Valemetostat and Trastuzumab Deruxtecan for the Treatment of HER2 Low/Ultra-low/Null Metastatic Breast Cancer

Inclusion Criteria

• >=18 years of age or the minimum legal adult age (whichever is greater) at the time the informed consent form (ICF) is signed
• Pathologically confirmed HER2 low/ultra-low/null breast cancer. HER2 low is defined as immunohistochemistry (IHC) 2+/in situ hybridization (ISH)- or IHC 1+/(ISH- or undefined), HER2 ultra-low is defined as IHC 0 with detectable faint/barely perceptible incomplete staining in =< 10% tumor cells and HER2 null is defined as IHC 0 without any observed tumor cell staining, regardless of hormone receptor expression status, and as determined by the Ventana 4B5 IHC assay The accrual numbers of HER2 ultra-low/null and HER2 low should be approximately 1:1 in the dose-escalation and dose-expansion cohort (i.e., 6 subjects for HER2 ultra-low/null and 6 subjects for HER2 low in dose-escalation cohort, 10 subjects for HER2 ultra-low/null and 10 subjects for HER2 low in dose-expansion cohort). Initial subject inclusion may be based on previously obtained HER2 testing results, however final HER2 status determination (HER2 low, ultra-low, or null) will be based on centralized pathologist (re)evaluation of HER2 IHC staining using the Ventana 4B5 assay at MD Anderson (MDA) Department of Pathology laboratory * If HER2 eligibility assessment and subject inclusion are based on results from a previous HER2 IHC test performed with an IHC assay different from the Ventana 4B5 assay, or if the IHC slides from the initial test are not available for re-evaluation, adequate material for HER2 testing using the Ventana 4B5 assay must be provided to MDA Department of Pathology laboratory.
• Metastatic breast cancer (MBC) or locally progressive breast cancer that is not a surgical candidate
• Has progressed on and would no longer benefit from endocrine therapy in hormone receptor-positive subjects
• Has been treated with at least 1 prior line of chemotherapy in the metastatic or locally progressive setting
• Has adequate treatment washout period by the time of enrollment, defined as: * Treatment: Major surgery; Washout Period: >=4 weeks * Treatment: Radiation therapy including palliative stereotactic radiation to chest; Washout Period: >=4 weeks * Treatment: Palliative stereotactic radiation therapy to other anatomic areas; Washout Period: >=2 weeks * Treatment: Anti-cancer chemotherapy (Immunotherapy [non-antibody based therapy]), retinoid therapy, hormonal therapy; Washout Period: >=3 weeks * Treatment: Targeted agents and small molecules; Washout Period: >= 2 weeks or 5 half-lives, whichever is longer * Treatment: Nitrosoureas or mitomycin C; Washout Period: >=6 weeks * Treatment: Antibody-based anti-cancer therapy; Washout Period: >=4 weeks * Treatment: Chloroquine/Hydroxychloroquine; Washout Period: >14 days
• Has at least one measurable lesion per RECIST (except for up to the first 5 subjects who enroll in dose escalation part where the measurable lesions meeting RECIST definition are not mandatory)
• Is willing to provide fresh tumor tissue via tumor biopsy only if the participant has a disease that can be safely accessed through a CT-guided/ultrasound (US)-guided or percutaneous biopsy for multiple core biopsies judged by the investigator. If the participant doesn’t have a disease that can be safely accessed, they are still eligible
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1
• Negative serum pregnancy test within 72 hours of receiving the first dose of the study medication for women of childbearing potential as per institutional guidelines. Post- menopausal women (defined as having no menses for at least 1 year in the absence of ovarian suppression) and surgically sterilized women are not required to undergo pregnancy tests
• Subjects of childbearing potential must be willing to use highly effective birth control methods or be surgically sterile or abstain from heterosexual activity for the course of the study through at least 4 months after the last dose of the study drug (for males) and 7 months after last dose of study drug (for females). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for at least 1 year. Methods considered as highly effective methods of contraception include: Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: Oral, intravaginal, transdermal, progestogen-only hormonal contraception associated with inhibition of ovulation: Oral, injectable, implantable, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion or vasectomized partner. Complete sexual abstinence defined as refraining from heterosexual intercourse during and upon completion of the study and for at least 7 months for females and 4 months for males after the last dose of study drug
• Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration
• Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and for at least 4 months after the final study drug administration
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x the upper limit of normal (ULN). * For those with liver metastasis, ALT and AST =< 5.0 x ULN
• Total bilirubin =< 1.5 x ULN, except for subjects with Gilbert's syndrome (e.g., a gene mutation in UGT1A1), who can have total bilirubin < 3.0 mg/dL
• Absolute neutrophil count (ANC) >= 1500/mm^3 (granulocyte colony-stimulating factor administration is not allowed within 1 week prior to Screening assessment)
• Hemoglobin >= 9.0 g/dL (red blood cell transfusion is not allowed within 1 week prior to Screening assessment)
• Platelet count >= 100,000/mm^3 (Platelet transfusion is not allowed within 1 week prior to Screening assessment)
• Creatinine clearance >= 30 mL/min (measured by the Cockcroft-Gault equation)
• Serum Albumin >= 2.5 g/dL
• Acute non-hematologic toxic effects (as evaluated by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 5.0) of any prior therapy (except alopecia) resolved from previous anticancer therapy, defined as toxicities (other than alopecia) resolved to grade ≤ 1 or baseline. Note: Subjects may be enrolled with chronic, stable grade 2 toxicities (defined as no worsening to > grade 2 for at least 3 months prior to [randomization/enrollment/cycle 1 day 1] and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, including: Chemotherapy-induced neuropathy, fatigue, residual toxicities from prior immuno-oncology [IO] treatment: Grade 1 or grade 2 endocrinopathies which may include: Hypothyroidism/hyperthyroidism, type I diabetes, hyperglycemia, adrenal insufficiency, adrenalitis and skin hypopigmentation (vitiligo)

Exclusion Criteria

• Has previously been treated with any anti-HER2 therapy, including T-DXd, or EZH inhibitors
• 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. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study registration
• Prior malignancy active within the previous 2 years except for locally curable cancer that is currently considered as cured, such as cutaneous basal or squamous cell carcinoma, superficial bladder cancer, or cervical carcinoma in situ, or an incidental histological finding of prostate cancer
• Uncontrolled or significant cardiovascular disease, including the following: * Left ventricular ejection fraction (LVEF) < 50% within 28 days * Evidence of prolongation of QT/corrected QT (QTc) (e.g., repeated episodes of QT corrected for heart rate using Fridericia’s method [QTcF] >450 ms) (average of triplicate determinations; over a 5 min time window when the subject has been supine position for at least 10 min without any environmental stimuli) * Diagnosed or suspected long QT syndrome, or known family history of long QT syndrome * History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes * Uncontrolled arrhythmia (subjects with asymptomatic, controllable atrial fibrillation may be enrolled), or asymptomatic persistent ventricular tachycardia * Subject has clinically relevant bradycardia of <50 bpm unless the subject has a pacemaker * History of second- or third-degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers, and have no history of fainting or clinically relevant arrhythmia with pacemakers, within 6 months prior to Screening * Myocardial infarction within 6 months prior to screening. Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial infarction (MI) related symptoms should have a cardiologic consultation before enrollment to rule out MI. * Angioplasty or stent graft implantation within 6 months prior to screening * Uncontrolled angina pectoris within 6 months prior to screening * New York Heart Association (NYHA) class 2-4 congestive heart failure * Coronary/peripheral artery bypass graft within 6 months prior to Screening * Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) * Complete left or right bundle branch block
• Systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents). Note: Short-course systemic corticosteroids (e.g., prevention/treatment for transfusion reaction, pre-treatment anti-emetics) or use for a non-cancer indication (e.g., adrenal replacement) is permissible
• Female who is pregnant or breastfeeding or intends to become pregnant during the study
• Has known human immunodeficiency virus (HIV) infection or active hepatitis B or C infection (screen test is not required). Subjects positive for hepatitis C (HCV) antibody are eligible only if the polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
• Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection requiring treatment with intravenous antibiotics, antivirals, or antifungals. Note: Subjects with localized fungal infections of skin or nails are eligible
• Any active uncontrolled systemic diseases or other medical conditions considered to be poorly controlled by the investigator, including, but not limited to, bleeding diatheses
• A history of (noninfectious) interstitial lung disease (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 including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study registration, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion etc.)
• Any autoimmune, connective tissue or inflammatory disorders (e.g., rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for subjects who are included in the study
• Current use of moderate or strong cytochrome P450 (CYP)3A inducers
• Prior complete pneumonectomy
• Medical history or complication considered inappropriate for participation in the study, or a serious physical or psychiatric disease, the risk of which may be increased by participation in the study in the investigator’s opinion
• A history of substance abuse or medical conditions such as substance abuse, medical or psychological conditions that may, in the opinion of the Investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results
• Known or suspected hypersensitivity to valemetostat and T-DXd or any of the excipients or other monoclonal antibodies
• Subjects with symptomatic brain metastases, or subjects with treated brain metastases that are no longer symptomatic but who require treatment with steroids
• Has history of receiving live, attenuated vaccine (messenger [m]RNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study intervention