Endoxifen for Breast Cancer
(EVANGELINE Trial)
Recruiting in Palo Alto (17 mi)
+10 other locations
Age: 18+
Sex: Female
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Atossa Therapeutics, Inc.
Must be taking: Z-endoxifen, Goserelin
Must not be taking: Hormonal therapies
Disqualifiers: Bilateral breast cancer, Uncontrolled illness, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial is testing (Z)-endoxifen, a drug that blocks estrogen, in pre-menopausal women with a specific type of breast cancer. The study aims to see if this drug can slow down cancer growth by measuring a marker called Ki-67. Participants will take the drug daily for several months before surgery.
Do I have to stop taking my current medications for the trial?
The trial protocol does not specify if you must stop taking your current medications. However, you cannot take hormonal therapies, including birth control and hormone replacement therapy, during the study or within 1 week of registration.
What data supports the idea that Endoxifen for Breast Cancer is an effective drug?
The available research shows that goserelin, a drug similar to Endoxifen, is effective in treating early breast cancer in premenopausal women. In the ZIPP study, goserelin improved survival rates when added to standard therapy. It was also found to be as effective as chemotherapy and helped women regain ovarian function after treatment. Additionally, exemestane, another related drug, was shown to be effective in patients who did not respond to other treatments, offering an early survival advantage in trials.
12345What safety data is available for Endoxifen in breast cancer treatment?
The safety data for Endoxifen, also known as Exemestane, Zoladex, and other names, indicates that it is generally well-tolerated with mild toxicity, primarily causing menopausal symptoms. Exemestane, a third-generation aromatase inhibitor, has shown superiority over tamoxifen in both efficacy and safety in various trials. Zoladex, used in combination with tamoxifen, has not shown adverse endocrinological interactions and is used in pre- and peri-menopausal women. Overall, these treatments are considered safe with manageable side effects in the context of breast cancer therapy.
56789Is the drug Exemestane, Goserelin, and Z-endoxifen a promising treatment for breast cancer?
Yes, the drug combination of Exemestane, Goserelin, and Z-endoxifen shows promise for treating breast cancer. Z-endoxifen, a powerful form of tamoxifen, has shown strong antitumor activity, especially in cases where other treatments have failed. Goserelin helps lower estrogen levels, which can be beneficial in hormone-sensitive breast cancer. Together, these drugs offer a promising approach to treating breast cancer.
210111213Eligibility Criteria
This trial is for premenopausal women over 18 with early-stage ER+/HER2- breast cancer. Participants must not be pregnant, lactating, or planning pregnancy within a year and agree to non-hormonal contraception. They should have an ECOG Performance Status of 0 to 2 and no prior breast cancer treatment or other active cancers in the last two years.Inclusion Criteria
My breast cancer is low or intermediate grade.
My breast cancer is ER positive and HER2 negative, meeting specific test scores.
My breast cancer is at stage IIA or IIB.
+6 more
Exclusion Criteria
I do not have serious ongoing health issues that are not under control.
I have not had breast cancer or any other cancer in the last 2 years.
Participation in another investigational clinical trial ≤ 6 months of registration
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Pharmacokinetic (PK) Part
Participants take (Z)-endoxifen capsules daily to determine the best dose by measuring drug levels in the blood
4 weeks
1 visit (in-person) for blood sampling
Treatment Part 2a
Participants with high Ki-67 levels receive either (Z)-endoxifen with goserelin or exemestane with goserelin
24 weeks
Monthly visits for goserelin injections
Treatment Part 2b
Participants with low Ki-67 levels take (Z)-endoxifen alone
24 weeks
Monthly monitoring visits
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
1 visit (in-person) for follow-up assessments
Participant Groups
(Z)-endoxifen, a drug that blocks estrogen from binding to cancer cells, is being tested against standard treatments exemestane and goserelin. The study has two parts: determining the proper dose of (Z)-endoxifen and comparing its effectiveness with standard treatments by measuring changes in a tumor marker after about four weeks.
7Treatment groups
Experimental Treatment
Active Control
Group I: Treatment Cohort Part 2b Single ArmExperimental Treatment1 Intervention
Participants with Ki-67 value of ≤ 10% at Pre-registration visit:
(Z)-endoxifen 40 mg capsules orally once daily for 4 weeks.
If Ki-67 ≤ 10% at Week 4, participant will be offered option to continue on this treatment for up to 6 cycles/Week 24. Each cycle is 28 days. And then go on to surgery.
If Ki-67 \> 10% at Week 4, participant will complete early termination visit and go on to surgery.
Group II: Treatment Cohort Part 2a Arm 1 Modified RegimenExperimental Treatment2 Interventions
Exemestane 25 mg orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days.
After 4 weeks of modified regimen, Ki-67 value will be collected by breast biopsy or surgery. Early termination assessments will follow.
Group III: Treatment Cohort Part 2a Arm 1 Initial RegimenExperimental Treatment2 Interventions
Participants with Ki-67 value of \>10% at Pre-registration visit:
(Z)-endoxifen 40mg capsules orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days. (Z)-endoxifen 40mg dose based on results of PK Cohort.
If Ki-67 ≤ 10% at Week 4, continue on this treatment for up to 6 cycles/Week 24. Each cycle is 28 days. And then go on to surgery within 3 weeks of Cycle 6 day 26.
If Ki-67 \> 10% at Week 4, participant will be offered to switch treatment to Exemestane 25 mg orally once daily + goserelin 3.6 mg by subcutaneous implant for 4 weeks and then collect Ki-67 value either by a breast biopsy or go on to surgery.
Group IV: PK Cohort 80 mg + OFSExperimental Treatment2 Interventions
(Z)-endoxifen 80 mg capsules orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days.
The PK Cohort participants may extend treatment based on Ki-67% at Week 4.
If Ki-67 ≤ 10% at Week 4, participant will be offered option to continue on this treatment for up to 6 cycles/Week 24. Each cycle is 28 days.
If Ki-67 \> 10% at Week 4, participant will be withdrawn and go on to surgery.
Group V: PK Cohort 80 mgExperimental Treatment1 Intervention
(Z)-endoxifen 80 mg capsules orally once daily for 4 weeks.
The PK Cohort participants may extend treatment based on Ki-67% at Week 4.
If Ki-67 ≤ 10% at Week 4, participant will be offered option to continue on this treatment for up to 6 cycles/Week 24. Each cycle is 28 days.
If Ki-67 \> 10% at Week 4, participant will be withdrawn and go on to surgery.
Group VI: PK CohortExperimental Treatment1 Intervention
(Z)-endoxifen capsules orally once daily for 4 weeks. Initial (Z)-endoxifen dose evaluated will be 40 mg with an option to evaluate 20 mg or 80 mg.
The PK Cohort participants may extend treatment based on Ki-67% at Week 4.
If Ki-67 ≤ 10% at Week 4, participant will be offered option to continue on this treatment for up to 6 cycles/Week 24. Each cycle is 28 days.
If Ki-67 \> 10% at Week 4, participant will be withdrawn and go on to surgery.
Group VII: Treatment Cohort Part 2a Arm 2 Initial RegimenActive Control2 Interventions
Participants with Ki-67 value of \>10% at Pre-registration visit:
Exemestane 25 mg orally once daily for 4 weeks + goserelin 3.6 mg by subcutaneous implant approximately every 28 days.
If Ki-67 ≤ 10% at Week 4, continue on this treatment for up to 6 cycles/Week 24. Each cycle is 28 days. And then go on to surgery within 3 weeks of Cycle 6 day 26.
If Ki-67 \> 10% at Week 4, participant will complete early termination assessments.
Exemestane is already approved in European Union, United States, Canada, Japan for the following indications:
🇪🇺 Approved in European Union as Aromasin for:
- Early breast cancer
- Advanced breast cancer
🇺🇸 Approved in United States as Aromasin for:
- Early breast cancer
- Advanced breast cancer
🇨🇦 Approved in Canada as Aromasin for:
- Early breast cancer
- Advanced breast cancer
🇯🇵 Approved in Japan as Aromasin for:
- Early breast cancer
- Advanced breast cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Tranquil Clinical ResearchWebster, TX
Avera Cancer InstituteSioux Falls, SD
University of ArizonaTucson, AZ
Northwestern UniversityChicago, IL
More Trial Locations
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Who Is Running the Clinical Trial?
Atossa Therapeutics, Inc.Lead Sponsor
InClinCollaborator
References
Quality of life in goserelin-treated versus cyclophosphamide + methotrexate + fluorouracil-treated premenopausal and perimenopausal patients with node-positive, early breast cancer: the Zoladex Early Breast Cancer Research Association Trialists Group. [2015]To compare quality of life (QoL) in premenopausal and perimenopausal patients with node-positive, early breast cancer treated with the endocrine agent goserelin (Zoladex; AstraZeneca Pharmaceuticals LP, Wilmington, DE) or cyclophosphamide + methotrexate + fluorouracil (CMF).
Goserelin: a review of its use in the treatment of early breast cancer in premenopausal and perimenopausal women. [2018]Goserelin (Zoladex), a gonadotropin-releasing hormone analogue, reduces plasma/serum estrogen levels in pre- or perimenopausal women (to postmenopausal levels), and is indicated in hormone receptor-positive early breast cancer in this population group. Adjuvant goserelin monotherapy has similar efficacy to adjuvant chemotherapy in pre- or perimenopausal women with early, hormone receptor-positive breast cancer. Furthermore, the addition of goserelin to adjuvant chemotherapy appeared to offer an advantage over chemotherapy alone in younger patients. Fewer patients remained amenorrheic after goserelin therapy than after chemotherapy. Complete endocrine blockade provided by the addition of tamoxifen to therapy including goserelin appears to improve outcomes. Thus, goserelin offers a valuable addition to the currently available options for treating pre- or perimenopausal women with hormone therapy-responsive early breast cancer, particularly for women wishing to regain ovarian function after treatment.
Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study. [2022]The Zoladex In Pre-menopausal Patients (ZIPP) study was designed to determine whether addition of goserelin ('Zoladex') and/or tamoxifen to adjuvant therapy (radiotherapy and/or chemotherapy), provided benefit to pre- or peri-menopausal women with operable, early breast cancer. A combined analysis of four randomised trials using a core protocol was performed. Patients (n = 2710) were randomised into a 2 x 2 factorial trial based on goserelin and tamoxifen (n = 1800) or randomised to receive goserelin or not (n = 910; some received elective tamoxifen) for 2 years. The analysis presented here compares women who did (n = 1354) or did not (n = 1356) receive goserelin. After a median follow-up of 5.5 years, goserelin provided a significant benefit for event-free survival (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.69, 0.92; P = 0.002) and overall survival (HR 0.81; 95% CI 0.67, 0.99; P = 0.038). Goserelin was well tolerated. These data show that the addition of goserelin to standard adjuvant therapy is more effective than standard therapy alone in pre-menopausal women with early breast cancer.
Zoladex in advanced breast cancer. [2018]In the treatment of 53 premenopausal patients with advanced breast cancer, the LHRH analogue, Zoladex (goserelin), produced a response rate similar to that of surgical oophorectomy. Endocrinologically, Zoladex caused castrate levels of serum oestradiol and progesterone except in a small number of patients, where intermittent, suppressed peaks of oestradiol persisted. Treatment of 34 premenopausal patients with Zoladex combined with the anti-oestrogen tamoxifen (Nolvadex) produced significantly lower levels of serum oestradiol; all patients had castrate serum oestradiol levels. It is suggested that a prospective randomised study is necessary to determine any clinical advantage from such a combination.
Exemestane: a novel aromatase inactivator for breast cancer. [2016]Exemestane is a unique inactivator of the aromatase enzyme and differs from the two approved aromatase inhibitors. It is well absorbed at a daily oral dose of 25 mg and produces significant suppression of aromatase and plasma estrogen levels without androgenic side effects. Toxicity is mild with menopausal symptoms predominating. Exemestane is approved for the treatment of postmenopausal women with recurrent breast cancer. In reported clinical trials, exemestane was effective in patients failing tamoxifen, megestrol acetate, or even other aromatase inhibitors in phase II trials and was superior to megestrol acetate in a phase III randomized trial in which an early survival advantage for exemestane was observed. Studies evaluating first-line exemestane for adjuvant use and as a chemopreventive agent are underway.
Drug safety evaluation of exemestane. [2016]Hormone-dependent breast cancer can be successfully treated by either blocking the estrogen receptor, as with tamoxifen, or reducing the production of estrogens, as with aromatase inhibitors. Exemestane is a third-generation aromatase inhibitor used in the treatment of estrogen-receptor-positive breast cancer in postmenopausal women. In various trials, exemestane has shown superiority over tamoxifen in both efficacy and safety. Furthermore, aromatase inhibitors are gaining territory in the metastatic, as well as the early, setting for treating patients with breast cancer.
Zoladex plus tamoxifen versus Zoladex alone in pre- and peri-menopausal metastatic breast cancer. [2019]Phase II studies examining the endocrinological and clinical efficacy of Zoladex and Zoladex plus tamoxifen have been examined in pre- and peri-menopausal women with advanced breast cancer. No adverse endocrinological interaction between the drugs have been observed. Although a higher proportion of static disease was observed with the combination of the drugs, which possibly occurred at the expense of partial remissions, the time to disease progression was extended in women who received Zoladex plus tamoxifen. Remissions were primarily restricted to patients whose tumours were ER positive. Only occasional responses were seen in ER negative disease. This was especially evident where the ER negative tumours were EGF-R positive and showed high rates of cell proliferation.
Effect of endocrine treatment on sexuality in premenopausal breast cancer patients: a prospective randomized study. [2017]To study the sexual effects of the 2-year adjuvant goserelin (Zoladex [Zeneca AB, Södertälje, Sweden]) alone, tamoxifen alone, and Zoladex and tamoxifen in combination (ZT) versus no adjuvant endocrine therapy among premenopausal breast cancer patients with or without chemotherapy in a controlled clinical trial (a European multicenter trial: Zoladex in Premenopausal Breast Cancer Patients).
[New drugs in endocrine treatment of breast cancer]. [2019]Therapeutic access in the treatment of breast cancer with the antiestrogen tamoxifen has been established by world-wide clinical trials since the drug was introduced by Cole et al, in 1971. In recent years, however, a new series of antiestrogens (the derivatives of tamoxifen) such as trioxifene, toremifene and droloxifene have been studied with regard to clinical efficacy as a first-line treatment for postmenopausal patients with breast cancer and occasionally even for patients who previously responded to tamoxifen and then relapsed. Luteinizing hormone releasing hormone (LHRH) agonists are now available for premenopausal patients that will produce a medical castration, when given continuously, by down-regulation of the pituitary LHRH receptors. Four compounds, leuprolide, buserelin, tryptorelin and goserelin have been available for clinical use, but goserelin (Zoladex) is now widely used by long-acting depot preparations, which are given subcutaneously once every 4 weeks. Another series of drugs which inhibit estrogen synthesis in postmenopausal patients and are termed "aromatase inhibitors" have been developed. The pure aromatase inhibitors newly developed include two types of both a steroidal compound (4-hydroxyandrostenedione) and a non-steroidal one which is a tetrahydroimidazopyrimidine derivative (CGS 16949A). This review describes the pharmacological and clinical aspects of these new agents.
Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer. [2022]The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrine-resistant estrogen receptor-positive (ER+) breast cancer. We compared the antitumor activity of Z-endoxifen with tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), as well as with tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus in a letrozole-resistant MCF7 model (MCF7LR).
Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. [2019]Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30-100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated. Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed. Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.
Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside. [2022]The selective estrogen receptor (ER) modulator, tamoxifen, is the only endocrine agent with approvals for both the prevention and treatment of premenopausal and postmenopausal estrogen-receptor positive breast cancer as well as for the treatment of male breast cancer. Endoxifen, a secondary metabolite resulting from CYP2D6-dependent biotransformation of the primary tamoxifen metabolite, N-desmethyltamoxifen (NDT), is a more potent antiestrogen than either NDT or the parent drug, tamoxifen. However, endoxifen's antitumor effects may be related to additional molecular mechanisms of action, apart from its effects on ER. In phase 1/2 clinical studies, the efficacy of Z-endoxifen, the active isomer of endoxifen, was evaluated in patients with endocrine-refractory metastatic breast cancer as well as in patients with gynecologic, desmoid, and hormone-receptor positive solid tumors, and demonstrated substantial oral bioavailability and promising antitumor activity. Apart from its potent anticancer effects, Z-endoxifen appears to result in similar or even greater bone agonistic effects while resulting in little or no endometrial proliferative effects compared with tamoxifen. In this review, we summarize the preclinical and clinical studies evaluating endoxifen in the context of breast and other solid tumors, the potential benefits of endoxifen in bone, as well as its emerging role as an antimanic agent in bipolar disorder. In total, the summarized body of literature provides compelling arguments for the ongoing development of Z-endoxifen as a novel drug for multiple indications.
Endocrine effects of combination antioestrogen and LH-RH agonist therapy in premenopausal patients with advanced breast cancer. [2019]Thirty-eight premenopausal breast cancer patients were treated for periods up to 12 months with a sustained-release formulation of the luteinizing hormone-releasing hormone agonist goserelin [Zoladex, (D-Ser(But)6Azgly10-LH-RH); 3.6 mg depot every 4 weeks] either alone or in combination with the antioestrogen tamoxifen citrate (Nolvadex 40 mg/day). In both treatment groups serum gonadotrophin concentrations fell durig the first month of therapy and were suppressed on continued treatment. In patients treated with the combination therapy FSH concentrations were significantly reduced in comparison with goserelin alone. Relatively normal ovarian activity was observed during the first few weeks of therapy. Thereafter, oestradiol and progesterone concentrations rapidly declined in both treatment groups. Slightly lower serum oestradiol concentrations were recorded in patients receiving combination therapy. No significant adverse side-effects were recorded in either group of patients.