GDC-9545 + Palbociclib/LHRH Agonist for Breast Cancer

Recruiting at 32 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

181 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD) activity, and preliminary anti-tumor activity of GDC-9545 as a single agent and in combination with palbociclib and/or luteinizing hormone-releasing hormone (LHRH) agonist in participants with advanced or metastatic estrogen receptor (ER)-positive (human epidermal growth factor receptor 2 \[HER2\]-negative) breast cancer.

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.

What evidence supports the effectiveness of the drug combination GDC-9545 and Palbociclib for breast cancer?

Palbociclib, when combined with hormone therapy, has been shown to significantly extend the time patients live without their cancer getting worse in advanced breast cancer cases. This combination has been effective in both women and men with hormone receptor-positive, HER2-negative breast cancer, as demonstrated in clinical trials like PALOMA-2 and PALOMA-3. ^{1 2 3 4 5}

Is the combination of GDC-9545, Palbociclib, and LHRH Agonist safe for treating breast cancer?

Palbociclib (Ibrance) is generally considered safe for treating advanced breast cancer, with neutropenia (a low level of neutrophils, a type of white blood cell) being the most common side effect. It has been used safely in both women and men with hormone receptor-positive, HER2-negative breast cancer, and its side effects are manageable. ^{1 2 3 4 6}

What makes the drug GDC-9545 + Palbociclib/LHRH Agonist unique for breast cancer treatment?

This drug combination is unique because it targets breast cancer cells expressing LHRH receptors, using a combination of GDC-9545, a novel estrogen receptor degrader, and Palbociclib, a cell cycle inhibitor, along with an LHRH agonist to suppress ovarian function, offering a targeted approach for hormone receptor-positive breast cancer. ^{7 8 9 10 11}

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

References

1. France pubmed.ncbi.nlm.nih.gov

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

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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. [2023]

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The safety and efficacy of palbociclib in the treatment of metastatic breast cancer. [2017]

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FDA Approval Summary: Palbociclib for Male Patients with Metastatic Breast Cancer. [2021]

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The effects of adding palbociclib to endocrine therapy to treat advanced breast cancer: a plain language summary of a study using the PALOMA-2 and PALOMA-3 trial results. [2023]

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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). [2022]

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10. Ireland pubmed.ncbi.nlm.nih.gov

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11. Germany pubmed.ncbi.nlm.nih.gov

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