a phase 1b study of t-dxd combinations in her2-low advanced or metastatic breast cancer

Conditions: Metastatic Breast Cancer

Summary: destiny-breast 08 will investigate the safety, tolerability, pk and preliminary anti-tumour activity of t-dxd in combination with other therapies in patients with metastatic her2-low advanced or metastatic breast cancer

this study is modular in design allowing assessment of the safety, tolerability, pk and preliminary anti-tumour activity of t-dxd in combination with other therapies. combination-treatment modules will have 2 parts: a dose-finding phase (part 1), and a dose expansion phase (part 2); the part 2 dose-expansion phase will use the rp2d determined in part 1. the target population of interest in this study is patients with her2-low (ihc 1+ or ihc 2+/ish -) (as per asco/cap 2018 guidelines) advanced/mbc. part 1 of each module will enroll patients with locally confirmed her2-low advanced/mbc in second-line or later (≥ 2l) settings part 2 of each module will enroll patients with her2-low mbc who have either not received prior treatment, or received only 1 prior treatment (depending on the module-specific exclusion criteria) for advanced/metastatic disease

Eligibility criteria:
key inclusion criteria: * patients must be at least 18 years of age * male or female patients who have pathologically documented breast cancer that: 1. has a history of her2-low expression, defined as ihc 2+/ish- or ihc 1+ (ish- or untested) with a validated assay 2. is documented as hr+ (either er and/or pgr positive \[er or pgr ≥1%\]) or er and pgr negative (er and pgr \<1%) per asco/cap guidelines in the metastatic setting * patient must have adequate tumor sample for biomarker assessment * ecog performance status of 0 or 1 for patients with hr+ disease: part 1: at least 1 prior treatment line of et with or without a targeted therapy (such as cdk4/6, mtor or pi3-k inhibitors), and at least 1 prior line of chemotherapy for mbc are required. part 2: only 1 prior treatment line of et with or without a targeted therapy (such as cdk4/6, mtor or pi3-k inhibitors) for mbc is allowed. no prior chemotherapy in the metastatic setting is allowed. note there are no patients with hr+ disease in part 2 of modules 2 and 3. for patients with hr- disease: part 1: at least 1 prior line of chemotherapy for mbc is required. note there are no patients with hr- disease in part 1 of modules 4 and 5. part 2: for module 2, no prior lines of therapy for mbc are allowed, and for modules 1 and 3, only 1 prior line of chemotherapy for mbc is allowed. note there are no patients with hr- disease in part 2 of modules 4 and 5. key exclusion criteria: * uncontrolled intercurrent illness * uncontrolled or siginificant cardiovascular disease * history of (non-infectious) ild/pneumonitis that required steroids, has current ild/pneumonitis, or where suspected ild/pneumonitis cannot be ruled out by imaging at screening. * lung-specific intercurrent clinically significant illnesses * has spinal cord compression or clinically active central nervous system metastases * active primary immunodeficiency * uncontrolled infection requiring iv antibiotics, antivirals, or antifungals * prior treatment with adc that comprises of an exatecan derivative that is a topoisomerase i inhibitor.

Keywords: breast cancer her2-negative her2-low trastuzumab deruxtecan t-dxd ds-8201a destiny-breast08 anti-her2 antibody drug conjugate (adc) triple-negative breast cancer (tnbc)