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Phase I Trial of Endoxifen Gel Versus Placebo in Women Undergoing Breast Surgery

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ClinicalTrials.gov Identifier: NCT03317405
Recruitment Status : Suspended (Schedule Interim Monitoring)
First Posted : October 23, 2017
Last Update Posted : February 24, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized phase I trial studies the side effects and best dose of Z-endoxifen hydrochloride in treating participants who are undergoing breast surgery. Z-endoxifen hydrochloride may treat or reduce the risk of breast cancer.

Condition or disease Intervention/treatment Phase
Ductal Breast Carcinoma In Situ Lobular Breast Carcinoma In Situ Stage 0 Breast Cancer AJCC v6 and v7 Stage I Breast Cancer AJCC v7 Stage IA Breast Cancer AJCC v7 Stage IB Breast Cancer AJCC v7 Stage II Breast Cancer AJCC v6 and v7 Stage IIA Breast Cancer AJCC v6 and v7 Stage IIB Breast Cancer AJCC v6 and v7 Stage III Breast Cancer AJCC v7 Stage IIIA Breast Cancer AJCC v7 Stage IIIB Breast Cancer AJCC v7 Stage IIIC Breast Cancer AJCC v7 Other: Placebo Administration Other: Questionnaire Administration Drug: Z-Endoxifen Hydrochloride Phase 1

Detailed Description:

PRIMARY OBJECTIVE:

I. To establish the dermal tolerability and safety of Z-endoxifen hydrochloride (endoxifen) (ENX) gel administered topically to both breasts at two doses: 10 mg daily (5 mg per breast) and 20 mg daily (10 mg per breast) in comparison to vehicle placebo gel, using objective assessments based on Common Terminology Criteria for Adverse Events (CTCAE) criteria.

SECONDARY OBJECTIVES:

I. To measure the breast tissue concentrations of (E) and (Z) isomers of N-desmethyl-4-hydroxytamoxifen (ENX) and 4-hydroxytamoxifen (4-OHT) at each dose (10 mg per day and 20 mg per day).

II. To measure the plasma concentrations of (E) and (Z) isomers ENX and 4-OHT at each dose (10 mg per day and 20 mg per day).

III. To measure plasma hormone levels for steroid hormones (estradiol, progesterone, dehydroepiandrostenedione [DHEA], androstenedione, testosterone) in comparison to vehicle placebo gel.

IV. To measure serum estrogenic response to topical ENX gel therapy in comparison to vehicle placebo gel (sex hormone binding globulin and insulin-like growth factor [IGF] pathway proteins).

V. To assess changes in coagulation parameters (factor VIII, factor IX, vWF, protein S) in response to ENX gel therapy in comparison to vehicle placebo gel.

VI. Using pre- and post-therapy tissue samples, to explore the potential therapeutic effects of the two doses of ENX gel in comparison to vehicle placebo gel: a) by IHC, Ki67 labelling (for cell proliferation), estrogen receptor (ER), progesterone receptor (PR) expression (for estrogen blockade); b) by expression of a panel of genes reported to change with ENX exposure (using nanostring assays).

VII. Bank germline deoxyribonucleic acid (DNA) for future pooled analyses of polymorphisms in tamoxifen metabolizing enzymes in comparison to vehicle placebo gel (optional).

VIII. To assess symptoms related to use of endoxifen gel in comparison to vehicle placebo gel, as assessed by the Breast Cancer Prevention Trial (BCPT) Eight Symptom Scale (BESS) questionnaire.

OUTLINE: Participants are randomized into 1 of 2 cohorts.

COHORT I: Participants apply Z-endoxifen hydrochloride gel to both breast skin and keep it untouched over at least 4 hours once daily for 21-28 days before breast surgery.

COHORT II: Participants apply placebo to both breast skin and keep it untouched over at least 4 hours once daily for 21-28 days before breast surgery.

After completion of study treatment, participants are followed up at 60 days.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase I Trial of Endoxifen Gel Versus Placebo Gel in Women Undergoing Breast Surgery
Actual Study Start Date : October 31, 2018
Estimated Primary Completion Date : September 1, 2020
Estimated Study Completion Date : September 1, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort I (Z-endoxifen hydrochloride)
Participants apply Z-endoxifen hydrochloride gel to both breast skin and keep it untouched over at least 4 hours once daily for 21-28 days before breast surgery.
Other: Questionnaire Administration
Ancillary studies

Drug: Z-Endoxifen Hydrochloride
Apply to the skin
Other Name: Z-Endoxifen HCl

Placebo Comparator: Cohort II (placebo)
Participants apply placebo to both breast skin and keep it untouched over at least 4 hours once daily for 21-28 days before breast surgery.
Other: Placebo Administration
Apply to the skin

Other: Questionnaire Administration
Ancillary studies




Primary Outcome Measures :
  1. Incidence of skin toxicity [ Time Frame: Up to 60 days ]
    Will be assessed by Common Terminology Criteria for Adverse Events version 4.


Secondary Outcome Measures :
  1. Drug concentration [ Time Frame: Up to 60 days ]
    Will be assessed in breast tissue and blood.

  2. Breast tissue biomarkers [ Time Frame: Up to 60 days ]
    Ki67 labeling index, progesterone receptor and estrogen receptor expression, and expression of a panel of genes reported to change with Z-endoxifen hydrochloride (ENX) exposure, will be measured in breast tissue samples obtained at diagnostic core needle biopsy performed prior to study entry, and compared to the measurements in post-therapy surgical samples.

  3. Coagulation proteins [ Time Frame: Up to 60 days ]
    Will assess coagulation proteins measures of systemic estrogenicity in plasma.

  4. Drug metabolism genes [ Time Frame: Up to 60 days ]
    Will study drug metabolism genes in germline deoxyribonucleic acid (DNA) from peripheral blood (buffy coat) for DNA/ribonucleic acid isolation.

  5. Plasma hormone levels for steroid hormones [ Time Frame: Up to 60 days ]
    Will be measured by liquid chromatography/mass spectrometer (MS)/MS.

  6. Analysis of symptoms as reported in the Behavioral and Emotional Screening System questionnaire [ Time Frame: Up to 60 days ]
    Average, median and range of scores for each noted group will be provided as descriptive measures of location and variance.

  7. Biobank germline DNA for future pooled analyses of polymorphisms in tamoxifen metabolizing enzymes [ Time Frame: Up to 60 days ]
    Statistical analysis will be used as needed.

  8. Tissue biologic response [ Time Frame: UP to 60 days ]
    Will be compared as pre- and post-therapy values, to explore the potential therapeutic effects of the two doses of ENX. A nonparametric test of the central parameter being zero will be performed.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Women scheduled for unilateral or bilateral mastectomy for breast cancer therapy, pathology confirmed stage 0-III (including ductal carcinoma in situ), or prophylaxis (BRCA1/2 mutation carriers, women with strong family history or lobular carcinoma in situ or other conditions where prophylactic mastectomy has been elected)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Total bilirubin < 1.5 x upper limit of normal (ULN) (in women with prior documented bilirubin elevations consistent with Gilbert's syndrome, total bilirubin up to 3 x ULN will be allowed)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) < 2.5 x ULN
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x ULN
  • Creatinine < 2 x ULN
  • Alkaline phosphatase < 2.5 x ULN
  • Blood urea nitrogen < 2 x ULN
  • Ability to understand and the willingness to sign a written informed consent document which includes a requirement to apply study agent to sensitive body parts daily
  • Willingness and ability to schedule mastectomy 21-28 days following start of study agent; women with breast implants may participate
  • Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e. tanning beds) for the duration of study agent dosing
  • Negative urine or serum pregnancy test result, for participants of child bearing potential; female of child-bearing potential is any woman (regardless of sexual orientation, whether she has undergone a tubal ligation, or remains celibate by choice) who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; AND has had a menstrual period at any time in the preceding 12 consecutive months)
  • The effects of topical ENX gel on the developing human fetus are unknown; for this reason, women of child-bearing potential and their male partners must agree to use effective forms of birth control (abstinence is not an allowed method) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately

Exclusion Criteria:

  • The presence of gross skin invasion/ulceration by the breast cancer, or inflammatory changes with skin edema AND erythema; Note: Paget's disease is permitted
  • Women receiving a "nipple delay" procedure prior to mastectomy
  • Women with skin diseases (psoriasis, eczema)
  • A history of thromboembolic disorder
  • Endometrial intraepithelial neoplasia (also known as atypical hyperplasia) or a high risk of uterine cancer, defined here as known carriers of Lynch syndrome mutations (MLH1, MSH2, MSH6, PMS2)
  • Participants may not have received any other investigational agents in the previous 3 months
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to tamoxifen
  • Taken tamoxifen or other selective estrogen/progesterone receptor modulators (SERMs/SPRMs) within two years prior to entering study or been required to discontinue SERM therapy due to thromboembolic or uterine toxicity
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • History of prior breast cancer-specific therapy within the previous 2 years (chemotherapy, radiation, anti-HER2 agents, endocrine agents, everolimus, CDK4-6 inhibitors); previous unilateral radiation of the contralateral side in women scheduled for mastectomy is allowed; study gel will be applied to both breasts
  • History of prior mastectomy
  • Pregnant or breastfeeding
  • Patients receiving neoadjuvant chemotherapy with curative intent
  • Men are excluded from this study since breast cancer is men is rare and there are no data regarding skin penetration of topical breast cancer prevention agents through male chest wall skin (which is thicker and harrier than female chest wall skin)
  • Current users of other topical medications on the breast skin must be willing and able to discontinue use for the duration of participation; body lotion and other non-medicinal topical compounds may be applied > 4 hours after study gel application

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03317405


Locations
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United States, California
Cedars Sinai Medical Center
Los Angeles, California, United States, 90048
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Seema A Khan Northwestern University

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03317405    
Other Study ID Numbers: NCI-2017-01921
NCI-2017-01921 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N01-CN-2012-00035
NCI2017-09-01 ( Other Identifier: Northwestern University )
NWU2017-09-01 ( Other Identifier: DCP )
N01CN00035 ( U.S. NIH Grant/Contract )
P30CA060553 ( U.S. NIH Grant/Contract )
First Posted: October 23, 2017    Key Record Dates
Last Update Posted: February 24, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Carcinoma in Situ
Carcinoma, Ductal, Breast
Breast Carcinoma In Situ
Carcinoma, Intraductal, Noninfiltrating
Carcinoma, Lobular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Carcinoma, Ductal
Adenocarcinoma
Neoplasms, Ductal, Lobular, and Medullary
Tamoxifen
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents