New Treatments for Metastatic Breast Cancer

(PRE-I-SPY-PI Trial)

Recruiting at 6 trial locations

Overseen By Maria Pitsiouni, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: QuantumLeap Healthcare Collaborative

Must not be taking: Anticancer therapy

Disqualifiers: Diabetes, Cardiovascular disease, Liver disease, others

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

Compensation: Varies

Number of Visits: Unknown

124 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for metastatic breast cancer, where cancer spreads beyond the breast to other body parts. It explores combinations of drugs like ALX148 (Evorpacept, an experimental treatment) and Fam-Trastuzumab Deruxtecan-Nxki (Enhertu) to determine if they can better fight cancer by enhancing the body’s natural immune response or targeting specific proteins in cancer cells. Individuals with HER2-positive breast cancer, characterized by a specific protein, might be suitable for this study. Participants should commit to the study schedule and have previously tried other cancer treatments. As a Phase 1 trial, this research aims to understand 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 a 'washout period' (time without taking certain medications) for some treatments before starting the study. For example, chemotherapy and investigational agents need a 3-week washout, while endocrine therapy does not require any washout. It's best to discuss your specific medications with the trial team.

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

A previous study found evorpacept (ALX148) to be safe for patients with HER2-positive metastatic breast cancer and well-tolerated with other cancer treatments. For fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu®), research in patients with metastatic HER2-positive breast cancer showed that most side effects were mild to moderate and manageable.

Research on zanidatamab indicates it is generally safe and manageable for patients with HER2-expressing cancers. Tucatinib, studied with other drugs for HER2-positive breast cancer, has shown a tolerable safety profile. Some patients experienced mild reactions like diarrhea or nausea, but serious reactions were rare.

Overall, these treatments have shown promising safety results in previous studies. However, discussing potential side effects with a healthcare provider before joining a clinical trial is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for metastatic breast cancer because they bring novel mechanisms to the table. The combination of ALX148 and Fam-Trastuzumab Deruxtecan-Nxki is unique due to ALX148’s ability to block CD47, which enhances the immune system's ability to attack cancer cells, alongside the potent anti-cancer activity of Trastuzumab Deruxtecan. On the other hand, Zanidatamab and Tucatinib work together to target HER2-positive cancer cells. Zanidatamab is a bispecific antibody that downregulates HER2 receptors, while Tucatinib is a tyrosine kinase inhibitor that can cross the blood-brain barrier to treat central nervous system involvement. These innovative approaches could offer more effective and better-tolerated options compared to current treatments.

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

In this trial, participants will receive one of two treatment combinations. Research has shown that combining ALX148 with Fam-Trastuzumab Deruxtecan-Nxki holds promise for treating HER2-positive breast cancer. Early findings suggest this combination can help the immune system attack cancer cells more effectively, potentially leading to better patient outcomes. In past studies, adding ALX148 improved response rates when used with other cancer treatments.

Another treatment arm in this trial involves the combination of Zanidatamab and Tucatinib. Research indicates that using these two drugs together can slow cancer growth more effectively than using just one. Both Zanidatamab and Tucatinib have proven effective in treating HER2-positive cancers and have good safety records. ^{1 6 7 8 9}

Who Is on the Research Team?

Paula Pohlmann, MD, PhD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with breast cancer who have a life expectancy over 12 weeks and can follow the study plan. They must not be pregnant, should agree to use contraception, and have recovered from previous treatments. People with uncontrolled brain cancer, recent major surgery, or severe illnesses that affect study participation cannot join.

Inclusion Criteria

Non-Pregnant: Serum or urine pregnancy test must be negative within 14 days of IMP treatment start in women of childbearing potential

Estimated life expectancy > 12 weeks at the start of investigational medicinal product (IMP) treatment

The participant must have ability to understand and willingness to provide signed written informed consent prior to any study related assessments and procedures and for collection of archival FFPE blocks (freshly cut 14 unstained tumor slides would be acceptable)

Exclusion Criteria

I have a significant history of liver disease, including hepatitis, alcohol abuse, or cirrhosis.

You are in a place because of a legal order, such as prison or a mental health facility.

Other conditions, which in the opinion of the investigator, would compromise the safety of the patient or the patient's ability to complete the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-finding (Part 1)

Participants receive varying doses of the study drugs to determine the maximum tolerated dose

6 months

Regular visits for dose adjustment and monitoring

Dose-expansion (Part 2)

Participants receive the recommended phase 2 dose to further evaluate safety and efficacy

6-12 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Periodic visits for follow-up assessments

What Are the Treatments Tested in This Trial?

Interventions

• ALX148
• Fam-Trastuzumab Deruxtecan-Nxki

Trial Overview The I-SPY Phase I/Ib trial tests new drugs (Tucatinib, Zanidatamab, Fam-Trastuzumab Deruxtecan-Nxki, ALX148) alone or in combinations for metastatic breast cancer. It aims to identify effective treatments quickly for further trials.

How Is the Trial Designed?

Group I: PRE2 Zanidatamab (Ziihera®, ZW25, zani) + Tucatinib (TUKYSA®) Experimental Treatment 2 Interventions

Zanidatamab is a bispecific IgG1-like antibody directed against two distinct HER2 epitopes. It induces formation of receptor clusters and internalization resulting in downregulation. It also inhibits growth factor-dependent and -independent tumor cell proliferation and potently activates ADCC, ADCP, and CDC. FDA approved for metastatic HER2+ bile duct cancer. Tucatinib is a highly selective, small molecule tyrosine kinase inhibitor (TKI) of HER2 compared to other TKI's (i.e., EGFR). It is well tolerated, crosses the blood brain barrier and can treat CNS disease. FDA approved for HER2+ breast cancer. Given the promising clinical data for each of these drugs which have different mechanisms, the effect of zanidatamab after T-DXd (Enhertu®) in breast cancer patients, and the favorable toxicity profile of both drugs, we hypothesize that the combination of tucatinib and zanidatamab will be well tolerated and more efficacious than either drug alone for the treatment of HER2+ breast cancer.

Group II: PRE1 ALX148 (Evorpacept) + Fam-Trastuzumab Deruxtecan-Nxki (T-DXd, Enhertu®) Experimental Treatment 2 Interventions

The combination of T-DXd and ALX148 aims to explore the anti-tumoral effects of trastuzumab, of the topoisomerase inhibitor DXd and of the CD47-blocking agent ALX148. The rationale for this combination is that ALX148 is hypothesized, based on preclinical data, to facilitate antibody-dependent cellular phagocytosis (ADCP) of HER2 expressing (\>HER2 1+) breast cancer binding T-DXd while cancer cell intrinsic or bystander cytotoxicity of T-DXd will result in the release of neoantigens promoting immune mediated antitumor activity in the tumor microenvironment.

Who Is Running the Clinical Trial?

QuantumLeap Healthcare Collaborative

Lead Sponsor

Trials

6

Recruited

7,000+

Published Research Related to This Trial

Fam-trastuzumab deruxtecan-nxki (T-DXd) has been approved for treating HER2-low metastatic breast cancer, showing significant improvements in progression-free survival (PFS) and overall survival (OS) in a phase III trial with 557 patients.

The study demonstrated a 50% reduction in the risk of disease progression and a 36% reduction in the risk of death compared to standard chemotherapy, with a safety profile consistent with previous uses of T-DXd and no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

US Food and Drug Administration Approval Summary: Fam-Trastuzumab Deruxtecan-nxki for Human Epidermal Growth Factor Receptor 2-Low Unresectable or Metastatic Breast Cancer. Narayan, P., Dilawari, A., Osgood, C., et al.[2023]

The Phase III DESTINY-Breast04 trial demonstrated that trastuzumab deruxtecan (T-DXd) significantly improves survival in patients with HER2-negative metastatic breast cancer, including those with low HER2 expression, which was previously thought to be untreatable.

This trial is prompting a reevaluation of treatment strategies for HER2-low breast cancer, highlighting the need for ongoing clinical trials to address emerging challenges and evidence gaps in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting HER2-low in metastatic breast cancer: an evolving treatment paradigm. Yang, C., Brezden-Masley, C., Joy, AA., et al.[2023]

In the DESTINY-Breast01 trial, trastuzumab deruxtecan (T-DXd) showed significantly longer overall survival (OS) compared to standard therapies like eribulin and capecitabine, with median OS estimates of 32.9 months and 29.9 months respectively, based on two different modeling methods.

Both modeling approaches indicated that T-DXd not only improves OS but also provides greater quality-adjusted life years (QALYs), suggesting it is a more effective treatment option for patients with HER2-positive metastatic breast cancer who have previously received multiple therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methods for Estimating Long-Term Outcomes for Trastuzumab Deruxtecan in HER2-Positive Unresectable or Metastatic Breast Cancer After Two or More Anti-HER2 Therapies. Dunton, K., Vondeling, G., Hancock, E., et al.[2022]

Fam-trastuzumab deruxtecan-nxki (ENHERTU) received accelerated FDA approval for treating HER2-positive breast cancer in patients who have already undergone two or more anti-HER2 therapies, based on a study involving 184 patients that showed a confirmed overall response rate of 60.3%.

While ENHERTU is effective, it carries significant risks, including severe interstitial lung disease and neutropenia, highlighting the importance of monitoring for serious side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. Narayan, P., Osgood, CL., Singh, H., et al.[2022]

Fam-trastuzumab deruxtecan-nxki is an effective treatment for advanced HER2-positive breast cancer, showing a response rate of 60.9% in major clinical trials, making it a viable option for patients who have not responded to standard therapies.

While the drug is effective, it comes with potential side effects, including serious risks like interstitial lung disease and left ventricular dysfunction, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Review of Fam-Trastuzumab Deruxtecan-nxki in HER2-Positive Breast Cancer. Nguyen, X., Hooper, M., Borlagdan, JP., et al.[2021]

Trastuzumab deruxtecan (Enhertu®) has been shown to significantly improve progression-free survival in adults with unresectable or metastatic HER2-positive breast cancer compared to the previous standard treatment, trastuzumab emtansine, in a pivotal phase 3 trial.

The treatment has a generally manageable safety profile, although it is associated with common adverse events like hematological and gastrointestinal disorders, and requires careful monitoring for interstitial lung disease (ILD)/pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. Nie, T., Blair, HA.[2023]

Trastuzumab deruxtecan (ENHERTU®) is an innovative treatment that combines an antibody targeting HER2 with a DNA topoisomerase I inhibitor, specifically designed for HER2-expressing solid tumors, including various types of cancer.

It received accelerated approval in the USA based on the promising results from the phase 2 DESTINY-Breast01 trial, which focused on patients with advanced HER2-positive breast cancer who had already undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. Keam, SJ.[2020]

In the DESTINY-Breast01 trial with 184 patients, trastuzumab deruxtecan (T-DXd) showed a confirmed objective response rate of 62.0% and a median overall survival of 29.1 months, indicating its effectiveness in treating HER2-positive metastatic breast cancer after previous treatment with trastuzumab emtansine.

While T-DXd demonstrated sustained antitumor activity, it also had a notable safety profile, with 99.5% of patients experiencing drug-related adverse events, including a 15.8% incidence of interstitial lung disease/pneumonitis, highlighting the importance of monitoring for serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated Patients With HER2-Positive Metastatic Breast Cancer: Updated Survival Results From a Phase 2 Trial (DESTINY-Breast01). Saura, C., Modi, S., Krop, I., et al.[2023]

Fam-trastuzumab deruxtecan (T-DXd) is an effective treatment for HER2-positive breast cancer, showing significant clinical activity in advanced cases and in patients with HER2-low disease, based on recent studies.

The toxicity of T-DXd is manageable, with fewer side effects reported when used as an earlier line of therapy, suggesting it may be safer and more beneficial for patients compared to later treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring DESTINY: the Past, Present, and Future of Trastuzumab Deruxtecan. Ali, A., Graff, SL.[2023]

Citations

1. ir.alxoncology.com ir.alxoncology.com/news-releases/news-release-details/alx-oncology-announces-new-data-demonstrating-evorpacept

Release Details Data from Phase 1b/2 clinical trial to be presented at 2024 San Antonio Breast Cancer Symposium (SABCS) show encouraging clinical activity ...

2. onclive.com onclive.com/view/zanidatamab-plus-evorpacept-shows-early-activity-tolerability-in-pretreated-her2-breast-cancer

Zanidatamab Plus Evorpacept Shows Early Activity ... Although efficacy outcomes were most pronounced in patients with HER2-positive disease, the cORR and median PFS were 20.0% (95% CI, 4.3%-48.1%) ...

3. enhertuhcp.com enhertuhcp.com/en/breast/efficacy/efficacy-data

Efficacy data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) In patients with metastatic breast cancer and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was ...

4. targetedonc.com targetedonc.com/view/evorpacept-shows-promising-efficacy-in-her2-positive-gastric-and-gej-cancers

Evorpacept Shows Promising Efficacy in HER2-Positive ... The ASPEN-06 trial found that adding evorpacept to trastuzumab, ramucirumab, and paclitaxel significantly improved overall response rates ...

5. ir.alxoncology.com ir.alxoncology.com/news-releases/news-release-details/alx-oncology-reports-first-quarter-2025-financial-results-and

ALX Oncology Reports First Quarter 2025 Financial ... The randomized Phase 2 ASPEN-Breast clinical trial will evaluate evorpacept with HERCEPTIN® (trastuzumab) and single-agent chemotherapy in ...

6. alxoncology.com alxoncology.com/wp-content/uploads/2025/10/ASPEN-09-Brc-TIP-ESMO-2025.pdf

Peter Schmid1, Paula R. Pohlmann2, Ritesh Parajuli3, ... in Participants with HER2-Positive Metastatic Breast Cancer (mBC) (ASPEN-09-03) ... Safety data confirmed that evorpacept can be safely ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.332

A phase 2/3 study of evorpacept (ALX148), a CD47 ... Background: Evorpacept (Evo) is a high affinity, CD47-blocker with an inactive Fc region designed to safely magnify anticancer antibody ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT05027139

A Study of Zanidatamab (ZW25) With Evorpacept (ALX148) ... This study is being done to find out if zanidatamab when given with evorpacept (ALX148) is safe and can treat patients with advanced (locally advanced [ ...

9. ctv.veeva.com ctv.veeva.com/study/aspen-09-a-study-of-evorpacept-in-combination-with-anti-cancer-therapies-in-advanced-metastatic-m

ASPEN-09: A Study of Evorpacept in Combination With Anti ... The purpose of this study is to evaluate evorpacept with anti-cancer therapies in advanced/metastatic malignancies.