Sacituzumab Govitecan + Zimberelimab + Radiation for Breast Cancer with Brain Metastases

Overseen By Kamran Ahmed, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Antiarrhythmics, Immunosuppressants

Disqualifiers: Leptomeningeal disease, HIV, Autoimmune, others

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

Compensation: Varies

Number of Visits: 4

Duration: 9 weeks

31 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase I/II Study to determine the safety and efficacy of Sacituzumab Govitecan and Zimberelimab with stereotactic radiation (SRS) in participants with metastatic triple negative breast cancer with brain metastases, compared to treatment with Sacituzumab Govitecan alone.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on certain investigational drugs or have had recent chemotherapy or targeted therapy, you may need to wait before joining the trial.

What data supports the effectiveness of the treatment Sacituzumab Govitecan + Zimberelimab + Radiation for breast cancer with brain metastases?

The combination of radiation therapy and systemic treatments has been explored for brain metastases from breast cancer, with some systemic treatments showing significant activity in the central nervous system. Additionally, combining radiation with chemotherapy has been a focus to improve survival and quality of life for these patients. ^{1 2 3 4 5}

What safety data exists for Sacituzumab Govitecan (Trodelvy) in humans?

Sacituzumab Govitecan (Trodelvy) has been studied for safety in patients with various cancers, including breast cancer. Common side effects include nausea, diarrhea, fatigue, and low blood cell counts, which can lead to infections. Serious side effects like colitis (inflammation of the colon) and sepsis (a severe infection) have been reported, so patients need close monitoring. ^{6 7 8 9 10}

How is the treatment of Sacituzumab Govitecan + Zimberelimab + Radiation unique for breast cancer with brain metastases?

This treatment is unique because it combines Sacituzumab Govitecan, an antibody-drug conjugate that targets cancer cells, with Zimberelimab, an immune checkpoint inhibitor that helps the immune system attack cancer, and radiation therapy, which directly targets brain metastases. This combination aims to enhance the effectiveness of treatment by using different mechanisms to target cancer cells and improve patient outcomes. ^{2 4 11 12 13}

Research Team

Kamran Ahmed, M.D.

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

This trial is for individuals with metastatic triple-negative breast cancer that has spread to the brain. Participants should not have had prior treatment with Sacituzumab Govitecan or immune checkpoint inhibitors, and must be suitable for stereotactic radiation.

Inclusion Criteria

I am 18 years old or older.

My breast cancer is triple negative with very low ER and PR levels.

I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

I do not have any health conditions that make this study risky for me.

I haven't taken any experimental drugs recently.

I have active hepatitis B or C.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive stereotactic radiation (SRS) as part of the treatment initiation

1 week

1 visit (in-person)

Treatment

Participants receive Sacituzumab Govitecan on days 1 and 8 and Zimberelimab on day 1, repeated every 3 weeks

9 weeks

3 cycles of treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment, with imaging response assessments every 9 weeks

Up to 33 months

Treatment Details

Interventions

• Sacituzumab govitecan
• Stereotactic Radiation
• Zimberelimab

Trial Overview The study is testing the combination of a drug called Zimberelimab and another drug, Sacituzumab Govitecan, along with focused radiation therapy (SRS), against using just Sacituzumab Govitecan. It aims to see if adding Zimberelimab and SRS improves outcomes.

Participant Groups

Group I: SG + Zimberelimab with SRS Experimental Treatment 3 Interventions

Treatment will be initiated with SRS followed 1 week later by SG on days 1 and 8 (10mg/kg) with zimberelimab on day 1 (360 mg IV) repeated every 3 weeks follow-up imaging response assessments will be conducted at q9 week intervals.

Sacituzumab govitecan is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Trodelvy for:

• Unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease
• Locally advanced or metastatic urothelial cancer (mUC) who previously received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor
• Unresectable locally advanced or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting

Approved in European Union as Trodelvy for:

• Unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease

Approved in Canada as Trodelvy for:

• Unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Gilead Sciences

Industry Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Findings from Research

In the LANDSCAPE study, a combination of capecitabine and lapatinib showed a significant volumetric response in about two-thirds of HER2-positive breast cancer patients with untreated brain metastases, indicating promising efficacy despite the challenges posed by the blood-brain barrier.

These findings suggest that targeted therapies like capecitabine and lapatinib could change treatment strategies for selected patients with brain metastases, highlighting the need for innovative approaches to improve survival rates in this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Systemic treatment of brain metastases from breast cancer: cytotoxic chemotherapy and targeted therapies]. Bachelot, T., Le Rhun, E., Labidi-Gally, I., et al.[2018]

The incidence of brain metastases from breast cancer is rising, particularly due to advancements in diagnosis and systemic therapies, highlighting the need for effective treatment strategies.

Whole brain radiation therapy is currently the standard treatment but has limited efficacy, with a median overall survival of only 6 months, indicating a pressing need for new approaches, such as combining radiation with chemotherapy to improve survival and quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Radiotherapy plus concomitant systemic therapies for patients with brain metastases from breast cancer]. Cao, KI., Kirova, YM.[2018]

In a study of 80 patients with brain metastases from HER2-positive breast cancer, the addition of lapatinib to trastuzumab significantly improved overall survival, with a median survival not reached in the lapatinib group compared to 13 months for trastuzumab alone.

Lapatinib was identified as an independent positive predictor for survival, suggesting that patients with a Karnofsky Performance Score of 70 or higher may benefit from this combination therapy after local treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases. Bartsch, R., Berghoff, A., Pluschnig, U., et al.[2021]

Younger age, negative hormone receptor status, and specific genetic mutations (like BRCA1) are linked to a higher risk of developing CNS metastases in breast cancer patients, influencing treatment decisions.

Surgery combined with whole brain radiation therapy (WBRT) is effective for patients with a single brain metastasis, while those with multiple metastases may benefit from stereotactic radiosurgery, highlighting the importance of individual prognostic factors in treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CNS complications of breast cancer: current and emerging treatment options. Kaal, EC., Vecht, CJ.[2021]

In a phase 2 study involving 45 patients with untreated brain metastases from HER2-positive breast cancer, the combination of lapatinib and capecitabine resulted in a significant objective CNS response rate of 65.9%, indicating its potential efficacy as a first-line treatment.

While 49% of patients experienced grade 3 or 4 treatment-related adverse events, including diarrhea and hand-foot syndrome, there were no toxic deaths, suggesting that the treatment is relatively safe despite the risk of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Bachelot, T., Romieu, G., Campone, M., et al.[2022]

Sacituzumab govitecan is an antibody-drug conjugate that targets Trop-2 and has shown a 33.3% overall response rate in patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies, based on a phase I/II study with 108 participants.

The treatment has a median duration of response of 7.7 months, and while it is generally well-tolerated, common side effects include nausea, neutropenia, and fatigue, indicating a need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacituzumab Govitecan-hziy: An Antibody-Drug Conjugate for the Treatment of Refractory, Metastatic, Triple-Negative Breast Cancer. Seligson, JM., Patron, AM., Berger, MJ., et al.[2021]

A total of 1,884 adverse event reports related to sacituzumab govitecan were analyzed, identifying 114 adverse event signals, with most occurring within 30 days of treatment initiation, highlighting the importance of monitoring for early reactions.

Risk factors for hospitalization due to adverse events included being male and experiencing conditions like colitis, febrile neutropenia, and sepsis, indicating specific patient profiles that may require closer observation during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postmarketing safety of Sacituzumab govitecan: a pharmacovigilance study based on FDA adverse event reporting system (FAERS). Li, X., Zhang, L., Hu, S., et al.[2023]

Sacituzumab govitecan-hziy (TRODELVY) received accelerated FDA approval for treating metastatic triple-negative breast cancer (mTNBC) based on a trial involving 108 patients, showing an objective response rate of 33.3% and a median duration of response of 7.7 months.

The safety profile was assessed in a larger group of 408 patients, with common side effects including nausea, neutropenia, and fatigue, occurring in 25% or more of patients, indicating that while effective, the treatment can have significant adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Sacituzumab Govitecan-hziy for Third-line Treatment of Metastatic Triple-negative Breast Cancer. Wahby, S., Fashoyin-Aje, L., Osgood, CL., et al.[2022]

Sacituzumab govitecan, an antibody-drug conjugate targeting Trop-2, showed promising therapeutic activity in a phase I trial with 25 patients suffering from various metastatic solid cancers, achieving partial responses in two patients and stable disease in 16 others.

The maximum tolerated dose was determined to be 12 mg/kg for the first cycle, with lower doses (8 and 10 mg/kg) being safer for extended treatment, leading to acceptable toxicity levels and disease control for up to 36 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors. Starodub, AN., Ocean, AJ., Shah, MA., et al.[2022]

Sacituzumab govitecan (IMMU-132) has been shown to prolong progression-free survival in patients with advanced triple-negative breast cancer, indicating its efficacy as a treatment option.

The treatment is well tolerated, resulting in fewer and more manageable side effects compared to traditional irinotecan, suggesting a safer profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An ADC for Triple-Negative Breast Cancer. [2018]

In a retrospective study of seven breast cancer patients with inoperable brain metastases, bevacizumab-based chemotherapy (BBCT) followed by whole-brain radiation therapy (WBRT) showed no severe brain toxicity, indicating a potentially safe treatment sequence.

The most common side effects reported were mild to moderate, including nausea and headache, and there were no signs of serious complications like necrosis or cerebral ischemia, suggesting that BBCT can be administered safely before WBRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary experience of whole-brain radiation therapy (WBRT) in breast cancer patients with brain metastases previously treated with bevacizumab-based chemotherapy. Chira, C., Jacob, J., Derhem, N., et al.[2021]

In a study involving 143 patients with HER2+ breast cancer and brain metastases, the addition of lapatinib to whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) did not improve the 12-week complete response rate compared to radiation therapy alone.

However, there was a short-term benefit observed, as the combination of radiation therapy and lapatinib showed a higher objective response rate at 4 weeks (55% vs 42%), although this did not translate into improved long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent Lapatinib With Brain Radiation Therapy in Patients With HER2+ Breast Cancer With Brain Metastases: NRG Oncology-KROG/RTOG 1119 Phase 2 Randomized Trial. Kim, IA., Winter, KA., Sperduto, PW., et al.[2023]

In a review of 28 breast cancer patients with brain metastases treated with radiotherapy, 92% showed neurologic functional improvement, with 46% achieving complete response, indicating that radiotherapy is effective for managing brain metastases in these patients.

Despite the potential for long-term survival (39% at 5 years), the presence of liver metastasis was identified as a significant risk factor for reduced survival, and careful management is needed to avoid severe radiation-related complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapeutic Management of Brain Metastases from Breast Cancer. Hayakawa, K., Yamakawa, M., Mitsuhashi, N., et al.[2019]

References

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

[Systemic treatment of brain metastases from breast cancer: cytotoxic chemotherapy and targeted therapies]. [2018]

2. France pubmed.ncbi.nlm.nih.gov

[Radiotherapy plus concomitant systemic therapies for patients with brain metastases from breast cancer]. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases. [2021]

4. New Zealand pubmed.ncbi.nlm.nih.gov

CNS complications of breast cancer: current and emerging treatment options. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. [2022]

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

Sacituzumab Govitecan-hziy: An Antibody-Drug Conjugate for the Treatment of Refractory, Metastatic, Triple-Negative Breast Cancer. [2021]

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

Postmarketing safety of Sacituzumab govitecan: a pharmacovigilance study based on FDA adverse event reporting system (FAERS). [2023]

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

FDA Approval Summary: Accelerated Approval of Sacituzumab Govitecan-hziy for Third-line Treatment of Metastatic Triple-negative Breast Cancer. [2022]

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

First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors. [2022]

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

An ADC for Triple-Negative Breast Cancer. [2018]

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

Preliminary experience of whole-brain radiation therapy (WBRT) in breast cancer patients with brain metastases previously treated with bevacizumab-based chemotherapy. [2021]

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

Concurrent Lapatinib With Brain Radiation Therapy in Patients With HER2+ Breast Cancer With Brain Metastases: NRG Oncology-KROG/RTOG 1119 Phase 2 Randomized Trial. [2023]

13. Japan pubmed.ncbi.nlm.nih.gov

Radiotherapeutic Management of Brain Metastases from Breast Cancer. [2019]