This phase I trial identifies the side effects and best dose of DS-8201a and olaparib in treating patients with HER2-expressing cancers that have spread to other places in the body or cannot be removed by surgery or ovarian cancer that remains despite treatment with a platinum treatment (platinum resistant). DS-8201a is an antibody-drug conjugate. This agent has two components: an antibody component and a chemotherapy component. The antibody component is attached to the chemotherapy molecules. Upon administration of DS-8201a, the antibody targets and binds to tumor cells that have abundant HER2 (human-epidermal growth factor receptor 2), which is a protein on the surface of some tumor cells. The chemotherapy then enters the cells and blocks deoxyribonucleic acid (DNA) replication in the tumor cells with abundant HER2, causing them to die. Olaparib is a drug that blocks an enzyme involved in many cell functions, including the repair of DNA damage. Blocking this enzyme may help keep tumor cells from repairing their damaged DNA, causing them to die. Giving DS-8201a and olaparib may shrink or stabilize the cancer.
Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
HER2 1-3+ expression by IHC OR
HER2 amplification by next generation sequencing panel (NGS) or in situ hybridization (ISH) OR
If local testing is not feasible, patients will submit archival tissue for central HER2 testing to determine eligibility. Patients with unknown or negative HER2 testing will not be eligible
Patients who have had chemotherapy (including antibody drug therapy) within 4 weeks with the following exceptions: 1 week for weekly paclitaxel; 2 weeks or five half-lives, whichever is longer, for small-molecule targeted agents such as 5-fluorouracil-based agents, folinate agents, hormonal agents; or 6 weeks for nitrosoureas or mitomycin C
Patients who have had radiation therapy within 4 weeks
Patients who have had a major surgery within 4 weeks
Patients who are receiving any other investigational agents
Single group
Biopsy Procedure
Procedure/SurgeryUndergo biopsy
Biospecimen Collection
Procedure/SurgeryUndergo collection of blood samples
Computed Tomography
Procedure/SurgeryUndergo CT
Echocardiography Test
Procedure/SurgeryUndergo echocardiography
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Olaparib
DrugGiven PO
Trastuzumab Deruxtecan
Biological/VaccineGiven IV
Maximum tolerated dose/recommended phase 2 dose
Will be measured by Common Terminology Criteria for Adverse Events version (v) 5.0 and analyzed using descriptive statistics.
Incidence of adverse events
Objective response rate (ORR)
ORR will be evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria to determine the best overall response for evaluable patients.
Clinical benefit rate (CBR)
CBR will be evaluated by RECIST 1.1 criteria to determine the best overall response for evaluable patients.
Duration of response (DOR)
DOR will be evaluated by RECIST 1.1 criteria to determine the best overall response for evaluable patients. DOR will be described using the method of Kaplan-Meier.
HER2 expression
HER2 expression on archival specimens will be analyzed using current American Society of Clinical Oncology/College of American Pathologists breast cancer and gastric cancer scoring methods. The levels of HER2 expression (0, 1+, 2+, or 3+) will be determined and the number and percentage of patients in each category will be reported. Chi-squared test and regression modeling may be used to investigate any possible relationship of HER2 biomarker levels with anti-tumor efficacy.
HER2 expression
Correlation between HER2 expression, immunohistochemistry (IHC), and response may be evaluated by Chi-squared test and regression model.
Formation of topoisomerase I cleaved complex formation (TOP1cc) in blood samples
Will measure the formation of formation TOP1cc in blood specimens and correlate with response in the dose escalation and in the dose expansion Will be analyzed using descriptive statistics.
Presence of topoisomerase I cleaved complex formation (TOP1cc) in paired on-treatment tumor specimens
Will assess the presence of TOP1cc in paired on-treatment tumor specimnes and correlate with response in patients with platinum resistant high grade serous ovarian carcinoma in the dose expansion. Will be analyzed using descriptive statistics.
Changes in HER2 expression
Will measure changes in HER2 expression over the course of treatment by IHC and immunoMRM and correlate with response in patients with platinum resistant high grade serous ovarian carcinoma in the dose expansion. Will be analyzed using descriptive statistics.
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