Dose Escalation Study in Female Subjects With Breast Cancer Receiving Aromatase Inhibitor or Tamoxifen

Study Overview
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Brief Summary
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Open-label, two dose study of Q-122, over a 4 week treatment period to explore the effects of Q-122 in a population of women with a history of breast cancer taking an aromatase inhibitor or tamoxifen.

Detailed Description
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Vasomotor symptoms are significant in postmenopausal women with the most effective medications for relief being hormonal preparations. Non-hormonal medications have demonstrated efficacy but at a far lower level than estrogen replacement therapy. For women with a history of breast cancer hormone replacement therapy is problematic especially if their therapeutic regime involves an aromatase inhibitor. Therefore, this study will explore the effect of Q-122 in a population of women with a history of breast cancer taking an aromatase inhibitor or tamoxifen. The study is an open-label, two dose study (Group 1: 100 mg once daily and Group 2: 200 mg once daily) of Q-122, over a 4 week treatment period. As eligible subjects are enrolled, they will be assigned to Group 1 until Group 1 is fully enrolled. Dose escalation to the 200 mg level will only occur following a review of the safety experience of at least 6 subjects treated with 100 mg Q-122 once daily for at least 2 weeks. Once Group 1 is fully enrolled, eligible subjects will be enrolled into Group 2. A two-week screening phase will be used to establish a stable baseline of vasomotor symptoms and to establish study eligibility. Qualified subjects will be treated with Q-122 for four weeks either at 100 mg/day dose or the 200 mg/day dose, during which time they will be evaluated for safety, tolerability, and pharmacokinetics of Q-122 and tamoxifen levels; subjects will continue to record their hot flashes in identical fashion to the screening period. Following the 28 day treatment, period subjects who complete the study will continue to record their hot flashes for a two week follow up period.

Official Title
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A Two Dose, Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Effect on Vasomotor Symptoms of Q-122 in Female Subjects With Breast Cancer and Receiving an Aromatase Inhibitor or Tamoxifen

Conditions
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Vasomotor Symptoms (VMS)

Intervention / Treatment
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* Drug: oral capsule of Q-122


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be a female of any race between the ages of 30-70 years. History of breast cancer and presently taking an aromatase inhibitor or tamoxifen. Naturally menopausal: ≥ 12 months spontaneous amenorrhea or > 6 but < 12 months amenorrhea with a serum follicle stimulating hormone (FSH) level of > 40 mIU/mL (Milli-international Units Per Milliliter). Surgically menopausal with an FSH level > 40 mIU/mL. Have a minimum of 7 moderate to severe hot flushes/day or 50 moderate to severe hot flushes per week, as verified for both weeks during the 14-day Screening Phase, prior to enrollment into the treatment phase of the study. Able to read, understand and complete the required subject diary. Willing and able to complete the daily subject diary, attend all study visits, and participate in all study procedures, including PK blood draws. Exclusion Criteria: Childbearing potential, including pregnancy, or lactation. Undiagnosed abnormal genital bleeding. Significant day-to-day variability in hot flushes. Participation in another clinical trial within 30 days prior to screening or during the study. Legal incapacity or limited legal capacity. Chronic renal (serum creatinine > 2.0 mg/dL) or hepatic disease [SGPT (ALT) or SGOT (AST) > 2X normal limits]. Gastrointestinal, liver, kidney or other conditions which could interfere with the absorption, distribution, metabolism or excretion of Q-122. Untreated overt hyperthyroidism. Use of thyroid medication of less than 12 weeks on a stable dose. Any clinically important systemic disease in the judgement of the investigator. Inability to complete all study visits and study assessments for scheduling or other reasons. Any other reason which in the investigator's opinion makes the subject unsuitable for a clinical trial. Abnormal laboratory findings including: Hematocrit < 30% or hemoglobin < 9.5 gm/dL Fasting blood sugar > 140 mg/dL Fasting serum triglycerides > 300 mg/dL Fasting SGOT, SGPT, GGT, or bilirubin greater than twice the upper limit of normal (a subject will not be excluded if a second measurement is less than twice the upper limit of normal) Creatinine > 2.0 mg/dL

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: open-label, two dose study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 100 mg Q-122<br>10 patients treated with Q-122, 100 mg. Dosage was 100 mg Q-122 administered orally as two 50 mg capsules once daily for 28 days. | Drug: oral capsule of Q-122<br> <br> |
| Experimental: 200 mg Q-122<br>11 patients treated with Q-122, 200 mg. Dosage was 200 mg Q-122 administered orally as four 50 mg capsules once daily for 28 days. | Drug: oral capsule of Q-122<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event (AE) Reporting of Q-122 | Number of participants with indicated AE receiving Q-122 | 4 weeks | 
| Serious Adverse Event (SAE) Reporting of Q-122 | Number of participants with indicated SAE receiving Q-122 | 4 weeks | 
| Change in Frequency of Moderate to Severe Vasomotor Symptoms. | Mean change in frequency of moderate to severe vasomotor symptoms. Daily patient (paper) diaries will be used as the primary efficacy collection tool. Change from baseline represents the mean change from the daily average frequency calculated at baseline to the daily average frequency calculated for the last week the subject was on drug. The hot flash severity categories are defined clinically as follow: mild, sensation of heat without perspiration; moderate, sensation of heat with perspiration, but subject is able to continue with activity; and severe. sensation of heat with sweating, sufficiently severe to result in discontinuation of activity. | Baseline to 4 weeks | 
| Percent Change in Frequency of Moderate to Severe Vasomotor Symptoms. | Percent reduction in frequency of moderate to severe vasomotor symptoms. Daily patient (paper) diaries will be used as the primary efficacy collection tool. The hot flash severity categories are defined clinically as follows: mild, sensation of heat without perspiration; moderate, sensation of heat with perspiration, but subject is able to continue with activity; and severe, sensation of heat with sweating, sufficiently severe to result in discontinuation of activity. | Baseline to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hot Flash Severity Score | For moderate-to-severe (mod/sev) hot flashes (HF), a score will be calculated by multiplying the number of moderate-to-severe HFs by their severity to determine the HF (mod/sev) index score, using the following formula: HFSSmod/sev = (number of moderate hot flashes/day × 2) + (number of severe hot flashes/day x 3). The Average Daily HFSSmod/sev for each week will be calculated by dividing the total of daily HFSSmod/sev by the number of days observations will be recorded in that week. The change in score is of clinical significance, with a lower score representing less moderate to severe hot flashes and a higher score representing a greater number of moderate to severe hot flashes. | Baseline to 4 weeks | 
| Percent Change in Hot Flash Severity Score | For moderate-to-severe (mod/sev) hot flashes (HF), a score will be calculated by multiplying the number of moderate-to-severe HFs by their severity to determine the HF (mod/sev) index score, using the following formula: HFSSmod/sev = (number of moderate hot flashes/day × 2) + (number of severe hot flashes/day x 3). The Average Daily HFSSmod/sev for each week will be calculated by dividing the total of daily HFSSmod/sev by the number of days observations will be recorded in that week. | Baseline to 4 weeks | 
| Symptoms Associated With Postmenopausal Status | Greene Climacteric Scale: A comprehensive assessment divided into psychological, physical and vasomotor areas. The scale includes 21 symptoms, subject will score the severity of each symptom with the following score system: 0 = not at all; 1 = a little; 2 = quite a bit; and 3 = extremely. The results represent the total combined score, which can range from 0 to 63. A lower score represents a better outcome. | Baseline and 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vasomotor Symptoms, Breast Cancer, Hot Flashes, Tamoxifen, Aromatase Inhibitors, Estrogen Antagonists, Hormone Antagonists, Hormones, Hormone Substitutes, Hormone Antagonists, Physiological Effects of Drugs, Antineoplastic Agents, Hormonal Antineoplastic, Selective Estrogen Receptor Modulators, Estrogen Receptor Modulators, Bone Density Conservation Agents, Steroid Synthesis Inhibitors, Enzyme Inhibitors, Molecular Mechanisms of Pharmacological Action