And I did them more than once. Each time it was a different response either, inconclusive, normal high, or high. I was then referred to the head of the Cleveland clinics pituitary department Dr. Kennedy. He said he is having a hard time believing when he looks at me that its Cushing’s. However all my labs say it is. I will say I do fit the mold of PCOS to a tee- which symptoms of that do coincide with Cushing’s but he still said we have to be sure its Cushing’s. To add to the mix I did have a normal MRI as well.

Dr. Kennedy started me on a 2 week midnight cortisol saliva test- Upon completion we noted levels of cortisol all over the place, some Normal, normal on high range, high, and really high. He confirmed with all the other tests this is Cushing’s. Now we are trying to figure out what is next…. and where is this damn little tumor at. he feels that it is most likely in the pituitary from my test results, but we still are not ruling out else where. He is thinking that the next step would be exploratory neurosurgery or the IPSS. I’m not sure what to think of all this, except I want to hope for the best like everyone- and just be cured!!

On a side note during all of this I also had episodes of severe pain in my chest and nausea. I went to see a GI who did an upper endo scope. They found I had eosinpphilic esophagitis. I also have never had any GI problems until now; and they came on suddenly. Im also having pain in my pancreas area- not sure if any of the two are related at all to Cushing’s. But once again I was fine until recently with all these issues at once it seems.

wish me luck on further testing, treatment, and ultimately a CURE!!

interview

Michelle was our guest in an interview on BlogTalk Radio  Wednesday, May 13, 2015.

The archived interview is available now through iTunes Podcasts (Cushie Chats) or BlogTalkRadio. There are currently 83 other past interviews for your listening pleasure!

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Day Twenty, Cushing’s Awareness Challenge 2015

Posted on April 20, 2015 by MaryO

And today, we talk about pink jeeps and ziplines…

How in the world did we get here in a Cushing’s Challenge?  I’m sliding these in because earlier I linked (possibly!) my growth hormone use as a cause of my cancer – and I took the GH due to Cushing’s issues.  Clear?  LOL

 

I had found out that I had my kidney cancer on Friday, April 28, 2006 and my surgery on May 9, 2006.  I was supposed to go on a Cushie Cruise to Bermuda on May 14, 2006.  My surgeon said that there was no way I could go on that cruise and I could not postpone my surgery until after that cruise.

 

I got out of the hospital on the day that they left for the cruise and realized that I wouldn’t have been much (ANY!) fun and I wouldn’t have had any.

An especially amusing thread from that cruise is The Adventures of Penelopee Cruise.  Someone had brought a UFC jug and  decorated her and had her pose around the ship.  The beginning text reads:

Penelopee had a lovely time on Explorer of the Seas which was a five day cruise to Bermuda. She needed something to cheer her up since her brother, Tom, went off the deep end, but that’s another story!

Penelopee wanted to take in all of the sights and sounds of this lovely vessel. Every day she needed to do at least one special thing. Being a Cushie, she didn’t have enough spoons to do too much every day.

On the first day, she went sunning on the Libido deck……she didn’t last too long, only about 10 minutes. Goodness, look at her color! Do you think maybe her ACTH is too high?

Although I missed this trip, I was feeling well enough to go to Sedona, Arizona in August, 2006.  I convinced everyone that I was well enough to go off-road in a pink jeep,  DH wanted to report me to my surgeon but I survived without to much pain and posed for the header image.

In 2009, I figured I have “extra years” since I survived the cancer and I wanted to do something kinda scary, yet fun. So, somehow, I decided on ziplining. Tom wouldn’t go with me but Michael would so I set this up almost as soon as we booked a Caribbean cruise to replace the Cushie Cruise to Bermuda.

Each person had a harness around their legs with attached pulleys and carabiners. Women had them on their chests as well. In addition, we had leather construction gloves and hard hats.

We climbed to the top of the first platform and were given brief instructions and off we went. Because of the heavy gloves, I couldn’t get any pictures. I had thought that they would take some of us on the hardest line to sell to us later but they didn’t. They also didn’t have cave pictures or T-Shirts. What a missed opportunity!

This was so cool, so much fun. I thought I might be afraid at first but I wasn’t. I just followed instructions and went.

Sometimes they told us to break. We did that with the right hand, which was always on the upper cable.

After the second line, I must have braked too soon because I stopped before I got to the platform. Michael was headed toward me. The guide on the end of the platform wanted me to do some hand over hand maneuver but I couldn’t figure out what he was saying so he came and got me by wrapping his legs around me and pulling me to the platform.

After that, no more problems with breaking!

The next platform was very high – over 70 feet in the air – and the climb up was difficult. It was very hot and the rocks were very uneven. I don’t know that I would have gotten to the next platform if Michael hadn’t cheered me on all the way.

We zipped down the next six lines up to 250-feet between platforms and 85-feet high in the trees, at canopy level. It seemed like it was all over too soon.

But, I did it! No fear, just fun.

Enough of adventures – fun ones like these, and scary ones like transsphenoidal surgery and radical nephrectomy!

 

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Does a normal urine free cortisol result rule out Cushing’s syndrome?

Posted on March 7, 2015 by MaryO

ENDO_2015

 

March 07, 2015

SAT 379-412-Cushing’s Syndrome

Does a normal urine free cortisol result rule out Cushing’s syndrome?

ST Sharma, LK Nieman

Summary: Researchers conducted this study to assess the diagnostic accuarcy of urine free cortisol (UFC) and 24-hour urine 17-hydroxycorticosteroids (170HCS) in patients with Cushing’s syndrome, concluding that in patients with mild CS, UFC can be falsely normal or only minimally elevated. Further, they found that to help in making a diagnosis and prevent treatment delays, clinicians may consider incorporating multiple collections and use of complimentary screening tests including 24-hour urine 17OHCS and late night salivary cortisol (LNSC) testing.

Methods:

  • For this retrospective study, researchers included all CS patients evaluated at the National Institutes of Health (NIH) from 2009 to 2014.
  • The screening tests used for CS included UFC, 17OHCS, midnight serum cortisol and low dose (1 mg overnight or 2-day 2 mg/day) dexamethasone suppression test (DST).
  • They defined abnormal as values above reference range for UFC, 17OHCS and LNSC, a midnight serum cortisol ≥7.5 mcg/dL, and post-dexamethasone cortisol values ≥1.8 mcg/dL.
  • Hourly 24-hour sampling for cortisol was performed in a few cases with a mild clinical phenotype and equivocal test results.
  • Researchers measured UFC using liquid chromatography/tandem mass spectrometry (LC-MS/MS), and 17OHCS was measured using colorimetric methodology with Porter-Silber reaction (reported as mg/g of creatinine).
  • For this study, they used the mean of the first two UFC and 17OHCS values (appropriate collection by urine volume and creatinine) obtained within 30 days of initial NIH presentation.

Results:

  • In all, 72 patients were diagnosed with CS (aged 18-77 years, 51 females), 51 of whom had CD, 10 had ectopic CS, and 2 had an adrenal source of Cushing’s based on pathology.
  • Biochemical tests such as inferior petrosal sinus sampling (IPSS) suggested ectopic CS, but no tumor was found (occult) in 6 patients.
  • In 2 patients with failed transsphenoidal surgery, IPSS was indicative of a pituitary source, and one patient did not complete evaluation for ACTH-dependent CS.
  • UFC results were available in all patients, 17OHCS in 70, LNSC in 21, midnight serum cortisol in 68, and DST results in 37 patients.
  • UFC was falsely normal in 6 patients and only minimally elevated (<2 x ULN) in 13 patients (normal renal function, no history of cyclicity, all had CD); of these 19 patients, 24-hour 17OHCS was abnormal in all, LNSC was abnormal in 12, midnight serum cortisol was abnormal in 18, and DST was abnormal in 12 patients.
  • Hourly 24-hour sampling for cortisol performed in 3 of these patients revealed abnormal nadir (>7.5 mcg/dL) and mean daily serum cortisol (>9 mcg/dL) levels.

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ5BA369FDE9DE4CED82CB6A7CD5BFD1BE/42581/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-ENDO2015&nonus=0

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