Zanidatamab + Palbociclib + Fulvestrant for Breast Cancer

No longer recruiting at 14 trial locations

Overseen By Zymeworks Clinical Trial Resource

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Zymeworks Inc.

Must not be taking: CDK4/6 inhibitors

Disqualifiers: Cardiac disease, Hepatitis, HIV, 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: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for breast cancer that cannot be surgically removed or has spread to other parts of the body. The goal is to assess the safety and effectiveness of combining zanidatamab (an experimental treatment), palbociclib, and fulvestrant for individuals with HER2-positive and hormone receptor-positive breast cancer. The trial seeks participants who have tried certain other treatments but still experienced cancer progression. Participants must have a confirmed diagnosis of this type of breast cancer and have previously undergone treatments like trastuzumab. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial requires that you stop any prior treatment with trastuzumab, pertuzumab, lapatinib, T-DM1, or other anti-HER2-targeted therapy, as well as chemotherapy, other anti-cancer therapy, or hormonal cancer therapy at least 3 weeks before starting the study treatment. If you are currently on these medications, you will need to stop them before joining the trial.

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

Research shows that the combination of zanidatamab, palbociclib, and fulvestrant is generally safe for patients. Studies indicate that most people tolerate this treatment without severe side effects.

Some side effects have been reported, but they are usually manageable and not serious for most patients. The treatment has shown promising results in fighting tumors, which is encouraging for its overall effectiveness.

Although researchers continue to study this treatment, current evidence suggests it is safe for individuals with HER2-positive, hormone receptor-positive breast cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Zanidatamab (ZW25), Palbociclib, and Fulvestrant for breast cancer because it offers a unique approach compared to current treatments. Unlike the standard treatments that primarily target hormone receptors or inhibit cancer cell division, Zanidatamab is a bispecific antibody designed to target two different sites on the HER2 protein, potentially leading to more effective tumor suppression. This dual-targeting mechanism could enhance the effectiveness of treatment by improving binding to cancer cells and enabling the immune system to better recognize and attack the tumor. Combining Zanidatamab with Palbociclib, a CDK4/6 inhibitor, and Fulvestrant, an estrogen receptor degrader, may offer a comprehensive strategy to tackle cancer growth from multiple fronts.

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

Research has shown that the combination of zanidatamab, palbociclib, and fulvestrant, which participants in this trial will receive, holds promise for treating HER2-positive and hormone receptor-positive breast cancer. Studies have found that this combination leads to lasting responses and has a manageable safety profile. Zanidatamab is a special type of antibody that targets HER2, a protein that can help cancer cells grow. This combination has demonstrated positive results in terms of progression-free survival (PFS), meaning patients lived longer without their cancer worsening. These findings support the potential effectiveness of this treatment for patients with advanced breast cancer. ^{1 2 3 5 6}

Who Is on the Research Team?

Elaina Gartner, MD

Principal Investigator

Zymeworks Inc.

Are You a Good Fit for This Trial?

This trial is for adults with advanced breast cancer that's both HER2-positive and hormone receptor-positive. They must have tried certain other treatments like trastuzumab without success, be in good physical condition (ECOG score of 0 or 1), and have no serious heart, lung, liver, or nervous system problems. People with active hepatitis B/C, HIV not well-controlled, recent heart attacks or unstable angina are excluded.

Inclusion Criteria

I've had specific treatments for my cancer and it has gotten worse despite them.

I am fully active or restricted in physically strenuous activity but can do light work.

My heart pumps blood well, meeting the normal standards.

Exclusion Criteria

I have severe lung inflammation or scarring not caused by cancer spread.

I do not have severe nerve damage in my hands or feet.

I haven't taken any HER2-targeted cancer treatments in the last 3 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Part 1

Evaluation of safety and tolerability of ZW25 in combination with palbociclib plus fulvestrant to confirm recommended doses

4 weeks

Cycle 1 Day 1 to Day 28

Treatment - Part 2

Evaluation of anti-tumor activity of ZW25 with palbociclib plus fulvestrant at recommended dose levels

Up to approximately 2 years 10 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days after last study dose

What Are the Treatments Tested in This Trial?

Interventions

• Fulvestrant
• Palbociclib
• ZW25 (Zanidatamab)

Trial Overview The study tests ZW25 (zanidatamab) combined with palbociclib plus fulvestrant to see how safe it is and how well it works against this type of breast cancer. It's an open-label Phase 2a trial where everyone knows what treatment they're getting.

How Is the Trial Designed?

Group I: ZW25 (zanidatamab) + palbociclib + fulvestrant Experimental Treatment 3 Interventions

ZW25 (zanidatamab) plus palbociclib, fulvestrant

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?

Zymeworks Inc.

Lead Sponsor

Trials

11

Recruited

2,400+

Jazz Pharmaceuticals

Lead Sponsor

Trials

252

Recruited

35,100+

Bruce C. Cozadd

Jazz Pharmaceuticals

Chief Executive Officer since 2009

BA in Economics from Yale University, MBA from Stanford University

Dr. Austin

Jazz Pharmaceuticals

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Published Research Related to This Trial

In a study involving 1723 women with HR+/HER2- advanced or metastatic breast cancer, palbociclib combined with aromatase inhibitors or fulvestrant showed low dose-reduction rates (18.9% and 12.3%, respectively), indicating good tolerability.

The treatment demonstrated favorable progression-free rates (PFR) at 12 months, with 88.1% for palbociclib + AI and 79.8% for palbociclib + fulvestrant, along with high survival rates (97.3% and 97.5%, respectively), suggesting its effectiveness in real-world clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world treatment of patients with palbociclib for HR+/HER2-advanced/metastatic breast cancer: the Europe IRIS study. Mycock, K., Zhan, L., Hart, K., et al.[2022]

In a study of 521 premenopausal and postmenopausal patients with endocrine-resistant metastatic breast cancer, those treated with palbociclib and fulvestrant showed a higher rate of prolonged benefit (29%) compared to those on placebo and fulvestrant (15%).

Long-term responders to palbociclib-fulvestrant tended to have less disease burden at baseline and lower rates of certain mutations, but no specific molecular or clinical factors were identified as predictors of long-term benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in PALOMA-3. Cristofanilli, M., DeMichele, A., Giorgetti, C., et al.[2022]

In the PALOMA-3 study involving 521 patients with hormone receptor-positive, HER2- metastatic breast cancer, the combination of palbociclib and fulvestrant significantly improved global quality of life (QoL) scores compared to fulvestrant plus placebo, indicating better patient-reported outcomes.

Patients receiving palbociclib plus fulvestrant also experienced a significant reduction in pain and a delay in deterioration of both global QoL and pain compared to those on fulvestrant alone, highlighting the efficacy of this combination therapy in managing symptoms and improving quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Harbeck, N., Iyer, S., Turner, N., et al.[2022]

In the FLIPPER trial, the combination of palbociclib and fulvestrant significantly improved progression-free survival (PFS) in postmenopausal women with HR+/HER2- advanced breast cancer compared to placebo and fulvestrant.

Patient-reported outcomes indicated that while global health status and quality of life (QoL) were maintained during treatment with palbociclib/fulvestrant, the time to deterioration in QoL was longer with placebo/fulvestrant, suggesting that palbociclib/fulvestrant is a beneficial treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. Tibau, A., Martínez, MT., Ramos, M., et al.[2023]

In a phase II study involving 190 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, the combination of palbociclib and fulvestrant significantly improved one-year progression-free survival (PFS-1y) rates (83.5% vs. 71.9% for placebo) and median PFS (31.8 months vs. 22.0 months).

While the palbociclib/fulvestrant combination showed better efficacy, it was associated with higher rates of grade 3-4 adverse events, particularly neutropenia (68.1% vs. 0% in the placebo group), indicating a need for careful monitoring of side effects in patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2-advanced breast cancer: GEICAM/2014-12 (FLIPPER). Albanell, J., Martínez, MT., Ramos, M., et al.[2022]

Palbociclib, when combined with fulvestrant, significantly improves progression-free survival in women with hormone receptor-positive, HER2-negative advanced breast cancer, showing a median PFS of 9.5 months compared to 4.6 months with placebo, based on a study of 521 women.

The safety profile of palbociclib includes common adverse reactions such as neutropenia and infections, which were observed in over 20% of patients, confirming its known side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval of Palbociclib in Combination with Fulvestrant for the Treatment of Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer. Walker, AJ., Wedam, S., Amiri-Kordestani, L., et al.[2022]

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]

Citations

1. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(25)00140-8/abstract

Zanidatamab plus palbociclib and fulvestrant in previously ... In an ongoing, two-part, phase 2a study, we assessed the safety and antitumour activity of zanidatamab, a HER2-targeted bispecific antibody, ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1470204525001408

Zanidatamab plus palbociclib and fulvestrant in previously ... Zanidatamab plus palbociclib and fulvestrant was generally safe and showed promising antitumour activity, supporting further evaluation of this chemotherapy- ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04224272

NCT04224272 | A Study of ZW25 (Zanidatamab) With ... This is a multicenter, Phase 2a, open-label, 2-part study to investigate the safety, tolerability, and anti-tumor activity of ZW25 (zanidatamab) in ...

4. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-025-13749-1

Exploring Zanidatamab's efficacy across HER2-positive ... Zanidatamab has shown promising clinical outcomes in several HER2-positive cancers, including biliary tract, breast, gastric, and lung cancers.

5. targetedonc.com targetedonc.com/view/zanidatamab-plus-palbociclib-fulvestrant-shows-promising-pfs-in-her2-hr-mbc

Zanidatamab Plus Palbociclib, Fulvestrant Shows ... Zanidatamab, in combination with palbociclib and fulvestrant demonstrated a promising PFS outcome, durable responses, and a manageable safety profile.

6. clin.larvol.com clin.larvol.com/trial-detail/NCT04224272

A Study of ZW25 (Zanidatamab) With Palbociclib Plus ... Zanidatamab in combination with palbociclib and fulvestrant, demonstrated meaningful PFS outcomes with a well tolerated safety profile in patients with heavily ...