Endoxifen for Breast Cancer

(EVANGELINE Trial)

Recruiting at 11 trial locations

Overseen By Hayley Erickson

Age: 18+

Sex: Female

Trial Phase: Phase 2

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 All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

214 Participants Needed

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. ^{1 2 3 4 5}

What 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. ^{5 6 7 8 9}

Is 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. ^{2 10 11 12 13}

Research Team

Matthew P. Goetz

Principal Investigator

Mayo Clinic

Eligibility 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.

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

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

Treatment Details

Interventions

• Exemestane
• Goserelin
• (Z)-endoxifen

Trial Overview (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.

Participant Groups

Group I: Treatment Cohort Part 2b Single Arm Experimental Treatment 1 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 Regimen Experimental Treatment 2 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 Regimen Experimental Treatment 2 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 + OFS Experimental Treatment 2 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 mg Experimental Treatment 1 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 Cohort Experimental Treatment 1 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 Regimen Active Control 2 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

Who Is Running the Clinical Trial?

Atossa Therapeutics, Inc.

Lead Sponsor

Trials

8

Recruited

640+

InClin

Collaborator

Trials

1

Recruited

210+

Findings from Research

In a study involving 1,010 premenopausal and perimenopausal patients with early breast cancer, goserelin showed significantly improved quality of life (QoL) compared to CMF chemotherapy during the first 6 months of treatment.

While goserelin was associated with worse hormonal symptoms during the 2-year treatment period, it ultimately provided equivalent efficacy to CMF and reversed the hormonal symptom trend by 3 years, supporting its use as an alternative treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. de Haes, H., Olschewski, M., Kaufmann, M., et al.[2015]

Goserelin is effective in reducing estrogen levels in pre- or perimenopausal women with hormone receptor-positive early breast cancer, showing similar efficacy to chemotherapy when used as monotherapy.

Combining goserelin with chemotherapy may provide additional benefits, especially for younger patients, and it allows for better preservation of ovarian function compared to chemotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Goserelin: a review of its use in the treatment of early breast cancer in premenopausal and perimenopausal women. Cheer, SM., Plosker, GL., Simpson, D., et al.[2018]

In the ZIPP study involving 2710 pre- and peri-menopausal women with early breast cancer, the addition of goserelin ('Zoladex') to standard adjuvant therapy significantly improved event-free survival (hazard ratio 0.80) and overall survival (hazard ratio 0.81) after a median follow-up of 5.5 years.

Goserelin was well tolerated by patients, indicating that it is a safe and effective addition to standard treatment for improving outcomes in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study. Baum, M., Hackshaw, A., Houghton, J., et al.[2022]

In a study of 53 premenopausal patients with advanced breast cancer, the LHRH analogue Zoladex (goserelin) achieved a response rate comparable to surgical oophorectomy, indicating its efficacy as a treatment option.

When Zoladex was combined with the anti-estrogen tamoxifen in 34 patients, it resulted in significantly lower serum oestradiol levels, achieving castrate levels in all patients, suggesting a potential benefit of this combination therapy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zoladex in advanced breast cancer. Robertson, JF., Nicholson, RI., Walker, KJ., et al.[2018]

Exemestane effectively suppresses aromatase and plasma estrogen levels in postmenopausal women with recurrent breast cancer, showing significant efficacy even in patients who have failed other treatments like tamoxifen and other aromatase inhibitors.

The drug has a favorable safety profile with mild toxicity primarily consisting of menopausal symptoms, and it has demonstrated an early survival advantage over megestrol acetate in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exemestane: a novel aromatase inactivator for breast cancer. Jones, SA., Jones, SE.[2016]

Exemestane, a third-generation aromatase inhibitor, has demonstrated superior efficacy and safety compared to tamoxifen in treating estrogen-receptor-positive breast cancer in postmenopausal women.

Due to its unique steroidal structure, exemestane works differently than nonsteroidal aromatase inhibitors, making it a valuable alternative for patients who may not respond to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug safety evaluation of exemestane. Lintermans, A., Neven, P., Paridaens, R.[2016]

In a Phase II study involving pre- and peri-menopausal women with advanced breast cancer, the combination of Zoladex and tamoxifen showed no adverse endocrinological interactions and extended the time to disease progression compared to Zoladex alone.

The combination treatment was particularly effective in patients with estrogen receptor (ER) positive tumors, leading to a higher proportion of static disease, while responses in ER negative tumors were rare, especially in those with high cell proliferation rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zoladex plus tamoxifen versus Zoladex alone in pre- and peri-menopausal metastatic breast cancer. Nicholson, RI., Walker, KJ., McClelland, RA., et al.[2019]

In a 2-year study of premenopausal breast cancer patients, those receiving chemotherapy experienced higher levels of sexual dysfunction compared to those who did not receive systemic treatment, regardless of endocrine therapy.

Among patients not receiving chemotherapy, the use of goserelin (Zoladex) and its combination with tamoxifen led to increased sexual dysfunction during treatment, but these issues were found to be reversible after stopping the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of endocrine treatment on sexuality in premenopausal breast cancer patients: a prospective randomized study. Berglund, G., Nystedt, M., Bolund, C., et al.[2017]

New antiestrogens derived from tamoxifen, such as trioxifene and toremifene, are being studied for their effectiveness as first-line treatments for postmenopausal breast cancer patients, showing promise for those who have relapsed after tamoxifen.

LHRH agonists like goserelin are now widely used for premenopausal patients, providing effective medical castration, while aromatase inhibitors have been developed to inhibit estrogen synthesis in postmenopausal patients, enhancing treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New drugs in endocrine treatment of breast cancer]. Izuo, M.[2019]

Z-endoxifen demonstrated superior antitumor activity compared to tamoxifen and letrozole in both endocrine-sensitive and letrozole-resistant breast cancer models, significantly reducing tumor volumes in treated mice.

In letrozole-resistant tumors, Z-endoxifen not only outperformed tamoxifen and letrozole but also showed comparable efficacy to combination therapies like exemestane plus everolimus and fulvestrant, indicating its potential as a robust treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer. Jayaraman, S., Hou, X., Kuffel, MJ., et al.[2022]

Endoxifen, a potent metabolite of tamoxifen, shows promise as an alternative therapy in breast cancer, but current research primarily focuses on its use in metastatic cases, indicating a need for further studies to establish its therapeutic role.

Pharmacogenetic factors, particularly CYP2D6 genotypes, significantly impact tamoxifen metabolism and clinical outcomes, suggesting that personalized treatment approaches based on genetic testing may be necessary, although evidence for monitoring endoxifen concentrations is still limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. Sanchez-Spitman, AB., Swen, JJ., Dezentje, VO., et al.[2019]

Z-endoxifen, a potent metabolite of tamoxifen, shows promising antitumor activity in patients with various cancers, including endocrine-refractory metastatic breast cancer, and has substantial oral bioavailability.

Unlike tamoxifen, Z-endoxifen appears to have beneficial effects on bone health while causing little to no endometrial proliferation, making it a potentially safer alternative for breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside. Jayaraman, S., Reid, JM., Hawse, JR., et al.[2022]

In a study of 38 premenopausal breast cancer patients treated with goserelin alone or in combination with tamoxifen for up to 12 months, both treatments effectively suppressed serum gonadotrophin levels, indicating a reduction in ovarian activity.

Combination therapy with goserelin and tamoxifen resulted in significantly lower FSH levels compared to goserelin alone, with no significant adverse side effects reported, suggesting a safe and effective approach to managing hormone levels in breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endocrine effects of combination antioestrogen and LH-RH agonist therapy in premenopausal patients with advanced breast cancer. Walker, KJ., Walker, RF., Turkes, A., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

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]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Goserelin: a review of its use in the treatment of early breast cancer in premenopausal and perimenopausal women. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Zoladex in advanced breast cancer. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Exemestane: a novel aromatase inactivator for breast cancer. [2016]

6. England pubmed.ncbi.nlm.nih.gov

Drug safety evaluation of exemestane. [2016]

7. England pubmed.ncbi.nlm.nih.gov

Zoladex plus tamoxifen versus Zoladex alone in pre- and peri-menopausal metastatic breast cancer. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Effect of endocrine treatment on sexuality in premenopausal breast cancer patients: a prospective randomized study. [2017]

9. Japan pubmed.ncbi.nlm.nih.gov

[New drugs in endocrine treatment of breast cancer]. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Endoxifen, an Estrogen Receptor Targeted Therapy: From Bench to Bedside. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Endocrine effects of combination antioestrogen and LH-RH agonist therapy in premenopausal patients with advanced breast cancer. [2019]