a study of valemetostat tosylate in combination with dxd adcs in subjects with solid tumors

Conditions: Advanced Solid Tumor

Summary: this study will evaluate the safety, tolerability, and efficacy of valemetostat tosylate in combination with dxd adc in patients with advanced solid tumors.

this is a 2-part study of valemetostat in combination with dxd adcs in patients with her2-positive gastric cancer, non-squamous nsclc, or unresectable or metastatic her2 low breast cancer. the study will begin with a part 1 dose-escalation phase and will continue until the recommended dose for expansion "rde" of valemetostat is determined and will then be followed by a part 2 dose-expansion phase to further evaluate the safety and tolerability of the combination.

Eligibility criteria:
key inclusion criteria all participants must meet all of the following criteria, as well as all criteria from the relevant sub-protocol to be eligible for enrollment: * at least 18 years or the minimum legal adult age (whichever is greater) at the time the icf is signed. * has at least 1 measurable lesion based on investigator imaging assessment (computed tomography or magnetic resonance imaging) using recist v 1.1 at screening. * is willing to provide an adequate tumor sample. * eastern cooperative oncology group performance status (ecog ps) of 0 or 1 at screening. additional key inclusion for sub-protocol a: * diagnosed with pathologically documented breast cancer that: 1. is unresectable or metastatic. 2. has progressed on and would no longer benefit from endocrine therapy in hormone receptor-positive subjects in the opinion of the investigator. 3. has been treated with at least 1 and at most 2 prior lines of chemotherapy in the recurrent or metastatic setting. 4. has a history of low her2 expression, defined as ihc 2+ /ish-negative or ihc 1+ (ish-negative or untested). ), as classified by the american society of clinical oncology/college of american pathologists 2018 her2 testing guidelines. 5. was never previously her2-positive (ihc 3+ or ihc 2+/ish+) on prior pathology testing (per american society of clinical oncology/college of american pathologists guidelines additional key inclusion for sub-protocol b: • gastric or gej adenocarcinoma that is (a) unresectable or metastatic or (b) has progressed on trastuzumab or approved trastuzumab biosimilar-containing regimen. additional key inclusion for sub-protocol c: * pathologically documented stage iiib, iiic, or iv non-squamous nsclc with or without aga at the time of enrollment. * must meet prior therapy requirements: * participants without aga: (a) received platinum-based chemotherapy in combination with α-pd-1/α -pd-l1 mab as a prior line of therapy or (b) received platinum-based chemotherapy and α -pd-1/ α -pd-l1 mab (in either order) sequentially as 2 prior lines of therapy. * participants with aga: (a) has been treated with at least 1 or 2 prior lines of applicable targeted therapy that is locally approved for participant's genomic alteration at the time of screening, (b) participants who have received platinum-based chemotherapy as a prior line of cytotoxic therapy, (c) may have received α -pd-1/α -pd-l1 mab alone or in combination with a cytotoxic agent key exclusion criteria * has previously been treated with any enhancer of zeste homolog inhibitors. * uncontrolled or significant cardiovascular disease. * has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. * has leptomeningeal carcinomatosis or metastasis. * clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses. * current use of moderate or strong cytochrome p450 (cyp)3a inducers. * systemic treatment with corticosteroids (\>10 mg daily prednisone equivalents). * history of severe hypersensitivity reactions to other monoclonal antibodies (mabs). * evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection requiring treatment with intravenous (iv) antibiotics, antivirals, or antifungals. * female who is pregnant or breastfeeding or intends to become pregnant during the study. * psychological, social, familial, or geographical factors that would prevent regular follow-up. additional key exclusion for sub-protocol a: * has previously received any anti-her2 therapy in the metastatic setting. * has received prior treatment with an antibody-drug conjugate that consists of an exatecan derivative that is a topoisomerase i inhibitor, including either as part of prior treatment history or within prior participation in a clinical study. additional key exclusion for sub-protocol b: \* participants who have received an antibody-drug conjugate consisting of an exatecan derivative that is a topoisomerase i inhibitor. additional key exclusion for sub-protocol c: \* has received any agent, including an adc, containing a chemotherapeutic agent targeting topoisomerase i or trop2-targeted therapy including dato-dxd

Keywords: advanced solid tumor valemetostat tosylate dxd antibody-drug conjugates