Neratinib and Fam-Trastuzumab Deruxtecan in Advanced Gastro-esophageal Cancer Patients

NCT05274048 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 21-1069GI-200
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 3

Brief Summary

This is Phase 1 dose finding trial with potential dose expansion to evaluate the safety, toxicity, recommended phase 2 dose (RP2D), and maximum tolerated dose (MTD) of Neratinib plus TDxD using a standard 3+3 dose escalation design in patients with metastatic or unresectable gastro-esophageal cancer that are HER2-overexpressing (IHC 3+ or IHC2+/ISH+) and any other gastrointestinal cancer with HER2 expression with IHC3+. Patients must have progressed or been intolerant of at least one prior line of chemotherapy + HER2 directed therapy.

Conditions

Gastric Cancer; Gastrointestinal Cancer; HER2 Gene Mutation

Outcome Measures

Primary Outcomes (1)

• Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination of TDxD and Neratinib

  The rate of dose-limiting toxicities (DLTs) for Neratinib + TDxD during DLT period of 28 days, in patients with advanced gastrointestinal cancer

  2 years

Secondary Outcomes (4)

• Determine the Objective Response Rate (ORR) (Complete Response (CR) + Partial Response (PR)) of the combination of TDxD and Neratinib

  2 years

• Determine the Disease Control Rate (DCR) (CR + PR + Stable Disease (SD)) of the combination of TDxD and Neratinib

  2 years

• Determine the Progression Free Survival (PFS) of the combination of TDxD and Neratinib

  2 years

• Determine the Overall Survival (OS) of the combination of TDxD and Neratinib

  2 years

Study Arms (1)

Neratinib plus TDxD

EXPERIMENTAL

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

Drug: Neratinib Pill; Drug: Fam-Trastuzumab Deruxtecan-Nxki (TDxD)

Interventions

Neratinib Pill DRUG

Patients will be enrolled in cohorts of 3 at each dose level of Neratinib (120 mg, 160 mg, 200 mg) daily (days 1 through 21)

Neratinib plus TDxD

Fam-Trastuzumab Deruxtecan-Nxki (TDxD) DRUG

standard dosing of TDxD (5.4mg/m2) on day 1of a 21 day treatment cycle

Neratinib plus TDxD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have been diagnosed with histologically or cytologically confirmed gastrointestinal cancer (esophagus, stomach, colon, biliary, pancreas or unknown primary likely GI), and been deemed unresectable or have at least one site of metastatic disease
• Patients must have evaluable or measurable disease by RECIST 1.1 criteria
• Patients' tumors must have HER2-overexpressing:
• (IHC 3+ or IHC2+/ISH+) advanced gastroesophageal cancer (including gastroesophageal junction adenocarcinoma).
• IHC 3+ for other GI cancers
• Patients must have received at least one prior line of HER2 directed therapy for metastatic/unresectable disease and completed treatment at least 2 weeks prior to C1D1 (only for Gastroesohageal cancers, not for other GI cancers)
• 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
• Age \> 18 years.
• ECOG performance status 0-2
• Patients must have normal organ and marrow function as defined below
• Leukocytes \> 3,000/mcL
• Absolute neutrophil count \> 1,500/mcL
• Platelets \> 90,000/mcL
• Hemoglobin \> 9 gm/dl
• Total bilirubin \< 2 times institutional normal limits

You may not qualify if:

• Patients who have had chemotherapy, or radiotherapy within 2 weeks prior to C1D1 or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier (secondary hypothyroidism from prior immunotherapy is permissible if controlled on thyroid hormone replacement). Recovery is defined as any treatment onset adverse events returning to baseline or otherwise deemed not clinically significant.
• Patients may not be receiving any other investigational agents for advanced cancer and must not have received prior treatment with TDxD
• Immunotherapy and treatments involving any investigational agents must be discontinued for \>21 days before Cycle 1 Day 1 (C1D1)
• 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
• Patients with ongoing diarrhea (\> 4 bowel movements/day) unresolved despite medical and best supportive care in the two weeks preceding therapy
• Patients will be excluded if they have had interstitial lung disease or pneumonitis or were suspected to have interstitial lung disease or pneumonitis that could not be ruled out on imaging at screening or if they had a history of noninfectious interstitial lung disease or pneumonitis that had been treated with glucocorticoids. Similarly, patients with clinically significant lung disease requiring O2 support or impaired lung function per investigator should be excluded
• History of allergic reactions attributed to compound of similar chemical or biologic composition to the agent(s) used in this study
• Patients receiving any medications or substances that are strong inhibitors or inducers of Neratinib and/or TDxD are ineligible.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• 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.
• Pregnant or breast feeding.

Sponsors & Collaborators

• Fox Chase Cancer Center: lead
• National Comprehensive Cancer Network: collaborator
• Puma Biotechnology, Inc.: collaborator

Study Sites (3)

Stanford Cancer Center

Palo Alto, California, 94304, United States

RECRUITING

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14263, United States

RECRUITING

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

RECRUITING

MeSH Terms

Conditions

Stomach Neoplasms; Gastrointestinal Neoplasms

Interventions

neratinib

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Study Officials

• Namrata Vijavergia, MD

  Fox Chase Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Namrata Vijavergia, MD

CONTACT

215-214-1676; Namrata.Vijayvergia@fccc.edu

Tanu Singh

CONTACT

215-214-1439; tanu.singh@fccc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 28, 2022
• First Posted: March 10, 2022
• Study Start: June 24, 2022
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2027
• Last Updated: October 29, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)