Alisertib +/− Fulvestrant for Breast Cancer

Not currently recruiting at 9 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must be taking: Fulvestrant

Must not be taking: Proton pump inhibitors

Disqualifiers: Infection, Heart failure, Hypertension, 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: 34

Duration: Up to 4.5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of two drugs, alisertib and fulvestrant, used alone or together, in treating breast cancer that has resisted hormone therapy and spread. Alisertib (MLN8237) may inhibit cancer cell growth by blocking certain enzymes, while fulvestrant (Faslodex) aims to block or reduce estrogen, which some breast cancers require for growth. This trial targets post-menopausal women with estrogen-receptor positive breast cancer that has spread, particularly when previous hormone therapies have failed. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before joining. Specifically, you must stop chemotherapy, immunotherapy, or biologic therapy at least 21 days before, and hormonal therapy at least 14 days before registration. Additionally, you should not be on certain enzyme-inducing drugs or corticosteroids close to the registration date.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that alisertib is generally well-tolerated in past studies. However, about 43% of participants experienced serious side effects related to the drug. This indicates that while some may encounter significant side effects, many find them manageable.

When combined with fulvestrant, the treatment has shown promise. Fulvestrant, already approved for breast cancer treatment, provides some reassurance about its safety. Together, alisertib and fulvestrant have been tested and shown promising results against breast cancer, though they did not significantly improve certain effectiveness measures.

This trial is in Phase 2, focusing on the treatment's effectiveness and continuing to assess its safety in more patients. This phase indicates that the treatment has passed initial safety checks, but more data is being gathered to ensure its safety for a larger group. Participants should consider these factors when deciding to join the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a novel approach to fighting breast cancer. Alisertib, a key component, stands out with its unique mechanism of action, targeting Aurora A kinase, an enzyme involved in cell division, potentially leading to more effective cancer cell inhibition. Fulvestrant, already used in treating hormone receptor-positive breast cancer, adds another layer by degrading estrogen receptors, which helps in cutting off the fuel for cancer growth. This combination could provide a more comprehensive attack on cancer cells compared to standard treatments like hormone therapies or chemotherapy alone.

What evidence suggests that this trial's treatments could be effective for breast cancer?

Research has shown that alisertib, which participants in this trial may receive, may help treat breast cancer unresponsive to hormone therapy. Alisertib blocks certain enzymes that aid cancer cell growth, and studies have demonstrated its ability to shrink tumors. In one study, about 20 out of 100 people experienced tumor shrinkage with alisertib. In this trial, some participants will receive alisertib alone, while others will receive a combination of alisertib and fulvestrant. When combined with fulvestrant, the results were similar, with about 20 out of 100 people seeing tumor shrinkage. This suggests that adding fulvestrant doesn't significantly change the outcome, though it still has some effect. Fulvestrant works by blocking estrogen, which some breast cancers need to grow. Together, these treatments could offer a new option for people with this type of breast cancer. ^{3 5 6 7 8}

Who Is on the Research Team?

Tufia C. Haddad, M.D.

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for post-menopausal women with advanced breast cancer that's resistant to hormone therapy. Participants must have ER positive, HER2 negative tumors and can have had no more than two chemotherapy treatments in the metastatic setting. They should not have taken certain medications recently and must be able to swallow pills.

Inclusion Criteria

I had brain cancer spread, treated, no symptoms, and stable scans for 3 months.

I have recovered from my last treatment and can care for myself.

The participant should not be taking certain medications for stomach problems, should limit alcohol, should not have certain heart or sleep issues, should not have certain types of cancer, should be able to understand and agree to take part in the study, should be able to return for follow-up visits, should not have had certain medical procedures or conditions in the past, should be able to swallow pills, should be willing to have a biopsy for research, and should have certain blood and organ function levels within a specific range.

Exclusion Criteria

I haven't had certain treatments or medications within specific days before signing up.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive alisertib with or without fulvestrant in 28-day cycles until disease progression or unacceptable toxicity

Up to 4.5 years

Visits every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Alisertib
• Fulvestrant

Trial Overview The study is testing alisertib, an enzyme inhibitor thought to slow tumor growth, both alone and combined with fulvestrant, a drug that blocks or reduces estrogen. The goal is to see if one or both drugs together are effective against endocrine-resistant breast cancer.

How Is the Trial Designed?

Group I: Arm II (alisertib, fulvestrant) Experimental Treatment 3 Interventions

Patients receive fulvestrant IM over 1-2 minutes on days 1 and 15 of course 1 and on day 1 of all subsequent courses. Patients also receive alisertib PO BID on days 1-3, 8-10, and 15-17. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (alisertib) Experimental Treatment 2 Interventions

Patients receive alisertib PO BID on days 1-3, 8-10, and 15-17. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression, may cross-over to Arm II.

Alisertib is already approved in United States, European Union for the following indications:

Approved in United States as Alisertib for:

• Acute myeloid leukemia (AML)

Approved in European Union as Alisertib for:

• None approved; under investigation for various cancers

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase I trial involving 10 postmenopausal patients with endocrine-resistant ER+ metastatic breast cancer, the combination of alisertib and fulvestrant was well tolerated, with no severe toxicities reported during the first treatment cycle.

The treatment showed promising antitumor activity, with a median progression-free survival of 12.4 months and a 6-month clinical benefit rate of 77.8%, indicating potential effectiveness even in patients who had previously progressed on fulvestrant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer. Haddad, TC., D'Assoro, A., Suman, V., et al.[2023]

In a study involving 587 postmenopausal women with advanced breast cancer, fulvestrant showed similar efficacy to tamoxifen in patients with hormone receptor-positive tumors, with no significant differences in time to progression (TTP) or objective response rates.

While tamoxifen had a slightly better overall efficacy in the general population, both treatments were well tolerated, indicating that fulvestrant can be a viable option for patients with ER+ and/or PgR+ tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. Howell, A., Robertson, JF., Abram, P., et al.[2022]

Alisertib, an investigational cancer treatment, showed a 26% increase in total systemic exposure when administered as an oral solution compared to its powder-in-capsule formulation, indicating better bioavailability.

The oral solution of alisertib was absorbed faster than the capsule form, with a quicker peak concentration reached in the bloodstream, suggesting it may be a more effective option for patients who have difficulty swallowing solid medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors. Falchook, GS., Venkatakrishnan, K., Sarantopoulos, J., et al.[2015]

In a study of 54 postmenopausal women with metastatic breast cancer, fulvestrant demonstrated clinical benefit in 38.9% of patients, with a median time to progression of 6.4 months, indicating its efficacy even after multiple prior treatments.

Fulvestrant was well tolerated, with no severe toxicities (grade 3/4) reported, suggesting it is a safe option for patients with advanced breast cancer who have limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant ('Faslodex') in heavily pretreated postmenopausal patients with advanced breast cancer: single centre clinical experience from the compassionate use programme. Mlineritsch, B., Psenak, O., Mayer, P., et al.[2018]

The combination of alisertib (20 mg twice daily) and docetaxel (75 mg/m²) was found to be safe and well-tolerated in a study involving 41 patients with metastatic cancer, with the recommended phase 2 dose established for future research.

Out of 28 patients evaluated for efficacy, 29% showed objective responses, including one complete response in bladder cancer and several partial responses in prostate cancer and angiosarcoma, indicating potential antitumor activity of the combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors. Graff, JN., Higano, CS., Hahn, NM., et al.[2018]

Fulvestrant was well tolerated and provided clinical benefit to 21% of heavily pre-treated postmenopausal women with advanced breast cancer, with 42% achieving stable disease for at least 12 weeks.

The efficacy of fulvestrant was similar whether given after disease progression or as maintenance therapy, with a median time to progression of 3 months and no significant toxicities reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant in heavily pre-treated patients with advanced breast cancer: results from a single compassionate use programme centre. Catania, C., Ascione, G., Adamoli, L., et al.[2018]

Faslodex (fulvestrant) is a novel selective estrogen receptor down-regulator (SERD) that effectively targets and degrades the estrogen receptor, offering a new treatment option for advanced breast cancer, especially in cases where tumors have become resistant to tamoxifen.

Unlike tamoxifen, which can lead to resistance and has risks such as endometrial carcinoma, Faslodex provides a 'pure' antiestrogen effect without agonistic activity, making it a promising alternative for both advanced and early breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Faslodex(TM) for the treatment of breast cancer. Smolnikar, K.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12210044/

Dual Targeting of Aurora‐A and Bcl‐xL Synergistically ... The Aurora‐A kinase inhibitor MLN8237 has shown efficacy in clinical trials for advanced breast cancer; however, its use as a monotherapy is limited by ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4365748/

The investigational Aurora kinase A inhibitor alisertib ... Results. ALS shows significantly higher cytotoxicity toward breast cancer cells than normal breast epithelial cells. In order to evaluate the cytotoxicity of ...

3. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2802267

Evaluation of Alisertib Alone or Combined With Fulvestrant ... The ORR was not significantly improved by the addition of fulvestrant to alisertib, with an ORR of approximately 20.0% for both regimens.

4. onclive.com onclive.com/view/alisertib-induces-early-signals-of-efficacy-in-endocrine-resistant-breast-cancer

Alisertib Induces Early Signals of Efficacy in Endocrine ... We saw a 19.6% ORR and a 24-week clinical benefit rate [CBR] of 41.3% for the patients who received alisertibmonotherapy. The median progression ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.3589

Phase I study of the combination of alisertib (MLN8237) ... Fourteen of 23 evaluable pts (61%) had stable disease and 2 pts (9%) had partial response (PR) as best overall response. Median PFS was 2.9 ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33877311/

Efficacy and Safety of Weekly Paclitaxel With or Without ... This randomized clinical trial found that the addition of oral alisertib to a reduced dose of weekly paclitaxel significantly improved PFS compared with ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01091428

Alisertib (MLN8237) in Participants With Ovarian, Fallopian ... Alisertib was tested to treat people who have ovarian and breast cancer. This study looked at safety, any anti-tumor effect, and it also determined a ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25728526/

Safety and activity of alisertib, an investigational aurora kinase ... Serious drug-related adverse events were reported in 108 (43%) patients. Interpretation: These data support further clinical assessment of alisertib in patients ...