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 that have spread from where it first started (primary site) to other places in the body (metastatic) or that cannot be removed by surgery (unresectable), and have changes in a gene called human epidermal growth factor receptor 2 (HER2). Neratinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps slow or stop the spread of tumor cells. Trastuzumab deruxtecan is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive tumor cells in a targeted way and delivers deruxtecan to kill them. Adding neratinib to trastuzumab deruxtecan may be able to shrink cancer with a change in the HER2 gene.
Patients enrolling in Part 1 (Dose Escalation) may have a diagnosis of any solid tumor
Patients enrolling in the Part 2 Pharmacodynamic Cohort may have a diagnosis of any solid tumor except pancreas cancer (NOTE: pancreatic cancer excluded from this cohort after Revision 11 activation due to the addition of the pancreatic specific cohort)
Patients enrolling in the Part 2 Pancreatic Cohort must have a diagnosis of pancreatic adenocarcinoma (PDAC) and meet the HER2 positivity guidance
HER2 overexpression defined by immunohistochemistry (IHC) 3+
Other anticancer therapy, including small-molecule targeted agents within 2 weeks or five half-lives, whichever is longer; chemotherapy otherwise not specified (including, but not limited to cytotoxic chemotherapy, antibody drug conjugates, retinoid therapy, hormonal therapy) within 3 weeks; immunotherapy or monoclonal antibody within 4 weeks; and nitrosoureas or mitomycin C within 6 weeks (concurrent use of hormones for noncancer-related conditions [e.g., insulin for diabetes and hormone replacement therapy] is acceptable)
Other investigational therapeutic agents
Patients who have had major surgery or radiation within 4 weeks; palliative stereotactic radiation within 2 weeks (except for palliative radiation to known metastatic sites as long as it does not affect assessment of response or interrupt treatment for more than the maximum time specified in dose modification section)
Radiotherapy to the thorax (palliative radiation to known metastatic sites in the thoracic spine is permitted in this study)
Single group
Biopsy Procedure
Procedure/SurgeryUndergo biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Computed Tomography
Procedure/SurgeryUndergo CT scan
Echocardiography Test
Procedure/SurgeryUndergo echocardiography
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA scan
Neratinib Maleate
DrugGiven PO
Trastuzumab Deruxtecan
Biological/VaccineGiven IV
Incidence of dose limiting toxicities (Part 1, Dose Escalation)
Safety endpoints will be listed for each dose level.
Incidence of treatment-emergent adverse events (Part 1, Dose Escalation)
Safety endpoints will be listed for each dose level and the tabulations of adverse events will also be produced by severity and by relationship to study drug.
Objective response rate (ORR) (Part 2, Pancreatic Cohort)
ORR will be determined as the proportion of subjects with a confirmed partial response (PR) or complete response (CR). The ORR and 90% confidence intervals (CIs) will be constructed using the Clopper-Pearson method for ORR to form repeated CIs according to Jennison and Turnbull at the interim analysis and primary analysis, respectively. The nominal p-value from the exact binomial test will also be reported.
Incidence of adverse events
Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Objective response rate
Defined as the percentage of patients who achieve CR or PR per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.
Duration of response (Pancreatic Expansion Cohort)
By RECIST v 1.1. Summary statistics of DOR will be calculated for responders.
Progression free survival (Pancreatic Expansion Cohort)
By RECIST v 1.1. Described using Kaplan-Meier product limit methods.
Deoxyribonucleic acid (DNA) damage
Measured by gammaH2AX and pNBS1 and pKAP1 immunofluorescence assay at cycle 1 days 3-5 and cycle 2 days 3-5 biopsies. Other pharmacodynamic biomarkers include cleaved PARP, Caspase 3, p-HER2, downstream signaling. Summarized using descriptive statistics (means, median, and standard deviations) at each measurement time point.
Quantitative HER2 protein
Summarized using descriptive statistics (means, median, and standard deviations) at each measurement time point.
Tumor mutation profile (Dose Escalation and PD Cohorts)
As measured by whole exome sequencing. Summarized using descriptive statistics (means, median, and standard deviations) at each measurement time point.
Circulating cell-free DNA (Dose Escalation and PD Cohorts)
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