Metastatic Malignant Solid Neoplasm Clinical Trial
Official title:
A Phase I Study of DS-8201a in Combination With Olaparib in HER2-Expressing Malignancies
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 endometrial cancer. Olaparib is a drug that blocks an enzyme involved in many cell functions, including the repair of deoxyribonucleic acid (DNA) damage. Blocking this enzyme may help keep tumor cells from repairing their damaged DNA, causing them to die. 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 DNA replication in the tumor cells with abundant HER2, causing them to die. Giving DS-8201a and olaparib may shrink or stabilize the cancer.
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of the combination of trastuzumab deruxtecan (DS-8201a) in combination with olaparib, and to determine the recommended phase 2 dose (RP2D). II. To evaluate the safety and tolerability of this combination in a dose expansion cohort in patients with uterine serous carcinoma. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity as measured by objective response rate (ORR), clinical benefit rate, progression-free survival (PFS), and duration of response (DoR). II. To measure baseline HER2 expression by immunohistochemistry (IHC) in a central laboratory and correlate with response in the dose escalation and in the dose expansion. III. To evaluate the plasma pharmacokinetic (PK) profiles of olaparib and DS-8201a metabolites when administered in combination in the dose escalation and in the dose expansion. IV. To determine markers of DNA damage response (DDR) in tumor specimens at baseline and on-treatment in patients with uterine serous carcinoma in the dose expansion. EXPLORATORY OBJECTIVES: I. To measure baseline HER2 expression by immune-mass spectroscopy, and correlate with baseline central IHC and with response in the dose escalation and in the dose expansion. II. To measure the formation of topoisomerase I cleaved complex formation (TOP1cc) in blood specimens and correlate with response in the dose escalation and in the dose expansion. III. To measure the formation of TOP1cc in tumor specimens at baseline and on-treatment and correlate with response in patients with uterine serous carcinoma in the dose expansion. IV. To measure changes in HER2 expression over the course of treatment by IHC and immune multiple reaction monitoring-mass spectrometry (immunoMRM) and correlate with response in patients with uterine serous carcinoma in the dose expansion. V. To determine biomarkers of response and resistance in tumor specimens and blood specimens, including whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing. OUTLINE: This is a dose-escalation study. Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 and olaparib orally (PO) twice daily (BID) on days 1-21 or days 8-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients taking olaparib BID on days 1-21 undergo collection of blood samples at the following times: baseline, days 1, 2, 8, and 15 of cycle 1, day 1 of cycle 2, days 1, 8, and 15 of cycle 3, day 1 of cycle 4, day 1 of every fourth cycle after cycle 4 and then at treatment end. Patients taking olaparib BID on days 8-14 undergo collection of blood samples at the following times: baseline, days 1, 2, 8, 9, and 15 of cycle 1, days 1 and 8 of cycle 2, days 1, 8, and 15 of cycle 3, day 1 of cycle 4, day 1 of every fourth cycle after that, and at treatment end. Patients undergo biopsy at baseline, and then on day 3 or day 10 of cycle 1. Patients also undergo echocardiography and computed tomography (CT) throughout the trial. After completion of study treatment, patients are followed up for 30 days. ;
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