Neratinib + TDxD for Esophageal and Stomach Cancer

Recruiting at 2 trial locations

Overseen By Namrata Vijavergia, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Namrata Vijayvergia

Must not be taking: Strong inhibitors, Strong inducers

Disqualifiers: Untreated brain metastases, Ongoing diarrhea, Interstitial lung disease, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 3

Duration: 21 days per cycle

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and optimal dosage of a new treatment combination for individuals with certain types of esophageal, stomach, and other gastrointestinal cancers. The focus is on tumors with high levels of a protein called HER2, and participants should have previously tried at least one other HER2-targeting treatment. The treatment combines two drugs: Neratinib, a daily oral medication, and Fam-Trastuzumab Deruxtecan-Nxki (TDxD), an intravenous drug administered every three weeks. Individuals with unresectable or metastatic cancers who have HER2-positive tumors and have undergone previous HER2 therapy might be suitable candidates for this trial. As a Phase 1 trial, the research aims to understand how the treatment works in people.

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

The trial protocol does not specify if you need to stop all current medications, but you cannot take any medications that strongly affect Neratinib or TDxD. It's best to discuss your current medications with the trial team.

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

Research shows that both Neratinib and Fam-Trastuzumab Deruxtecan-Nxki (TDxD) have undergone safety testing in humans. TDxD has treated various cancers but can cause serious side effects, such as lung problems and low white blood cell counts. Due to these side effects, doctors must closely monitor patients.

Neratinib has been studied with other treatments and is generally well-tolerated, though some individuals have experienced diarrhea. This is a Phase 1 trial, aiming to find the safest effective dose while minimizing side effects.

While early studies provide some information, Phase 1 trials typically represent the first time a treatment is tested in humans. They primarily assess safety rather than efficacy. Participants in this trial will receive close monitoring to manage any possible side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for esophageal and stomach cancer?

Researchers are excited about combining Neratinib and Fam-Trastuzumab Deruxtecan-Nxki (TDxD) for treating esophageal and stomach cancers because of their unique approach. Unlike most treatments that target cancer cells broadly, Neratinib is a potent inhibitor specifically blocking HER2, a protein that can promote the growth of cancer cells. TDxD combines targeted delivery with chemotherapy, directly attacking cancer cells with reduced impact on healthy cells. This combination could potentially lead to more effective and precise cancer cell eradication compared to conventional treatments, such as standard chemotherapy or HER2-targeted therapies alone.

What evidence suggests that this trial's treatments could be effective for esophageal and stomach cancer?

Research has shown that Trastuzumab deruxtecan (TDxD) outperforms standard chemotherapy in extending the lives and improving the health outcomes of patients with advanced gastro-esophageal cancer. In this trial, participants will receive a combination of TDxD and another drug, Neratinib, to determine if it can further enhance results. Neratinib targets cancer cells with specific genetic features. Early studies suggest that these two drugs together might be more effective against HER2-overexpressing gastro-esophageal cancers, which have a specific protein on their surface that aids growth. This combination is being tested to see if it can offer better treatment options for patients who haven't responded to other therapies. ^{1 2 3 4 5}

Who Is on the Research Team?

Namrata Vijavergia, MD

Principal Investigator

Fox Chase Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with advanced gastro-esophageal cancer that's HER2-overexpressing and has worsened despite previous chemotherapy and HER2 therapy. Participants need good blood counts, organ function, no severe heart issues or uncontrolled illnesses, not pregnant or breastfeeding, willing to use contraception, and able to take oral meds.

Inclusion Criteria

Hemoglobin > 9 gm/dl

Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

ECOG performance status 0-2

Exclusion Criteria

Has a QT interval corrected by Fridericia's formula (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on average of the Screening triplicate12-lead ECG

Patients may not be receiving any other investigational agents for advanced cancer and must not have received prior treatment with TDxD

Patients with known untreated brain metastases are excluded from this study because of their poor prognosis and frequent development of neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Treated brain metastases are allowed (requires stability on MRI at least 4 weeks after initial treatment). Patients with treated brain metastases are allowed to be treated with steroid and/or anti-convulsants if the dose remains stable or decreases over the last 4 weeks prior to C1D1

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Neratinib oral daily days 1-21 plus TDxD on day 1 administered intravenously of a 21-day treatment cycle

21 days per cycle

1 visit per cycle (in-person)

Dose Limiting Toxicity (DLT) Assessment

Assessment of dose-limiting toxicities to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D)

28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

1 visit every 12 weeks (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Fam-Trastuzumab Deruxtecan-Nxki (TDxD)
• Neratinib

Trial Overview The study tests the combination of Neratinib (a pill) with Fam-Trastuzumab Deruxtecan-Nxki (TDxD) in a Phase 1 trial to find safe dosages. It uses a '3+3' method where small groups are given increasing doses until the maximum tolerated dose is found for patients who've had prior treatments fail.

How Is the Trial Designed?

Group I: Neratinib plus TDxD Experimental Treatment 2 Interventions

Neratinib oral daily days 1-21 plus TDxD on day 1 administered intravenously of a 21 day treatment cycle.

Fam-Trastuzumab Deruxtecan-Nxki (TDxD) is already approved in United States, European Union, Japan for the following indications:

Approved in United States as Enhertu for:

• Metastatic breast cancer
• Gastric adenocarcinoma
• Gastroesophageal junction adenocarcinoma

Approved in European Union as Enhertu for:

• Metastatic breast cancer
• Gastric adenocarcinoma

Approved in Japan as Enhertu for:

• Metastatic breast cancer
• Gastric adenocarcinoma

Who Is Running the Clinical Trial?

Namrata Vijayvergia

Lead Sponsor

Trials

1

Recruited

20+

Fox Chase Cancer Center

Lead Sponsor

Trials

236

Recruited

39,300+

National Comprehensive Cancer Network

Collaborator

Trials

121

Recruited

7,400+

Puma Biotechnology, Inc.

Industry Sponsor

Trials

58

Recruited

10,100+

Published Research Related to This Trial

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 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 (T-DXd) demonstrated clinical activity in patients with HER2-low gastric or gastroesophageal junction adenocarcinoma, showing a confirmed objective response rate of 26.3% in cohort 1 and 9.5% in cohort 2, with many patients experiencing reduced tumor size.

The treatment was generally well-tolerated, with no drug-related deaths reported, although some patients experienced significant adverse events like anemia and decreased neutrophil counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Anti-Human Epidermal Growth Factor Receptor 2 Treatment-Naive Patients With Human Epidermal Growth Factor Receptor 2-Low Gastric or Gastroesophageal Junction Adenocarcinoma: Exploratory Cohort Results in a Phase II Trial. Yamaguchi, K., Bang, YJ., Iwasa, S., et al.[2023]

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-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]

In an expanded-access study involving 64 patients with HER2-positive gastric or gastroesophageal junction adenocarcinomas, trastuzumab deruxtecan (T-DXd) was administered safely, with no new safety concerns identified prior to its marketing approval in Japan.

Serious adverse events (SAEs) were reported in 26.6% of patients, with febrile neutropenia being the most common; however, drug-related SAEs led to death in only one patient, indicating a manageable safety profile for T-DXd.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study. Shitara, K., Yamaguchi, K., Muro, K., et al.[2023]

Trastuzumab deruxtecan (T-DXd) has shown significant antitumor activity in patients with HER2-positive advanced gastric cancer (AGC) who have previously undergone at least two therapies, leading to its approval in Japan and by the US FDA.

The treatment resulted in a higher objective response rate and longer overall survival compared to previous therapies, with an acceptable safety profile, indicating its potential as an effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan for the treatment of HER2-positive gastric cancer. Mishima, S., Shitara, K.[2022]

Trastuzumab deruxtecan (T-DXd) is a promising new antibody-drug conjugate that has been approved for treating HER2-positive metastatic breast cancer and gastric cancer, showing potential for use in other solid tumors as well.

T-DXd is expected to become the standard second-line treatment for HER2-positive metastatic breast cancer and may also benefit patients with hormone receptor-positive and triple-negative breast cancer that express low levels of HER2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. Perez, J., Garrigós, L., Gion, M., et al.[2022]

Trastuzumab deruxtecan (Enhertu®) has been shown to be significantly more effective than standard chemotherapy in improving overall survival and achieving objective responses in adults with advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma, based on results from the phase II DESTINY-Gastric01 trial.

The treatment is generally well-tolerated, with common side effects including nausea and fatigue, but it does carry important safety warnings for interstitial lung disease and embryo-foetal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Gastric or Gastro-Oesophageal Junction Adenocarcinoma. Kang, C.[2023]

In the DESTINY-Gastric02 trial involving 79 patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer, trastuzumab deruxtecan demonstrated a confirmed objective response rate of 42% after a median follow-up of 10.2 months, indicating its efficacy as a second-line therapy.

While trastuzumab deruxtecan showed promising results, it was associated with some serious adverse events, including two treatment-related deaths due to interstitial lung disease or pneumonitis, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Van Cutsem, E., di Bartolomeo, M., Smyth, E., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05274048

Study Details | NCT05274048 | Neratinib and Fam ... This is Phase 1 dose finding trial with potential dose expansion to evaluate the safety, toxicity, recommended phase 2 dose (RP2D), and maximum tolerated ...

2. jnccn.org jnccn.org/view/journals/jnccn/22/2.5/article-TIP24-198.xml?utm_source=TrendMD&utm_medium=cpc&utm_campaign=JNCCN_TrendMD_0&print

TIP24-198: A Multi-Center Phase I Trial of Neratinib and ... Based on available data, a combination strategy of neratinib plus TDxd is worth exploring to help improve outcomes for patients with advanced gastro-esophageal ...

3. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/335884

Neratinib and Fam-Trastuzumab Deruxtecan in Advanced ... Neratinib and Fam-Trastuzumab Deruxtecan in Advanced Gastro-esophageal Cancer Patients · Eligibility Criteria · Study Plan · Outcome Measures · More ...

4. withpower.com withpower.com/trial/phase-1-esophageal-neoplasms-3-2022-99036

Neratinib + TDxD for Esophageal and Stomach Cancer Trastuzumab deruxtecan (Enhertu®) has been shown to be significantly more effective than standard chemotherapy in improving overall survival and achieving ...

5. med.stanford.edu med.stanford.edu/chinlab/clinicaltrials/_jcr_content/main/panel_builder_1623764811/panel_0/clinicaltrials.html?view=formSubmission&source=browseConditions&serviceLineId=&condition=Stomach%20%28Gastric%29%20Cancer&conditionId=14&recruitingStatus=RECRUITING

Stomach (Gastric) Cancer Neratinib and Fam-Trastuzumab Deruxtecan in Advanced Gastro-esophageal Cancer Patients. This is Phase 1 dose finding trial with potential dose expansion to ...