GDC-9545 + Palbociclib/LHRH Agonist for Breast Cancer

Not currently recruiting at 37 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Genentech, Inc.

Must be taking: LHRH agonist

Must not be taking: Warfarin, Phenytoin, Beta blockers, others

Disqualifiers: Brain metastases, Secondary malignancy, Liver disease, others

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

Compensation: Varies

Number of Visits: 36

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for advanced breast cancer that is estrogen receptor-positive and HER2-negative, meaning the cancer grows with estrogen and is not affected by the HER2 protein. The trial aims to evaluate the safety and effectiveness of the drug GDC-9545, an experimental treatment, used alone or with other drugs like palbociclib and LHRH agonists. Individuals with advanced or metastatic breast cancer that has not responded to other treatments and who have not tried certain other medications might be suitable for this study. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that at least 2 weeks have passed since using any other endocrine, targeted therapy, or chemotherapy. Additionally, if you are undergoing specific imaging, you may need to stop certain medications like tamoxifen for 2 months or fulvestrant for 6 months before starting the trial. Please consult with the trial team for guidance on your specific medications.

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

Research has shown that GDC-9545, a treatment under testing, is generally safe for people. In earlier studies, GDC-9545 performed well on its own, even in patients with specific genetic changes called ESR1 mutations. These findings suggest that the drug is safe and does not cause many serious side effects.

When combined with palbociclib, a medicine already approved for breast cancer, the treatment remains generally safe. Palbociclib is a drug that helps stop cancer cells from growing.

Although current trials are still in the early stages, earlier research indicates that the safety of GDC-9545, both alone and with palbociclib, looks promising. Participants should feel encouraged by the safety information available so far. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about GDC-9545 for breast cancer because it represents a new approach to treatment. Unlike traditional hormone therapies that generally target estrogen receptors broadly, GDC-9545 is a selective estrogen receptor degrader (SERD) that aims to degrade the receptor itself, potentially leading to more effective tumor suppression. Additionally, when combined with palbociclib, a CDK4/6 inhibitor, it offers a potent one-two punch that could improve outcomes by attacking cancer cells from multiple fronts. This combination could offer a more targeted and effective treatment option for both premenopausal and postmenopausal women, addressing an unmet need in breast cancer care.

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

Studies have shown that GDC-9545, a drug targeting estrogen receptors, effectively slows the progression of estrogen receptor-positive breast cancer. In this trial, some participants will receive GDC-9545 combined with palbociclib, a drug that stops cancer cells from dividing. Research indicates this combination improves the treatment's ability to fight tumors in patients whose cancer has worsened despite previous hormone treatments. Palbociclib, when used with hormone therapy, has already been proven to help patients with hormone receptor-positive, HER2-negative breast cancer live longer. Early findings suggest that adding an LHRH agonist, which reduces estrogen levels, could enhance the treatment's effectiveness for pre- or perimenopausal women. This trial tests the combination of GDC-9545, palbociclib, and an LHRH agonist, which looks promising based on these initial results. ^{6 7 8 9 10}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

This trial is for postmenopausal women with advanced or metastatic ER-positive/HER2-negative breast cancer. Participants should have an ECOG Performance Status ≤1, no more than two prior treatments for their condition, and adequate organ function. They must not have had certain recent surgeries or therapies, severe medical conditions that could affect safety or results, known HIV infection, significant heart disease risks, untreated brain metastases, or a history of certain malignancies within the last three years.

Inclusion Criteria

I have cancer that can be measured or seen in my bones.

My breast cancer has returned or spread and cannot be removed or cured with surgery or radiation.

My breast cancer is HER2-negative.

Exclusion Criteria

I have not had major surgery in the last 4 weeks.

I have not had radiation therapy in the last 2 weeks.

You have a history of significant heart rhythm problems or a past heart attack.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of GDC-9545 to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD)

Varies per participant

Visits every 28 days

Dose Expansion

Participants receive GDC-9545 alone or in combination with palbociclib and/or LHRH agonist at predefined dose levels

Up to 84 months

Visits every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• GDC-9545
• LHRH Agonist
• Palbociclib

Trial Overview The study tests GDC-9545's effectiveness and safety alone and in combination with palbociclib and/or LHRH agonist in treating estrogen receptor-positive breast cancer. It will assess how the body processes these drugs (PK), their impact on the body (PD), and preliminary anti-tumor activity through various stages including dose escalation.

How Is the Trial Designed?

Group I: Dose Expansion: Cohort X: GDC-9545 Dose 3 Experimental Treatment 1 Intervention

GDC-9545 will be administered at a pre-defined dose level (Dose 3) to postmenopausal participants currently receiving clinical benefit with GDC-0927 or GDC-0810 on Studies GO29656 (NCT02316509) or GO29642 (NCT01823835), respectively, upon completion of their studies.

Group II: Dose Expansion: Cohort C2: GDC-9545 Dose 2 + Palbociclib Experimental Treatment 2 Interventions

GDC-9545 will be administered to postmenopausal participants at a pre-defined dose level (Dose 2), in combination with the label-recommended dose of palbociclib.

Group III: Dose Expansion: Cohort C1: GDC-9545 Dose 2 +/- Palbociclib Experimental Treatment 2 Interventions

GDC-9545 will be administered to postmenopausal participants at a pre-defined dose level (Dose 2) as a single agent for 14 days, followed by treatment with either GDC-9545 (Dose 2) plus palbociclib or GDC-9545 (Dose 2) alone for the duration of the study, as determined by the investigator.

Group IV: Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH Experimental Treatment 3 Interventions

GDC-9545 will be administered to pre- or perimenopausal participants, at a dose that is less than or equal to the MTD/MAD, in combination with the label-recommended dose of palbociclib and an approved LHRH agonist.

Group V: Dose Expansion: Cohort B1: GDC-9545 + Palbociclib Experimental Treatment 2 Interventions

GDC-9545 will be administered to postmenopausal participants, at a dose that is less than or equal to the MTD/MAD, in combination with the label-recommended dose of palbociclib.

Group VI: Dose Expansion: Cohort A5: GDC-9545 Dose 3 Experimental Treatment 1 Intervention

GDC-9545 will be administered to postmenopausal participants as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 3).

Group VII: Dose Expansion: Cohort A4: GDC-9545 Dose 2 + LHRH Experimental Treatment 2 Interventions

GDC-9545 will be administered to pre- or perimenopausal participants at a dose that is less than or equal to the MTD/MAD (Dose 2) in combination with an LHRH agonist.

Group VIII: Dose Expansion: Cohort A3: GDC-9545 Dose 2 Experimental Treatment 1 Intervention

GDC-9545 will be administered to postmenopausal participants as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 2).

Group IX: Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRH Experimental Treatment 2 Interventions

GDC-9545 will be administered to pre- or perimenopausal participants at a dose that is less than or equal to the MTD/MAD (Dose 1) in combination with an approved LHRH agonist.

Group X: Dose Expansion: Cohort A1: GDC-9545 Dose 1 Experimental Treatment 1 Intervention

GDC-9545 will be administered to postmenopausal participants as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 1).

Group XI: Dose Escalation: GDC-9545 Experimental Treatment 1 Intervention

During dose escalation, postmenopausal participants will be assigned sequentially to escalating doses of GDC-9545, up to the maximum tolerated dose (MTD) or maximum administered dose (MAD).

Group XII: Dose Escalation: Cohort B0: GDC-9545 + Palbociclib Experimental Treatment 2 Interventions

GDC-9545 will be administered to postmenopausal participants, at a dose lower than the MTD or MAD determined in single-agent dose escalation, in combination with the label-recommended dose of palbociclib.

Who Is Running the Clinical Trial?

Genentech, Inc.

Lead Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

The FDA approved palbociclib (IBRANCE) for use in men with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, expanding its indications beyond women, based on data from the PALOMA-2 and PALOMA-3 trials.

The approval was supported by safety data from phase I studies and real-world evidence, confirming that palbociclib is a viable treatment option for male patients with this type of breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Palbociclib for Male Patients with Metastatic Breast Cancer. Wedam, S., Fashoyin-Aje, L., Bloomquist, E., et al.[2021]

In a study of 517 patients with hormone receptor-positive metastatic breast cancer, palbociclib combined with fulvestrant was found to be well-tolerated, with neutropenia being the most common adverse effect, occurring in 55% of patients as grade 3 and 10% as grade 4.

Despite the occurrence of neutropenia, dose modifications were effective in managing this side effect without negatively impacting progression-free survival, indicating that palbociclib can be safely integrated into treatment regimens for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3). Verma, S., Bartlett, CH., Schnell, P., et al.[2022]

In a study of 191 patients with metastatic breast cancer receiving palbociclib, the median progression-free survival was 22.8 months for first-line treatment, indicating significant efficacy of the drug in delaying disease progression.

While 47% of patients experienced severe neutropenia, the overall survival rate at 24 months was 74.2% for first-line treatment, suggesting that palbociclib is effective but requires monitoring for potential adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world study of the first use of palbociclib for the treatment of advanced breast cancer within the UK National Health Service as part of the novel Ibrance® Patient Program. Palmieri, C., Musson, A., Harper-Wynne, C., et al.[2023]

Palbociclib is the first CDK4/6 inhibitor approved for treating estrogen receptor-positive, HER2-negative metastatic breast cancer, and it works by selectively inhibiting CDK4 and CDK6, enhancing the effects of anti-estrogens like letrozole and fulvestrant.

Clinical trials show that palbociclib significantly doubles the treatment efficacy of letrozole and fulvestrant while maintaining a manageable safety profile, positively impacting patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of palbociclib in the treatment of metastatic breast cancer. Ettl, J., Harbeck, N.[2017]

Oral palbociclib is an effective treatment for HR-positive, HER2-negative advanced or metastatic breast cancer, significantly prolonging progression-free survival when used with letrozole or fulvestrant in clinical trials involving postmenopausal women.

The most common side effect was neutropenia, which was manageable and rarely led to serious complications, indicating that palbociclib can be safely administered without significantly compromising its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer. Kim, ES., Scott, LJ.[2022]

Citations

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Roche's phase III evERA data showed giredestrant ... Giredestrant plus everolimus reduced the risk of disease progression or death by 44% and 62% in ITT and ESR1-mutated populations, ...

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A Study of GDC-9545 Alone or in Combination With ... This study will evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD) activity, and preliminary anti-tumor activity of GDC-9545 as a single agent ...

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Safety and activity of single-agent giredestrant (GDC-9545) ... Giredestrant, a highly potent, nonsteroidal oral selective ER degrader, achieves robust ER occupancy, is active despite ESR1 mutations, and was well tolerated.

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NCT03332797 | A Study of GDC-9545 Alone or in ... This study will evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD) activity, and preliminary anti-tumor activity of GDC-9545 as a single agent ...

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Giredestrant for Estrogen Receptor–Positive, HER2-Negative ... Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data ...

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Clinical Trial – Breast Cancer – Efficacy and Safety of G... A clinical trial to compare GDC-9545 with a doctor's choice of hormonal therapy in people with advanced or metastatic breast cancer after previous treatment