Title
Phase I Trial of DS-8201a (Trastuzumab Deruxtecan) in Combination with Neratinib in Solid Tumors with HER2 Alterations

Description
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 to other parts of 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.

Objective
PRIMARY OBJECTIVE:

I. To assess dose limiting toxicities and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of neratinib maleate (neratinib) and trastuzumab deruxtecan (DS-8201a) in patients with advanced solid tumors harboring alterations in HER2 (including HER2 overexpression/amplification and selected HER2-activating mutations).

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity of neratinib and DS-8201a, as measured by objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by investigator assessment, and overall survival (OS).

II. To assess the safety and tolerability for the combination neratinib and DS-8201a.

III. To assess the effect of neratinib on DS-8201a payload (DXd/MAAA-1181a) tissue concentration in part 2 at the RP2D chosen in part 1 (and potentially at a lower dose[s] of neratinib) before and after addition of neratinib to DS-8201a.

IV. To assess the pharmacokinetics of DS-8201a and neratinib in combination.

EXPLORATORY OBJECTIVES:

I. To assess the pharmacodynamic response to neratinib and DS-8201a as measured by markers of DS-8201a-induced deoxyribonucleic acid (DNA) damage using gammaH2AX, phosphorylated (p)NBS1 immunofluorescence assay (IFA), multiplex multiple reaction monitoring mass spectrometry (MRM)- based proteomic assay panel of DNA repair response pathway biomarkers, induction of apoptosis, and HER2 signaling along with other pharmacodynamic (PD) biomarkers such as cleaved caspase3 (apoptosis) and TOP1CC (target engagement) pending National Clinical Laboratory Network (NCLN) assay availability.

II. To assess quantifiable HER2 protein expression of pre-treatment or archival tumor biopsies, and at disease progression in correlation with treatment response.

III. To assess tumor tissue mutation profile pre-treatment and at progression in correlation with treatment response.

IV. To assess circulating cell-free DNA (cfDNA) mutation profiles pre-treatment, C2D1, and at progression in correlation with treatment response.

OUTLINE: This is a dose-escalation study of neratinib followed by a dose-expansion (PD) study.

Treatment Experimental: Treatment (neratinib, trastuzumab deruxtecan)
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.

Procedure: Biopsy
Correlative studies
Other Names:
BIOPSY_TYPE
Bx

Drug: Neratinib Maleate
Given PO
Other Names:
2-Butenamide, N-(4-((3-chloro-4-(2-pyridinylmethoxy)phenyl)amino)-3-cyano-7-ethoxy-6-quinolinyl)-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate (1:1)
HKI-272 Maleate
NERATINIB MALEATE ANHYDROUS
Nerlynx

Biological: Trastuzumab Deruxtecan
Given IV
Other Names:
DS-8201
DS-8201a
Enhertu
Fam-trastuzumab Deruxtecan-nxki
WHO 10516

Key Eligibility For full study eligibility, see this study's ClinicalTrials.gov record.

Applicable Disease Sites
Anal; Any Site; Bladder; Brain/Central Nervous System; Breast; Cervix; Colon and Rectum; Endocrine cancers; Esophagus; Gastrointestinal cancers, other; Genitourinary cancers, other; Head and Neck; Ill-Defined Sites; Kidney; Liver; Lung; Melanoma/Skin cancer; Ovary; Pancreas; Prostate; Sarcoma; Stomach; Thyroid; Unknown Sites; Uterus

Participating Institutions
UW Health University Hospital