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 is testing a combination of two drugs, Neratinib and TDxD, in patients with advanced stomach cancer that overexpresses HER2. These patients have not responded to previous treatments. The drugs work by blocking cancer growth and directly killing cancer cells.

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 the combination of Neratinib and TDxD safe for treating esophageal and stomach cancer?

Fam-Trastuzumab Deruxtecan-nxki (TDxD) has been used in treating various cancers and has shown some serious side effects like lung disease, low white blood cell count, and heart problems. Common side effects include nausea, fatigue, and hair loss. While these safety concerns are noted in other conditions, they may still be relevant for esophageal and stomach cancer. ^{1 2 3 4 5}

What makes the drug Neratinib + TDxD unique for esophageal and stomach cancer?

Neratinib + TDxD is unique because it combines two drugs: Neratinib, which blocks signals that help cancer cells grow, and TDxD, an antibody-drug conjugate that targets and delivers chemotherapy directly to HER2-positive cancer cells. This combination targets HER2, a protein that can promote the growth of cancer cells, and is being explored for its effectiveness in treating esophageal and stomach cancers, which have limited treatment options. ^{1 2 6 7 8}

What data supports the effectiveness of the drug Neratinib + TDxD for esophageal and stomach cancer?

Trastuzumab deruxtecan (part of the treatment) has been shown to be effective in improving response and overall survival in patients with advanced HER2-positive gastric or gastroesophageal junction cancer, as demonstrated in the DESTINY-Gastric01 and DESTINY-Gastric02 trials. ^{1 2 8 9 10}

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

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]

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]

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]

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]

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 (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]

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) 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]

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. United States 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. [2023]

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

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

3. England 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. [2023]

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. Japan 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. [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. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan for the treatment of HER2-positive gastric cancer. [2022]

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

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

9. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond. [2022]

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

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