Testing the Combination of Two Anti-cancer Drugs, DS-8201a and AZD6738, for The Treatment of Advanced Solid Tumors Expressing the HER2 Protein or Gene, The DASH Trial

Inclusion Criteria:

• DOSE-ESCALATION PHASE: Must have histologically confirmed advanced solid tumorincluding but not restricted to breast cancer, gastric or gastroesophageal cancer,colon cancer, endometrial cancer, salivary gland tumors, and hepatobiliary tumors

• DOSE-EXPANSION PHASE: Must have histologically confirmed advanced/metastaticgastroesophageal cancer (cohort A) or colorectal cancer (cohort B)

• DOSE-EXPANSION PHASE: Patients must have a biopsiable lesion and provide consent foron treatment biopsy

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of AZD6738 in combination with DS-8201a in patients < 18 years of age,children are excluded from this study

• Patients must have HER2-positive or HER2-expressing tumors determined by a ClinicalLaboratory Improvement Act (CLIA)-certified laboratory. As a rule, for HER2immunohistochemistry (IHC) scoring system trastuzumab for gastric cancer (TOGA)criteria used for gastric/gastroesophageal junction (GEJ) cancers will be employed (Note: in escalation phase, for breast cancer patients that are included, breastcancer criteria can be used). Specific requirement of HER2 status is outlined below:

• HER2 expression (1-3+) by IHC locally and confirmed centrally OR

• HER2 expression (1-3+) by IHC tested centrally OR

• HER2 amplification based on fluorescence in situ hybridization (FISH) or nextgeneration sequencing

• Must have received at least one line of systemic chemotherapy for either locallyadvanced or metastatic disease and should have either progressed on this therapy orbeen intolerant to this therapy

• For tumors where anti-HER2 therapy is standard of care, patients must haveprogressed on at least 1 line of anti-HER2 therapy if eligible. For patients whereDS8201a is approved as standard of care, prior treatment with DS8201a is not allowed

• Must have unresectable, advanced/metastatic disease

• Must have at least 1 measurable lesion on CT scan per Response Evaluation Criteriain Solid Tumors (RECIST) 1.1. Patient without measurable but evaluable disease areallowed for dose-escalation phase

• Must be willing and able to provide an adequate archival tumor sample available toconfirm HER2 status by Central Laboratory (if local testing is used for enrollment),else must be willing and able to provide an adequate archival tumor sample for HER2testing centrally

• Must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

• Must have life expectancy of at least 3 months

• Must have left ventricular ejection fraction (LVEF) >= 50% within 28 days beforeenrollment (study drug treatment) by either an echocardiogram (ECHO) or multigatedacquisition (MUGA) scan

• Must have a negative pregnancy test (if female)

• Platelets >= 100,000/mcL (within 14 days before enrollment)

• No transfusions with red blood cells or platelets are allowed within 1 weekprior to screening assessment

• Hemoglobin >= 9.0 g/dL (within 14 days before enrollment)

• Absolute neutrophil count >= 1,500/mcL (within 14 days before enrollment)

• No administration of granulocyte colony-stimulating factor (G-CSF) is allowedwithin 1 week prior to screening assessment

• Creatinine clearance > 45/mL/min (using the Cockcroft-Gault equation) (within 14days before enrollment)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional upper limit of normal (ULN) (within 14 days beforeenrollment)

• Total bilirubin =< 1.5 x ULN if no liver metastases or < 3 x ULN with Gilbert'sSyndrome or liver metastases at baseline (within 14 days before enrollment)

• Leukocytes >= 3,000/mcL (within 14 days before enrollment)

• Albumin > 2.5 g/dL (GEJ patients only) (within 14 days before enrollment)

• International normalized ratio (INR) and either partial thromboplastin time (PTT) oractivated (a)PTT =< 1.5 x ULN (within 14 days before enrollment)

• Must have adequate treatment washout period before study treatment, defined as:Major surgery (>= 4 weeks), radiation therapy (>= 3 weeks; in case of palliativeradiation >= 2 weeks), systemic therapy (>= 3 weeks; in case of investigational druguse >= 2 weeks or 5 half-lives, whichever is longer)

• Patients who are human immunodeficiency virus (HIV) positive may participate IF theymeet the following eligibility requirements:

• They must be stable on their anti-retroviral regimen, and they must be healthyfrom an HIV perspective

• They must have a CD4 count of greater than 250 cells/mcL over the past 6 monthson this same anti-retroviral regimen and must not have had a CD4 count < 200cells/mcl over the past 2 years, unless it was deemed related to THE CANCERAND/OR CHEMOTHERAPY-induced bone marrow suppression

• For patients who have received chemotherapy in the past 6 months, a CD4count < 250 cells/mcl during chemotherapy is permitted as long as viralloads were undetectable during this same chemotherapy

• They must have an undetectable viral load and a CD4 count >= 250 cells/mcLwithin 7 days of enrollment

• They must not be currently receiving prophylactic therapy for an opportunisticinfection and must not have had an opportunistic infection within the past 6months. HIV-infected patients should be monitored every 12 weeks for viral loadand CD4 counts

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Subjects with clinically inactive brain metastases may be included. Subjects withtreated brain metastases that are no longer symptomatic and who require no treatmentwith corticosteroids 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 radiation therapy and study treatment

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate central nervous system (CNS) specific treatment is not required and isunlikely to be required for at least 4 weeks (or scheduled assessment after thefirst cycle of treatment), and a risk-benefit analysis (discussion) by the patientand the investigator favors participation in the clinical trial

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• HER2 antibody conjugated to a topoisomerase 1 inhibitor agents as well as AZD6738are known to be teratogenic; thus, women of child-bearing potential must agree touse adequate contraception (hormonal or barrier method of birth control; abstinence)prior to study entry, for the duration of study participation, and for at least 7months (women of childbearing potential [WOCBP] only) after the last dose of studydrug. Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, she should inform her treating physicianimmediately. Men treated or enrolled on this protocol must also agree to useadequate contraception prior to the study, for the duration of study participation,and 6 months after completion of study drug administration

• Women of non-child-bearing potential defined as pre-menopausal females with adocumented tubal ligation or hysterectomy; or postmenopausal defined as 12 months ofspontaneous amenorrhea (in questionable cases, a blood sample with simultaneousfollicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147pmol/L] is confirmatory) are eligible. Females on hormone replacement therapy (HRT)and whose menopausal status is in doubt will be required to use one of thecontraception methods outlined for women of child-bearing potential if they wish tocontinue their HRT during the study. Otherwise, they must discontinue HRT to allowconfirmation of post-menopausal status prior to study enrollment. For most forms ofHRT, at least 2-4 weeks will elapse between the cessation of therapy and the blooddraw; this interval depends on the type and dosage of HRT. Following confirmation oftheir post-menopausal status, they can resume use of HRT during the study withoutuse of a contraceptive method

• Male subjects must not freeze or donate sperm starting at screening and throughoutthe study period, and at least 6 months after the final study drug administration.Preservation of sperm should be considered prior to enrolment in this study

• 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 7 months afterthe final study drug administration

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally-authorized representative (LAR) and/or family member available will also beeligible

Exclusion Criteria:

• Patients with a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or wheresuspected ILD/pneumonitis cannot be ruled out by imaging at screening. Patient usinge-cigarettes/vaping are also excluded

• Patients with a medical history of myocardial infarction within 6 months beforeenrollment (study treatment), symptomatic congestive heart failure (New York HeartAssociation Class II to IV, corrected QT interval (Fridericia's formula-corrected QTinterval [QTcF]) prolongation to > 470 ms (females) or > 450 ms (males) as correctedby Framingham's formula

• Patients with spinal cord compression or clinically active central nervous systemmetastases, defined as untreated and symptomatic, or requiring therapy withcorticosteroids or anticonvulsants to control associated symptoms

• Patients with multiple primary malignancies within 2 years, except adequatelyresected non-melanoma skin cancer, curatively treated in situ disease, or othercuratively treated solid tumors

• Patients with a history of severe hypersensitivity reactions to either the drugsubstances or inactive ingredients in the drug product

• Patients with an uncontrolled infection requiring IV antibiotics, antivirals, orantifungals

• Patients with substance abuse or any other medical conditions that would increasethe safety risk to the subject or interfere with participation of the subject orevaluation of the clinical study in the opinion of the investigator

• Patients with a concomitant medical condition that would increase the risk oftoxicity in the opinion of the investigator

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities grade >1) with the exception of alopecia. Subjectswith chronic grade 2 toxicities may be eligible per discretion of the investigatorafter discussion with study principal investigator (PI) (e.g., grade 2 chemo-inducedneuropathy).

• Any previous treatment with an ATR inhibitor

• Patients with any clinically apparent pulmonary compromise resulting fromintercurrent pulmonary illnesses including, but not limited to, any underlyingpulmonary disorder (i.e., pulmonary emboli within three months of the studyenrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD],restrictive lung disease, pleural effusion, etc.), and any autoimmune, connectivetissue or inflammatory disorders with potential pulmonary involvement (i.e.,Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy

• Patients with myelodysplastic syndrome/acute myeloid leukemia or with featuressuggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

• Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication

• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin,clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,saquinavir, nelfinavir, boceprevir, telaprevir). The required washout period priorto starting study treatment is 2 weeks. Concomitant use of known strong (e.g.,phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine,carbamazepine, nevirapine and St John's Wort ). The required washout period prior tostarting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeksfor other agents

• Patients with a pleural effusion, ascites, or pericardial effusion that requiresdrainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screeningassessment)

• Patients with previous allogeneic bone marrow transplant or double umbilical cordblood transplantation (dUCBT)

• Whole blood transfusions in the last 120 days prior to entry to the study (packedred blood cells and platelet transfusions are acceptable within the last 28 days aslong as they are not within 1 week prior to screening assessment)

• Patients at risk of brain perfusion problems, e.g., medical history of carotidstenosis or pre-syncopal or syncopal episodes, history of transient ischemic attacks (TIAs)

• Uncontrolled hypertension (grade 2 or above) requiring clinical intervention

• Patients with relative hypotension (< 90/60 mm Hg) or clinically relevantorthostatic hypotension, including a fall in blood pressure of > 20 mm Hg

• Patients who have received corticosteroids (at a dose > 10 mg prednisone/day orequivalent) for any reason within 2 weeks prior to first dose

• Patients with uncontrolled intercurrent illness

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Pregnant women are excluded from this study because DS-8201a is a HER2 antibodyconjugated to a topoisomerase 1 inhibitor agent with the potential for teratogenicor abortifacient effects. Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with DS-8201a,breastfeeding should be discontinued if the mother is treated with DS-8201a. Thesepotential risks may also apply to AZD6738

• Patients cannot be receiving chloroquine or hydroxychloroquine. Patients receivingthese drugs must have a washout period of > 14 days before enrollment/randomization