a phase 1b/2 study of t-dxd combinations in her2-positive metastatic breast cancer

Conditions: Metastatic Breast Cancer

Summary: destiny-breast07 will investigate the safety, tolerability, and anti-tumour activity of trastuzumab deruxtecan (t-dxd) in combination with other anti-cancer agents in patients with her2-positive metastatic breast cancer

this study is modular in design allowing assessment of safety, tolerability and anti-tumour activity of t-dxd in combination with other anti-cancer agents. combination-treatment modules will have 2 parts: a dose-finding phase (part 1), and a dose expansion phase (part 2); the recommended phase 2 dose (rp2d) determined in part 1 will be used for the dose-expansion in part 2. the target population of interest in this study is patients with her2-positive (as per asco/cap 2018 guidelines) advanced/mbc inclusive of patients with active and stable brain metastases. part 1 of each module will enroll patients with locally assessed her2-positive advanced/mbc in second-line or later patients. part 2 of each module will enroll patients with locally assessed her2-positive breast cancer who have not received prior treatment for advanced/metastatic disease.

Eligibility criteria:
key inclusion criteria: * patients must be at least 18 years of age * pathologically documented breast cancer that: 1. is advanced/unresectable (patients that can be treated with curative intent are not eligible) or metastatic 2. her2-positive (ihc 3+ or ihc 2+/ish+) based on local assessment. the local her2 result must be from a tumour sample obtained in the metastatic setting. 3. is documented as hormone receptor-positive (estrogen or progesterone receptor) or negative in the metastatic setting * patient must have adequate tumor sample from the metastatic setting for biomarker assessment * ecog performance status of 0 or 1 * part 1 1. disease progression on or after the last systemic therapy prior to starting study treatment 2. at least 1 prior treatment line in metastatic setting required. * part 2 (modules 0 - 5) a) no prior lines of therapy for advanced/mbc allowed * part 2 (module 6 and 7) a) zero or one prior lines of therapy for advanced/mbc allowed cns inclusion * modules 0 - 5 patients must have no brain metastases or stable brain metastases. * module 6 and 7 patients must have untreated brain metastases not needing local therapy or previously treated brain metastases that have progressed since prior local therapy key exclusion criteria: * uncontrolled or significant cardiovascular disease * active or prior documented (non-infectious) ild/pneumonitis that required steroids, or suspected ild/pneumonitis that cannot be ruled out by imaging at screening * lung-specific intercurrent clinically significant illnesses * uncontrolled infection requiring iv antibiotics, antivirals, or antifungals * spinal cord compression or a history of leptomeningeal carcinomatosis * prior treatment with immune checkpoint inhibitors * prior treatment with an adc containing a topoisomerase i inhibitor * prior treatment with tucatinib cns exclusion * modules 0 - 5: has untreated brain metastasis * module 6 and 7: ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of \> 2 mg dexamethasone or any brain lesion thought to require immediate local therapy

Keywords: breast cancer her2-positive brain metastases trastuzumab deruxtecan t-dxd ds-8201a destiny-breast07 anti-her2 antibody drug conjugate (adc)