RLY-2608 + Fulvestrant for Breast Cancer

Recruiting at 34 trial locations

Overseen By Relay Therapeutics Inc

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Relay Therapeutics, Inc.

Must be taking: GnRH agonist

Must not be taking: Antihyperglycemics, PI3K inhibitors

Disqualifiers: Diabetes, Cardiovascular disease, CNS metastases, others

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

Compensation: Varies

Number of Visits: Unknown

890 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, FIH study designed to evaluate the maximum tolerated dose, recommended Phase 2 dose, safety, tolerability, PK, pharmacodynamics, and preliminary antineoplastic activity of RLY-2608, in advanced solid tumor patients with a Phosphatidylinositol-4,5-bisphosphate-3 kinase, catalytic subunit alpha (PIK3CA) mutation in blood and/or tumor per local assessment. The study will evaluate RLY-2608 as a single agent for patients with unresectable or metastatic solid tumors. It will also evaluate RLY-2608 in combination RLY-2608 + fulvestrant and in triple combination RLY-2608 + fulvestrant + CDK4/6 inhibitor (palbociclib or ribociclib) or CDK4 inhibitor (PF-07220060) for patients with HR+ HER2- locally advanced or metastatic breast cancer or endometrial cancer (palbociclib or ribociclib Part 1). The RLY-2608 single agent arm, RLY-2608 + fulvestrant combination arm, and triple combination arms will have 2 parts: a dose escalation (Part 1) and a dose expansion (Part 2).

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you have Type 1 or Type 2 diabetes requiring medication, you may not be eligible. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Fulvestrant in treating breast cancer?

Fulvestrant, also known as Faslodex, is effective in treating advanced breast cancer, especially when used early in the treatment sequence. It has shown clinical benefits in 39% of patients in a compassionate use program, with better outcomes in those whose tumors express certain receptors. ^{1 2 3 4 5}

Is the combination of RLY-2608 and Fulvestrant safe for humans?

Fulvestrant, also known as Faslodex, has been used in many patients with advanced breast cancer and is generally well tolerated, with only a small percentage experiencing side effects. However, specific safety data for the combination of RLY-2608 and Fulvestrant is not provided in the available research. ^{1 2 5 6 7}

What makes the drug RLY-2608 + Fulvestrant unique for breast cancer treatment?

RLY-2608 + Fulvestrant is unique because Fulvestrant is a selective estrogen receptor down-regulator (SERD) that targets and degrades estrogen receptors, unlike traditional treatments like tamoxifen, which can eventually lead to resistance and have risks like endometrial cancer. This combination offers a promising new approach for treating advanced breast cancer, especially in patients who have progressed after other endocrine therapies. ^{1 4 5 6 7}

Eligibility Criteria

This trial is for adults with advanced solid tumors or breast cancer that can't be removed by surgery, have worsened despite standard treatments, or who cannot tolerate such treatments. Participants must have a specific gene mutation (PIK3CA), be in good physical condition (ECOG 0-1), and not have certain health issues like uncontrolled diabetes or heart disease.

Inclusion Criteria

I stopped a PI3Kα inhibitor treatment due to side effects, not because my disease got worse.

I can provide a sample of my tumor or am willing to have a biopsy for testing.

I have breast cancer that cannot be surgically removed or cured, and it is hormone receptor positive and HER2 negative.

Exclusion Criteria

I have diabetes and take medication, or my blood sugar and HbA1c levels are high.

My family has a history of prolonged QT syndrome.

I have a history of abnormal heart rhythms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of RLY-2608, alone or in combination with fulvestrant and other inhibitors, to determine the maximum tolerated dose

8-12 weeks

Dose Expansion

Participants receive the recommended Phase 2 dose of RLY-2608, alone or in combination, to further evaluate safety and preliminary antineoplastic activity

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Fulvestrant
• RLY-2608

Trial Overview The study tests RLY-2608 alone and combined with fulvestrant, plus CDK4/6 inhibitors palbociclib or ribociclib in patients with hormone receptor-positive, HER2-negative advanced breast cancer. It aims to find the safest dose that works best (dose escalation) and then see how well it works at this dose (dose expansion).

Participant Groups

Group I: RLY-2608+fulvestrant+ribo600mg for HR+HER2 locally advanced/metastatic breast cancer/endometrial ca Experimental Treatment 3 Interventions

Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 600mg as determined during Part 1 Dose Escalation.

Group II: RLY-2608+fulvestrant+ribo400mg for HR+HER2 locally advanced/metastatic breast cancer/endometrial ca Experimental Treatment 3 Interventions

Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 400mg as determined during Part 1 Dose Escalation.

Group III: RLY-2608+fulvestrant+palbo125mg for HR+HER2 locally advanced/metastatic breast cancer/endometrial ca Experimental Treatment 3 Interventions

Oral dose of RLY-2608 in addition to fulvestrant and palbociclib 125mg as determined during Part 1 Dose Escalation.

Group IV: RLY-2608+fulvestrant+PF-07220060 300 mg for HR+ HER2- locally advanced or metastatic breast cancer Experimental Treatment 3 Interventions

Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 300 mg as determined during Part 1 Dose Escalation

Group V: RLY-2608+fulvestrant+PF-07220060 100 mg for HR+ HER2- locally advanced or metastatic breast cancer Experimental Treatment 3 Interventions

Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 100 mg as determined during Part 1 Dose Escalation

Group VI: RLY-2608 for patients with unresectable or metastatic solid tumors Experimental Treatment 2 Interventions

Multiple doses of RLY-2608 for oral administration.

Group VII: RLY-2608 + fulvestrant combination for HR+ HER2- locally advanced or metastatic breast cancer Experimental Treatment 2 Interventions

Oral dose of RLY-2608 in addition to fulvestrant as determined during Part 1 Dose Escalation.

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?

Relay Therapeutics, Inc.

Lead Sponsor

Trials

5

Recruited

1,900+

Findings from Research

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]

Fulvestrant, an estrogen receptor antagonist, was effective in treating advanced breast cancer in postmenopausal women, showing an overall clinical benefit in 39% of the 339 patients studied, with better outcomes when used as a first-line treatment.

The treatment was well tolerated, with only 5% of patients experiencing adverse events, and it was particularly beneficial for patients with tumors expressing both estrogen and progesterone receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant ("Faslodex"): clinical experience from the Compassionate Use Programme. Steger, GG., Gips, M., Simon, SD., et al.[2018]

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]

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]

Fulvestrant is an effective estrogen receptor antagonist for postmenopausal women with advanced breast cancer who have progressed after previous endocrine therapies, as demonstrated in a Compassionate Use Programme with diverse patient cases.

Clinical experience from the Compassionate Use Programme aligns with clinical trial data, indicating that fulvestrant is a valuable treatment option even for patients with challenging disease characteristics, such as visceral metastases and HER2-positive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case studies of fulvestrant ("Faslodex") in postmenopausal women with advanced breast cancer. Abram, P., Maass, N., Rea, D., 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]

In a study of 402 postmenopausal women with advanced breast cancer receiving fulvestrant through a Compassionate Use Program, 29.9% experienced clinical benefits, including partial responses and stable disease for over 6 months.

Fulvestrant was well tolerated, with only 1.5% of patients discontinuing treatment due to adverse events, indicating its safety and potential as an effective option for patients who have not responded to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fulvestrant (Faslodex) in advanced breast cancer: clinical experience from a Belgian cooperative study. Neven, P., Paridaens, R., Pelgrims, G., et al.[2018]

References

1. Spain pubmed.ncbi.nlm.nih.gov

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

2. Netherlands pubmed.ncbi.nlm.nih.gov

Fulvestrant ("Faslodex"): clinical experience from the Compassionate Use Programme. [2018]

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

Fulvestrant ('Faslodex') in heavily pretreated postmenopausal patients with advanced breast cancer: single centre clinical experience from the compassionate use programme. [2018]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Case studies of fulvestrant ("Faslodex") in postmenopausal women with advanced breast cancer. [2018]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Fulvestrant in heavily pre-treated patients with advanced breast cancer: results from a single compassionate use programme centre. [2018]

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

Fulvestrant (Faslodex) in advanced breast cancer: clinical experience from a Belgian cooperative study. [2018]