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Trial registered on ANZCTR


Registration number
ACTRN12617000477325
Ethics application status
Approved
Date submitted
8/03/2017
Date registered
3/04/2017
Date last updated
30/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase I, placebo controlled, dose escalation safety and pharmacokinetic study of (Z)-Endoxifen in healthy female volunteers.
Scientific title
A phase I, placebo controlled, dose escalation safety and pharmacokinetic study of (Z)-Endoxifen in healthy female volunteers.
Secondary ID [1] 291357 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Estrogen Receptor Positive Breast Cancer 302390 0
Condition category
Condition code
Cancer 301967 301967 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There are two parts for this study. Healthy female volunteers for both these parts will be screened within 28 days prior to commencement of dosing.

Part A (Topical Application) consists of 3 cohorts, each cohort consisting of 8 participants with 6 participants receiving (Z)-Endoxifen topical and 2 participants receiving placebo topical. Three dose levels of topically applied (Z)-Endoxifen (2mg, 6mg, and 10 mg) will be investigated in the 3 cohorts. Participants will be admitted in the clinical facility on Day-1 and will receive the IMP in pre-sealed sachets for topical application on Day 1. They will be discharged on Day 2 and supplied with study drug sachets and asked to self-administer daily one sachet to each of the breast for 28 days.
Participants will return to the clinic weekly for PK sampling and assessment, as well as on Days 4, 31, 33 and 35.

Part B (Oral Administration) consists of 3 cohorts, each cohort consisting of 8 participants with 6 participants receiving (Z)-Endoxifen capsule and 2 participants receiving placebo capsule. Three dose levels of orally administered (Z)-Endoxifen (1 mg, 2 mg, and 4 mg) will be investigated in 3 cohorts. Two participants (Sentinels) will be dosed 24 hours prior to the remaining participants. One sentinel will be dosed with (Z)-Endoxifen and the other with placebo. The remaining six participants will only be dosed if no safety concerns are identified in the sentinel participants. There will be no sentinels in the other two cohorts.
Participants will be admitted in the clinical facility on Day-1 and will receive the oral capsules on Day 1. PK blood draws will be performed, prior to discharge on Day 2. Additional PK sampling and safety assessments will be performed on Days 4 and 6.
On Day 8 participants will commence daily administration of (Z)-Endoxifen capsules or placebo capsules for 14 consecutive days (Days 8-21) and will be supplied with study drug capsules and asked to self administer daily. Participants will visit the clinical facility on Days 11, 14 and 17, prior to dose administration, for PK blood draws and safety assessments. On Day 21, participants will return to the clinical facility prior to dose administration to allow for the collection of PK blood draws and safety assessments, and discharged the following day. Participants will return for PK blood draws and safety assessments on study Days 24, 26, and 28.

Intervention code [1] 297646 0
Treatment: Drugs
Comparator / control treatment
For Part A it is placebo topical while for Part B it is placebo capsules containing methylcellulose (1 mg/ 4mg).
Control group
Placebo

Outcomes
Primary outcome [1] 301379 0
To assess the safety and tolerability of (Z)-Endoxifen when administered as a topical application to the breast or orally as a capsule to healthy female volunteers and will include recording the incidence and severity of adverse events, vital sign parameters, physical examination findings, electrocardiogram parameters and clinical laboratory parameters (serum chemistry, hematology, coagulation, urinalysis).
The most common AEs from taking (Z)-Endoxifen include hot flushes, headaches, coagulopathies, insomnia etc.
Timepoint [1] 301379 0
The safety assessments mentioned above are composite primary outcome and will be done at each of the visits i.e. Part A - weekly for a month and on days 4, 31, 33 and 35 while for Part B - on days 4, 6, 8, 11, 14, 17, 21, 24, 26 and 28.
The blood pressure and pulse will be assessed by pulse oximetry while respiratory rate, physical examination will be assessed clinically. Temperature will be assessed by using a tympanic thermometer while an ECG will be recorded by an instrument which involves the placement of electrodes on the chest wall.
Blood will be collected for hematology, coagulation and clinical chemistry lab assessments while urine will be collected for urinalysis.
Secondary outcome [1] 332497 0
To assess the pharmacokinetics of multiple doses of (Z)-Endoxifen when administered as a topical application to the breast or orally as a capsule to healthy female volunteers.
Pharmacokinetic parameters which will be assessed include Cmax, Tmax, AUC0-24h, t1/2
Timepoint [1] 332497 0
Blood sampling for pharmacokinetic analysis for Part A will be performed at Day 1, Day 4, Day 7, Day 14, Day 21, Day 28, Day 29, Day 31, Day 33 and Day 35.
Blood sampling for pharmacokinetic analysis for Part B will be performed at Day 1, Day 2, Day 4, Day 6, Day 8, Day 11, Day 14, Day 17, Day 21, Day 22, Day 24, Day 26 and Day 28.
Secondary outcome [2] 332498 0
To assess the side effects associated with (Z)-Endoxifen treatment using the modified FACT-ES questionnaire.
Timepoint [2] 332498 0
Part A will be performed on Day 1, Day 7, Day 14, Day 21, Day 28 and Day 35.
Part B will be performed on Day 1, Day 14, Day 21 and Day 28.

Eligibility
Key inclusion criteria
1. Body Mass Index (BMI) within the range of 18 to 30 kg/m2 inclusive at screening;
2. Absence of significant diseases based on physician's discretion;
3. Medically healthy without clinically significant abnormalities at the screening visit or Day -1, including:
a. Electrocardiogram (ECG),
b. Physical examination, vital signs including temperature, heart rate, respiratory rate and blood pressure;
4. Screening laboratory tests that are deemed to be non-clinically significant by the investigator;
5. Negative cotinine, drug and alcohol tests at screening and check in;
6. Ability to understand the nature and objectives of the trial, including risks and adverse events; willingness to cooperate with the researcher and proceed according to all study requirements;
7. Participants of child-bearing potential (a woman is considered of child-bearing potential unless she is permanently sterilized or post-menopausal for at least 12 months with no menses and no alternative medical cause) must agree to use one of the following appropriate contraceptive methods:
a. Complete abstinence from intercourse (with a male partner) for at least 14 days prior to dosing with study drug through the End-of-Study and at least 60 days after the conclusion of study drug administration
b. If unplanned intercourse a double-barrier method, i.e., condom and diaphragm or IUD must be used (hormonal contraception is not permitted);
c. Sterilization (vasectomy) of male partner prior to commencement of the volunteer’s last normal menstrual period prior to Screening, and the male partner is the sole partner for that female volunteer;
d. If the volunteer has a same sex partner, they must be willing to abstain from penile-vaginal intercourse. If penile-vaginal intercourse is to occur, the volunteer must be willing to comply with the contraceptive requirements above.
8. Have no air travel commitments during the study and for four weeks following completion of the study treatment;
9. Have suitable venous access for blood sampling;
Minimum age
18 Years
Maximum age
65 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History or presence of a clinically significant disorder including but not limited to: cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or surgery within the past three months determined by the PI to be clinically relevant;
2. History of drug addiction, including alcohol within 1 year;
3. Have a hypersensitivity or allergy to the investigational compound/compound class being used in this study or any ingredients of this medication;
4. Treatment, within 3 months before the trial, with any drugs known to have a well established toxic potential to major organs;
5. Have participated in any other investigational study within 30 days of screening;
6. Use of any medications or over the-counter products within 7 days or 5 half-lives (whichever is longer) prior to administration of study medication (including analgesics (paracetamol up to and including 2 g per day is permitted), herbal products or diet aids);
7. Have received hormonal treatment (including use of hormonal contraceptives (oral contraceptive pills or implant)) within 3 months prior to commencement of study treatment;
8. Pregnancy, labour or miscarriage within 12 weeks before commencement of study treatment;
9. Have recent history or evidence of procoagulant disorder, Deep Vein Thrombosis (DVT) or pulmonary embolism;
10. Donation of blood or plasma within 30 days prior to randomization, or loss of whole blood of more than 500 mL within 30 days prior to randomization, or receipt of a blood transfusion within 1 year of study enrollment.
11. Any conditions, that according to investigator's best judgment, prevent participation in the trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 295826 0
Commercial sector/Industry
Name [1] 295826 0
Atossa Genetics, Inc.
Address [1] 295826 0
107 Spring St
Seattle, WA 98104
Country [1] 295826 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Atossa Genetics, Inc.
Address
107 Spring St
Seattle, WA 98104
Country
United States of America
Secondary sponsor category [1] 294674 0
None
Name [1] 294674 0
Address [1] 294674 0
Country [1] 294674 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297109 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 297109 0
129 Glen Osmond Road, Eastwood SA 5063
Ethics committee country [1] 297109 0
Date submitted for ethics approval [1] 297109 0
22/02/2017
Approval date [1] 297109 0
23/03/2017
Ethics approval number [1] 297109 0
2017-02-127

Summary
Brief summary
This study aims to evaluate the safety and pharmacokinetic study of (Z)-Endoxifen escalated doses in healthy female volunteers.
Who is it for?
You may be eligible to join this study if you are a healthy female aged between 18 and 65 years of age.
Study details:
This is a placebo controlled, dose escalation study. The study will be conducted in two parts in a total of 6 cohorts. In Part A, each participant will receive twenty eight doses of (Z)-Endoxifen or placebo as a topical application to the breast. In Part B, participants will receive fifteen doses of (Z)-Endoxifen or placebo capsules orally. Three different dose levels of (Z)-Endoxifen will be investigated in each part of the study. In both parts, sequential cohorts will be exposed to increasing doses of (Z)-Endoxifen.
By substituting Tamoxifen treatment with Endoxifen the study will help in providing an improved approach towards treating patients with breast cancer because it bypasses the CYP2D6 enzyme that is required for metabolic activation of Tamoxifen.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 73006 0
Dr Jason Lickliter
Address 73006 0
Nucleus Network Pty Ltd
The Burnet Tower, 5th Floor
89 Commercial Road
Melbourne
Victoria, 3004
Country 73006 0
Australia
Phone 73006 0
+61 407 527 307
Fax 73006 0
Email 73006 0
J.Lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 73007 0
Ms Janet R Rea MSPH
Address 73007 0
C/O Atossa Genetics Inc.
107 Spring St
Seattle, WA 98104
Country 73007 0
United States of America
Phone 73007 0
+1.206.799.7186
Fax 73007 0
Email 73007 0
janet.rea@atossagenetics.com
Contact person for scientific queries
Name 73008 0
Ms Janet R Rea, MSPH
Address 73008 0
C/O Atossa Genetics Inc.
107 Spring St
Seattle, WA 98104
Country 73008 0
United States of America
Phone 73008 0
+1.206.799.7186
Fax 73008 0
Email 73008 0
janet.rea@atossagenetics.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary