Phase 1b Study of EZH1/2 Inhibitor Valemetostat in Combination With Trastuzumab Deruxtecan in Subjects With HER2 Low/Ultra-low/Null Metastatic Breast Cancer

Inclusion Criteria:

1. ≥18 years of age or the minimum legal adult age (whichever is greater) at the timethe informed consent form (ICF) is signed.

2. Pathologically confirmed HER2 low/ultra-low/null breast cancer. HER2 low is definedas IHC 2+/ISH- or IHC 1+/(ISH- or undefined), HER2 ultra-low is defined as IHC 0with detectable faint/barely perceptible incomplete staining in ≤10% tumor cells andHER2 null is defined as IHC 0 without any observed tumor cell staining, regardlessof hormone receptor expression status, and as determined by the Ventana 4B5 IHCassay The accrual numbers of HER2 ultra-low/null and HER2 low should beapproximately 1:1 in the dose-escalation and dose-expansion cohort (i.e., 6 subjectsfor HER2 ultra-low/null and 6 subjects for HER2 low in dose-escalation cohort, 10subjects for HER2 ultra-low/null and 10 subjects for HER2 low in dose-expansioncohort). Initial subject inclusion may be based on previously obtained HER2 testingresults, however final HER2 status determination (HER2 low, ultra-low, or null) willbe based on centralized pathologist (re)evaluation of HER2 IHC staining using theVentana 4B5 assay at MDA Department of Pathology laboratory. If HER2 eligibility assessment and subject inclusion are based on results from aprevious HER2 IHC test performed with an IHC assay different from the Ventana 4B5assay, or if the IHC slides from the initial test are not available forre-evaluation, adequate material for HER2 testing using the Ventana 4B5 assay mustbe provided to MDA Department of Pathology laboratory.

3. MBC or locally progressive breast cancer that is not a surgical candidate.

4. Has progressed on and would no longer benefit from endocrine therapy in hormonereceptor-positive subjects.

5. Has been treated with at least 1 prior line of chemotherapy in the metastatic orlocally progressive setting.

6. Has adequate treatment washout period by the time of enrollment, defined as: Treatment Washout Period Major surgery ≥ 4 weeks Radiation therapy includingpalliative stereotactic radiation to chest ≥ 4 weeks Palliative stereotacticradiation therapy to other anatomic areas ≥ 2 weeks Anti-cancer chemotherapy (Immunotherapy [non-antibody based therapy]), retinoid therapy, hormonal therapy

• 3 weeks Targeted agents and small molecules ≥ 2 weeks or 5 half-lives,whichever is longer Nitrosoureas or mitomycin C ≥ 6 weeks Antibody-basedanti-cancer therapy ≥ 4 weeks Chloroquine/Hydroxychloroquine >14 days

7. Has at least one measurable lesion per RECIST (except for up to the first 5 subjectswho enroll in dose escalation part where the measurable lesions meeting RECISTdefinition are not mandatory).

8. Is willing to provide fresh tumor tissue via tumor biopsy only if the participanthas a disease that can be safely accessed through a CT-guided/US-guided orpercutaneous biopsy for multiple core biopsies judged by the investigator. If theparticipant doesn't have a disease that can be safely accessed, they are stilleligible.

9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.

10. Negative serum pregnancy test within 72 hours of receiving the first dose of thestudy medication for women of childbearing potential as per institutionalguidelines. Post-menopausal women (defined as having no menses for at least 1 year)and surgically sterilized women are not required to undergo pregnancy tests.

11. Subjects of childbearing potential must be willing to use effective birth controlmethods or be surgically sterile or abstain from heterosexual activity for thecourse 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 ofchildbearing potential are those who have not been surgically sterilized or have notbeen free from menses for at least 1 year.

12. Female subjects must not donate, or retrieve for their own use, ova from the time ofscreening and throughout the study treatment period, and for at least 3 months afterthe final study drug administration.

13. Male subjects must not freeze or donate sperm starting at Screening and throughoutthe study period, and for at least 3 months after the final study drugadministration.

14. The patient must have adequate organ function as determined by the followinglaboratory values:

15. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × theupper limit of normal (ULN). For those with liver metastasis, ALT and AST ≤5.0 × ULN.

16. Total bilirubin ≤1.5 × ULN, except for subjects with Gilbert's syndrome (e.g.,a gene mutation in UGT1A1), who can have total bilirubin <3.0 mg/dL.

17. Absolute neutrophil count (ANC) ≥1500/mm3 (granulocyte colony-stimulatingfactor administration is not allowed within 1 week prior to Screeningassessment).

18. Hemoglobin ≥9.0 g/dL (red blood cell transfusion is not allowed within 1 weekprior to Screening assessment).

19. Platelet count ≥100,000/mm3 (Platelet transfusion is not allowed within 1 weekprior to Screening assessment).

20. Creatinine clearance ≥30 mL/min (measured by the Cockcroft-Gault equation*).

• Female: ([140-age] × weight in kg)/(serum creatinine × 72) × 0.85 Male: ([140-age] × weight in kg)/(serum creatinine × 72)

7. Serum Albumin ≥ 2.5 g/dL

8. Acute non-hematologic toxic effects (as evaluated by National Cancer Institute [NCI]Common Terminology Criteria for Adverse Events [CTCAE], Version 5.0) of any priortherapy (except alopecia) resolved as shown below:

9. Peripheral neuropathy: Grade ≤2

10. Fatigue: Grade ≤2

11. All others: Grade ≤1

Exclusion Criteria:

1. Has previously been treated with any anti-HER2 therapy, including T-DXd, or EZHinhibitors.

2. Has spinal cord compression or clinically active central nervous system metastases,defined as untreated and symptomatic, or requiring therapy with corticosteroids oranticonvulsants to control associated symptoms. Subjects with clinically inactivebrain metastases may be included in the study. Subjects with treated brainmetastases that are no longer symptomatic and who require no treatment withcorticosteroids or anticonvulsants may be included in the study if they haverecovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks musthave elapsed between the end of whole brain radiotherapy and study registration.

3. Prior malignancy active within the previous 2 years except for locally curablecancer that is currently considered as cured, such as cutaneous basal or squamouscell carcinoma, superficial bladder cancer, or cervical carcinoma in situ, or anincidental histological finding of prostate cancer

4. Uncontrolled or significant cardiovascular disease, including the following:

5. LVEF < 50% within 28 days

6. Evidence of prolongation of QT/QTc (e.g., repeated episodes of QT corrected forheart rate using Fridericia's method [QTcF] >450 ms) (average of triplicatedeterminations; over a 5 min time window when the subject has been supineposition for at least 10 min without any environmental stimuli).

7. Diagnosed or suspected long QT syndrome, or known family history of long QTsyndrome

8. History of clinically relevant ventricular arrhythmias, such as ventriculartachycardia, ventricular fibrillation, or Torsade de Pointes

9. Uncontrolled arrhythmia (subjects with asymptomatic, controllable atrialfibrillation may be enrolled), or asymptomatic persistent ventriculartachycardia

10. Subject has clinically relevant bradycardia of 50 bpm unless the subject has apacemaker

11. History of second or third-degree heart block. Candidates with a history ofheart block may be eligible if they currently have pacemakers, and have nohistory of fainting or clinically relevant arrhythmia with pacemakers, within 6months prior to Screening

12. Myocardial infarction within 6 months prior to Screening

13. Angioplasty or stent graft implantation within 6 months prior to Screening

14. Uncontrolled angina pectoris within 6 months prior to Screening

15. New York Heart Association (NYHA) Class 2-4 congestive heart failure

16. Coronary/peripheral artery bypass graft within 6 months prior to Screening

17. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg ordiastolic blood pressure >110 mmHg)

18. Complete left or right bundle branch block

19. Systemic treatment with corticosteroids (>10 mg daily prednisone equivalents). Note:Short-course systemic corticosteroids (e.g., prevention/treatment for transfusionreaction) or use for a non-cancer indication (e.g., adrenal replacement) ispermissible.

20. Female who is pregnant or breastfeeding or intends to become pregnant during thestudy

21. Has known human immunodeficiency virus (HIV) infection or active hepatitis B or Cinfection (screen test is not required). Subjects positive for hepatitis C (HCV)antibody are eligible only if the polymerase chain reaction is negative for HCV RNA.

22. Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infectionrequiring treatment with intravenous antibiotics, antivirals, or antifungals. Note:Subjects with localized fungal infections of skin or nails are eligible.

23. Any active uncontrolled systemic diseases or other medical conditions considered tobe poorly controlled by the investigator, including, but not limited to, bleedingdiatheses

24. A history of (noninfectious) ILD/pneumonitis that required steroids, has currentILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imagingat Screening.

25. Lung-specific intercurrent clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder (e.g. pulmonary emboli within threemonths of the study registration, severe asthma, severe COPD, restrictive lungdisease, pleural effusion etc.).

26. Any autoimmune, connective tissue or inflammatory disorders (e.g., rheumatoidarthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion ofpulmonary involvement at the time of screening. Full details of the disorder shouldbe recorded in the eCRF for subjects who are included in the study.

27. Current use of moderate or strong cytochrome P450 (CYP)3A inducers (Table 17)

28. Prior complete pneumonectomy

29. Medical history or complication considered inappropriate for participation in thestudy, or a serious physical or psychiatric disease, the risk of which may beincreased by participation in the study in the investigator's opinion

30. A history of substance abuse or medical conditions such as clinically significantcardiac or pulmonary diseases or psychological conditions that may, in the opinionof the Investigator, interfere with the subject's participation in the clinicalstudy or evaluation of the clinical study results.

31. Known or suspected hypersensitivity to valemetostat and T-DXd or any of theexcipients.

32. Subjects with symptomatic brain metastases, or subjects with treated brainmetastases that are no longer symptomatic but who require treatment with steroids.