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

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: QuantumLeap Healthcare Collaborative

Must not be taking: Anticancer therapy

Disqualifiers: Diabetes, Cardiovascular disease, Liver disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing different medicines or combinations of medicines to treat cancer. It focuses on patients with certain solid tumors, including breast cancer. The study aims to find the safest and most effective dose and then tests that dose on more patients to see if it works. Dinaciclib is being evaluated for its potential in combination therapies for breast cancer.

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.

What data supports the effectiveness of the drug fam-trastuzumab deruxtecan-nxki in treating metastatic breast cancer?

Fam-trastuzumab deruxtecan-nxki has shown strong antitumor activity in patients with HER2-positive metastatic breast cancer, as demonstrated in the DESTINY-Breast01 trial, which led to its approval for patients who have already tried other treatments. This drug has been effective in extending survival for patients with this type of cancer. ^{1 2 3 4 5}

Is fam-trastuzumab deruxtecan-nxki (Enhertu) generally safe for humans?

Fam-trastuzumab deruxtecan-nxki (Enhertu) has been shown to have a generally manageable safety profile, but it can cause serious side effects like interstitial lung disease (lung inflammation) and heart problems. Common side effects include nausea, fatigue, and low blood cell counts, so patients need careful monitoring. ^{1 2 4 6 7}

What makes the drug ALX148, Fam-Trastuzumab Deruxtecan-Nxki unique for treating metastatic breast cancer?

This drug is unique because it targets HER2-low breast cancer, a type previously considered untreatable with HER2-targeted therapies, and has shown significant survival benefits in patients with low HER2 expression. ^{1 2 4 8 9}

Research Team

Paula Pohlmann, MD, PhD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• ALX148 (Monoclonal Antibodies)
• Fam-Trastuzumab Deruxtecan-Nxki (Monoclonal Antibodies)

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

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

A Review of Fam-Trastuzumab Deruxtecan-nxki in HER2-Positive Breast Cancer. [2021]

2. England 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). [2023]

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

Trastuzumab Deruxtecan: First Approval. [2020]

4. United States 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. [2023]

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

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

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

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. [2022]

7. France pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Targeting HER2-low in metastatic breast cancer: an evolving treatment paradigm. [2023]

9. France 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. [2022]