Repotrectinib + Fulvestrant for Breast Cancer

Overseen By Jason Mouabbi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: CDK4/6 inhibitors

Must not be taking: Tyrosine kinase inhibitors

Disqualifiers: Symptomatic visceral disease, untreated brain metastases, 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: Unknown

Duration: 6 months

58 Participants Needed

Trial Summary

What is the purpose of this trial?

To find out if the combination of repotrectinib and fulvestrant can control the disease in participants with metastatic invasive lobular carcinoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have had chemotherapy, hormonal therapy, biotherapy, immunotherapy, or radiotherapy within 4 weeks before starting the study, and you must not be on any other investigational drugs.

What data supports the effectiveness of the drug combination Repotrectinib + Fulvestrant for breast cancer?

Research shows that fulvestrant, a part of this drug combination, is effective in treating estrogen receptor-positive breast cancer. Additionally, targeted therapies combined with fulvestrant have shown promise in improving outcomes for advanced breast cancer, suggesting potential benefits of combining Repotrectinib with fulvestrant. ^{1 2 3 4 5}

What makes the drug Repotrectinib + Fulvestrant unique for breast cancer treatment?

Repotrectinib is a novel drug that targets specific proteins involved in cancer cell growth, making it potentially effective for cancers with certain genetic mutations. When combined with Fulvestrant, which blocks estrogen receptors, this combination may offer a new approach for treating breast cancer, especially in cases where traditional therapies are less effective. ^{6 7 8 9 10}

Research Team

Jason Mouabbi, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for individuals with a specific breast cancer type (hormone receptor-positive, HER2-negative metastatic invasive lobular carcinoma) who have previously been treated with endocrine therapy and CDK4/6 inhibitors.

Inclusion Criteria

WOCBP must agree to use adequate contraception for the duration of study treatment and 7 months after the last dose of study treatment

My organs and bone marrow are working well.

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Participants with psychiatric illness/social situations that would limit compliance with study requirements

Participants who are receiving any other investigational agents

I haven't had cancer treatment like chemo or immunotherapy in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive repotrectinib with or without fulvestrant. Cohort 1 includes participants who have never received fulvestrant before, while Cohort 2 includes those who have.

6 months

Regular visits as per treatment cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including evaluation of progression-free survival and overall response rate.

6 months

Extension

Participants may continue to be monitored for long-term outcomes such as overall survival and clinical benefit rate.

Long-term

Treatment Details

Interventions

• Fulvestrant
• Repotrectinib

Trial Overview The study is testing the effectiveness of combining two drugs, repotrectinib and fulvestrant, to manage this form of breast cancer. Participants will be randomly assigned to receive either both drugs or just one.

Participant Groups

Group I: Cohort 2 Experimental Treatment 1 Intervention

About 6 months after the first 15 participants are enrolled, based on their study data, Cohort 2 will begin enrolling up to 29 participants who have received fulvestrant in earlier treatments. Participants in Cohort 2 will receive repotrectinib alone.

Group II: Cohort 1 Experimental Treatment 2 Interventions

Cohort 1 will include participants who have never received fulvestrant before. The first 15 participants enrolled in Cohort 1 will receive the study drug combination starting on Day 1 of their first treatment cycle. The next 14 participants enrolled in Cohort 1 will begin with fulvestrant alone for at least 12 days and then start repotrectinib sometime between Days 13 and 20 (depending on when their Cycle 1 biopsy is performed). This is done in order to use the biopsy results to study the effects of fulvestrant alone in these patients.

Fulvestrant is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in United States as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Canada as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Approved in Japan as Faslodex for:

• Hormone receptor-positive metastatic breast cancer
• Locally advanced breast cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

This phase I clinical trial is investigating the safety and tolerability of combining bosutinib, a Src/Abl pathway inhibitor, with palbociclib and fulvestrant in patients with metastatic hormone-positive breast cancer who have previously shown resistance to standard therapies.

The study aims to evaluate the anti-tumor effects of this combination therapy, with a focus on overall response rate and clinical benefit after 6 months, potentially offering a new strategy to overcome endocrine resistance in breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of palbociclib and bosutinib with fulvestrant in patients with metastatic hormone receptor positive and HER2 negative (HR+ HER2-) breast cancer refractory to an aromatase inhibitor and a CDK4/6 inhibitor. Roy, T., Barrows, E., Mainor, C., et al.[2023]

In postmenopausal patients with hormone receptor-positive advanced breast cancer, combining targeted therapy with fulvestrant significantly improved progression-free survival (PFS) and objective response rate (ORR) compared to fulvestrant alone, with a hazard ratio of 0.77 for PFS and a relative risk of 1.78 for ORR based on 13 studies involving randomized control trials.

However, this combination therapy also resulted in a higher risk of adverse events and treatment discontinuation due to side effects, indicating that while it is more effective, it comes with increased safety concerns that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of targeted therapy plus fulvestrant in postmenopausal women with hormone-receptor positive advanced breast cancer: A meta-analysis of randomized-control trials. Chanchan, G., Xiangyu, S., Fangfang, S., et al.[2023]

A study involving 134 patients with metastatic estrogen receptor-positive breast cancer identified a novel gene signature that can predict response to fulvestrant treatment, highlighting potential new therapeutic targets.

Increased expression of the gene TFAP2C was linked to a decreased response to fulvestrant, suggesting it could serve as a predictive biomarker for treatment outcomes in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer. Jeselsohn, R., Barry, WT., Migliaccio, I., et al.[2018]

High expression of the RET receptor tyrosine kinase in ER-positive breast cancer patients is linked to significantly worse survival outcomes, indicating it may be a critical biomarker for identifying high-risk patients.

Patients with high RET and GDNF expression may benefit from targeted therapies, as their tumors show enrichment for pathways that can be targeted with tyrosine kinase inhibitors, suggesting a potential new treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High expression of the RET receptor tyrosine kinase and its ligand GDNF identifies a high-risk subset of estrogen receptor positive breast cancer. Kakati, RT., Kim, H., Whitman, A., et al.[2023]

In a study of 86 postmenopausal patients with ER-positive metastatic breast cancer, 500 mg of fulvestrant demonstrated a clinical benefit rate of 36.0%, indicating its efficacy in managing the disease.

Patients who had not previously undergone endocrine therapy showed significantly prolonged median progression-free survival (mPFS) of 6.5 months, suggesting that fulvestrant is particularly effective when used as a first-line treatment in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of fulvestrant in treating postmenopausal patients with estrogen receptor-positive metastatic breast cancer and prognostic analysis. Li, T., Jiao, L.[2021]

In a phase 2 study involving 49 patients with untreated metastatic renal-cell carcinoma, regorafenib demonstrated significant antitumor activity, with 39.6% of patients achieving a partial response.

However, the treatment was associated with a high incidence of adverse events (98%), including serious ones like cardiac issues and renal failure, highlighting the need for careful monitoring of patients during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Eisen, T., Joensuu, H., Nathan, PD., et al.[2020]

In a study of 43 patients aged 70 and older with metastatic colorectal cancer, regorafenib showed a disease control rate of 31.4% after 2 months, indicating it can be an effective treatment option for older patients who have failed previous therapies.

However, the treatment was associated with significant toxicities, with 35 out of 42 patients experiencing grade 3-4 adverse events, particularly fatigue, hypertension, and hand-foot skin reactions, suggesting that careful monitoring is needed, especially for patients over 80 or with impaired autonomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 - REGOLD. Aparicio, T., Darut-Jouve, A., Khemissa Akouz, F., et al.[2021]

Three novel RET fusion-positive lung cancer cell lines were developed, showing different sensitivities to RET inhibitors, which can help understand patient variability in treatment responses.

The study revealed that while CUTO42 cells were effectively inhibited by the RET inhibitor BLU-667, CUTO32 cells were resistant, suggesting the need for alternative therapies for certain RET+ patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Human-Derived RET Fusion NSCLC Cell Lines Have Heterogeneous Responses to RET Inhibitors and Differential Regulation of Downstream Signaling. Schubert, L., Le, AT., Estrada-Bernal, A., et al.[2021]

Regorafenib shows promising efficacy in gastric and colorectal cancer cells, particularly in those with amplification of the fibroblast growth factor receptor 2 (FGFR2), which is linked to sensitivity to the drug.

In preclinical models, regorafenib effectively inhibited FGFR2 signaling and induced cell cycle arrest and apoptosis in FGFR2-amplified cancer cells, suggesting it could be a targeted treatment option for patients with this specific genetic alteration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro. Cha, Y., Kim, HP., Lim, Y., et al.[2022]

In a study involving 181 patients with metastatic colorectal cancer, the combination of regorafenib and FOLFIRI resulted in a modest increase in progression-free survival (PFS) compared to FOLFIRI alone, with a median PFS of 6.1 months versus 5.3 months.

While the addition of regorafenib improved the response rate (34% vs 21%), it did not significantly extend overall survival, and patients experienced increased rates of serious side effects such as diarrhea and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. Sanoff, HK., Goldberg, RM., Ivanova, A., et al.[2019]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

A phase I trial of palbociclib and bosutinib with fulvestrant in patients with metastatic hormone receptor positive and HER2 negative (HR+ HER2-) breast cancer refractory to an aromatase inhibitor and a CDK4/6 inhibitor. [2023]

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

The efficacy and safety of targeted therapy plus fulvestrant in postmenopausal women with hormone-receptor positive advanced breast cancer: A meta-analysis of randomized-control trials. [2023]

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

TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer. [2018]

4. Netherlands pubmed.ncbi.nlm.nih.gov

High expression of the RET receptor tyrosine kinase and its ligand GDNF identifies a high-risk subset of estrogen receptor positive breast cancer. [2023]

5. Cyprus pubmed.ncbi.nlm.nih.gov

Efficacy of fulvestrant in treating postmenopausal patients with estrogen receptor-positive metastatic breast cancer and prognostic analysis. [2021]

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

Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. [2020]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 - REGOLD. [2021]

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

Novel Human-Derived RET Fusion NSCLC Cell Lines Have Heterogeneous Responses to RET Inhibitors and Differential Regulation of Downstream Signaling. [2021]

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

FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro. [2022]

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

Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer. [2019]