Trastuzumab Deruxtecan + Neratinib for Cancer

Recruiting at 20 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, P-glycoprotein inducers

Disqualifiers: Interstitial lung disease, Severe COPD, Myocardial infarction, others

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

Compensation: Varies

Number of Visits: 9

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective dose of a drug combination for treating certain difficult-to-treat cancers. It focuses on using two drugs, neratinib (neratinib maleate) and trastuzumab deruxtecan (also known as Enhertu or DS-8201a), to target cancers with changes in the HER2 gene. The goal is to assess whether these drugs can shrink tumors that have spread or cannot be surgically removed. Individuals with HER2-altered cancer who have undergone at least one prior treatment may be suitable candidates for this trial. As a Phase 1 trial, the research seeks to understand how the treatment works in people, offering participants a chance to contribute to groundbreaking cancer research.

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

Research shows that the combination of the drugs neratinib and trastuzumab deruxtecan is under study to assess its safety and possible side effects. Previous studies have found that using these two drugs together can more effectively block HER2, a protein that can promote cancer cell growth. Although this combination remains under investigation, early results have noted common side effects such as diarrhea, nausea, and tiredness. These side effects are typical for cancer treatments and can usually be managed with supportive care.

The safety of trastuzumab deruxtecan alone was reviewed in 645 patients with different types of tumors, demonstrating a known safety record. However, since this trial is in its early stages, it primarily focuses on how well participants can tolerate these two drugs together. The trial will carefully monitor for any unexpected side effects.

Participants in the trial will have their health closely monitored by medical staff to manage any side effects that may occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Trastuzumab Deruxtecan and Neratinib because these treatments offer a new approach to targeting cancer cells. Trastuzumab Deruxtecan is an antibody-drug conjugate that delivers chemotherapy directly to cancer cells, potentially minimizing damage to healthy cells, unlike traditional chemotherapy that affects both. Neratinib, on the other hand, is a tyrosine kinase inhibitor that blocks signals that help cancer cells grow. Together, they form a one-two punch that could be more effective than current treatments like Herceptin and other HER2-targeting therapies, by potentially overcoming resistance and offering more precise, potent cancer cell targeting.

What evidence suggests that this trial's treatments could be effective for metastatic or unresectable solid tumors with HER2 gene changes?

Research has shown that using neratinib with trastuzumab deruxtecan might help treat certain HER2-positive cancers. In this trial, participants will receive a combination of these two treatments. Neratinib blocks a protein that signals cancer cells to grow, potentially stopping or slowing the cancer. Trastuzumab deruxtecan targets HER2-positive cancer cells and delivers chemotherapy directly to them. Early findings suggest that this combination could effectively shrink tumors with HER2 changes. Initial studies have shown promise, particularly in breast cancers with low HER2 levels. ^{1 2 4 6 7}

Who Is on the Research Team?

Andrew A Davis

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with advanced solid tumors that can't be removed by surgery or have spread, and have changes in the HER2 gene. They must not have had previous treatments with neratinib or DS-8201a, should not be pregnant or breastfeeding, and need to agree to use contraception. People with certain heart conditions, severe lung issues, recent major surgeries or radiation therapy are excluded.

Inclusion Criteria

Absolute neutrophil count >= 1.5 K/cumm

I have a tumor that can be safely biopsied.

Platelets >= 100 K/cumm

Exclusion Criteria

Pregnant or breastfeeding women

Patients with prior allogeneic organ transplantation including allogeneic stem cell transplantation

Patients receiving prohibited medications, treatments, or procedures during the treatment period

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Patients receive neratinib and trastuzumab deruxtecan to assess dose limiting toxicities and determine the maximum tolerated dose

6 weeks

3 visits (in-person)

Dose Expansion

Patients continue to receive neratinib and trastuzumab deruxtecan at the recommended phase 2 dose to observe anti-tumor activity

Up to 1 year

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Every 3 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Neratinib Maleate
• Trastuzumab Deruxtecan

Trial Overview The trial is testing the combination of two anti-cancer drugs: Trastuzumab Deruxtecan and Neratinib Maleate for safety and optimal dosing against cancers with HER2 gene alterations. It includes various assessments like scans and biopsies to monitor effects.

How Is the Trial Designed?

Group I: Treatment (neratinib, trastuzumab deruxtecan) Experimental Treatment 7 Interventions

Patients receive neratinib PO QD on days 1-21 (days 8-21 of cycle 1, then days 1-21 in cycles thereafter for PD study) of each cycle and trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT scan and echocardiography or MUGA scan throughout study. Additionally, patients may undergo a tissue biopsy at baseline and disease progression.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11182766/

Neratinib could be effective as monotherapy or in combination ... This study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low breast cancers.

2. aacrjournals.org aacrjournals.org/cancerres/article/85/8_Supplement_2/CT071/761598/Abstract-CT071-Phase-I-trial-of-trastuzumab

Abstract CT071: Phase I trial of trastuzumab deruxtecan in ... This is a multi-center, phase I clinical trial (NCT05372614) with a 3+3 design to evaluate the safety and tolerability of T-DXd in combination with neratinib.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05372614?term=NERATINIB&viewType=Table&rank=3

Testing the Safety and Tolerability of the Anti-cancer Drugs ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

4. dana-farber.org dana-farber.org/clinical-trials/22-552

Phase I Trial of DS-8201a (Trastuzumab Deruxtecan) in ... This phase I trial tests the safety, side effects, and best dose of neratinib in combination with trastuzumab deruxtecan in treating patients with solid tumors.

5. onclive.com onclive.com/view/dr-davis-on-the-investigation-of-neratinib-plus-trastuzumab-deruxtecan-in-advanced-her2-solid-tumors

Dr Davis on the Investigation of Neratinib Plus ... - OncLive Andrew Davis, MD, discusses an ongoing phase 1 trial combining neratinib and trastuzumab deruxtecan in metastatic HER2-positive solid tumors.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12328084/

KCSG AL20‐17/KM23 trial Preclinical and clinical studies demonstrate that combining neratinib with trastuzumab enhances HER2 signaling inhibition and improves outcomes in HER2‐mutated ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2019/761139Orig1s000MultidisciplineR.pdf

Multi-Discipline Review - accessdata.fda.gov Review of Safety. Data: The safety profile of fam-trastuzumab deruxtecan is based on data from 645 subjects with various tumor types treated ...