Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors

Inclusion Criteria:

• In the dose escalation, patients must have a histologically documented locallyadvanced, unresectable, or metastatic solid tumor that has progressed following atleast one prior line of treatment in the metastatic setting or has no satisfactoryalternative treatment option and all of the following:

• HER2 expression by immunohistochemistry (IHC) (1+, 2+, or 3+) or HER2amplification by in situ hybridization (ISH) or next generation sequencing (NGS) (on any Clinical Laboratory Improvements Amendments [CLIA] platform), AND

• T-DXd (DS-8201a)-naive disease

• In the dose expansion, patients must have histologically documented locallyadvanced, unresectable or metastatic gastric or gastroesophageal junction (GEJ)cancer that has progressed following at least one prior line of treatment in themetastatic setting and have all of the following:

• CCNE1 amplification, AND

• HER2 expression by IHC (1+, 2+, or 3+) or HER2 amplification by ISH or NGS (onany CLIA platform), AND

• T-DXd (DS-8201a)-naive disease

• Received prior trastuzumab-based treatment, if eligible for such treatment

• For the dose escalation and dose expansion, patients can have evaluable ormeasurable disease

• Potential trial participants should have recovered from clinically significantadverse events (AEs) of their most recent therapy/intervention prior to enrollment

• Age ≥ 18 years. Because no dosing or AE data are currently available on the use ofT-DXd (DS-8201a) in combination with azenosertib (ZN-c3) in patients < 18 years ofage, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (Karnofsky ≥ 70%). Both T-DXd (DS-8201a) and azenosertib (ZN-c3) have fatigue as an adverseeffect. Due to the overlapping adverse effect, the performance status cannot be lessrestrictive

• Absolute neutrophil count ≥ 1.5 × 10^9/L (within 7 days of study treatmentinitiation)

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

• No administration of granulocyte colony-stimulating factor is allowed within 1week prior to screening assessment

• Hemoglobin > 9.0 g/dL (within 7 days of study treatment initiation)

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

• No administration of granulocyte colony-stimulating factor is allowed within 1week prior to screening assessment

• Platelets ≥ 100 × 10^9/L (within 7 days of study treatment initiation)

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

• No administration of granulocyte colony-stimulating factor is allowed within 1week prior to screening assessment

• Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN). Documented Gilbertsyndrome is allowed if total bilirubin is ≤ 3 × institutional ULN (within 7 days ofstudy treatment initiation)

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

• No administration of granulocyte colony-stimulating factor is allowed within 1week prior to screening assessment

• Aspartate aminotransferase (AST [serum glutamic-oxaloacetic transaminase (SGOT)])/alanine aminotransferase (ALT [serum glutamate pyruvate transaminase (SGPT)]) ≤ 3 × institutional ULN. In the presence of liver metastases, AST or ALT upto 5 × institutional ULN is permitted (within 7 days of study treatment initiation)

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

• No administration of granulocyte colony-stimulating factor is allowed within 1week prior to screening assessment

• Measured of calculated creatinine clearance (CrCl) ≥ 60 mL/min (CrCl should becalculated per institutional standard; glomerular filtration rate can also be usedin place of CrCl) ≥ 60 mL/min for patients with creatinine levels > 1.5 xinstitutional ULN (within 7 days of study treatment initiation)

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

• No administration of granulocyte colony-stimulating factor is allowed within 1week prior to screening assessment

• International normalized ratio/prothrombin time and activated partial thromboplastintime ≤ 1.5 × institutional ULN (within 7 days of study treatment initiation)

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

• No administration of granulocyte colony-stimulating factor is allowed within 1week prior to screening assessment

• Patients must have left ventricular ejection fraction (LVEF) ≥ 50% by either anechocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days beforeenrollment

• Human immunodeficiency virus-infected patients on effective anti-retroviral therapywith undetectable viral load within 6 months are eligible for this trial

• 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

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS-specific treatment is not required and is unlikely to be requiredduring the first cycle of study treatment

• 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

• Life expectancy ≥ 3 months

• Women of childbearing potential (WOCBP) must have a negative serum pregnancy testresult within 3 days of study treatment initiation

• Agents composed of HER2 antibody conjugated to a topoisomerase 1 inhibitor andazenosertib (ZN-c3) are known to be teratogenic; thus, WOCBP must agree to usehighly effective contraception from time of screening and throughout the studytreatment period and for at least 7 months after final study treatmentadministration. Should a woman become pregnant or suspect she is pregnant while sheor her partner is participating in this study, she should inform her treatingphysician immediately. Female patients must not donate, or retrieve for their ownuse, ova from the time of screening and throughout the study treatment period andfor at least 7 months after the final study treatment administration

• Women of non-childbearing potential defined as premenopausal females with documentedtubal ligation or hysterectomy; or postmenopausal defined as 12 months ofspontaneous amenorrhea (in questionable cases, a blood sample with simultaneousfollicle-stimulating hormone > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] isconfirmatory) are eligible. Females on hormone replacement therapy (HRT) and whosemenopausal status is in doubt will be required to use one of the contraceptionmethods outlined for WOCBP if they wish to continue their HRT during the study.Otherwise, they must discontinue HRT to allow confirmation of postmenopausal statusprior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapsebetween the cessation of therapy and the blood draw; this interval depends on thetype and dosage of HRT. Following confirmation of their postmenopausal status, theycan resume use of HRT during the study without use of a contraception method

• Male patients involved with WOCBP must agree to use a highly effective form ofcontraception or avoid intercourse from time of screening and throughout the studytreatment period and for at least 4 months after the last dose of study treatment.Male patients must not freeze or donate sperm starting at screening and throughoutthe study period and at least 4 months after the final study treatmentadministration. Preservation of sperm should be considered prior to enrollment inthis study

• Ability to understand and the willingness to sign a written informed consentdocument. Legally authorized representatives may sign and give informed consent onbehalf of study participants

• Willing to undergo biopsy as required by the study (dose expansion only)

Exclusion Criteria:

• As azenosertib (ZN-c3) is a substrate of CYP3A4, use of prescription ornon-prescription drugs known to be moderate or strong inhibitors or inducers ofCYP3A4 are prohibited with the exception of moderate or strong inhibitors orinducers of CYP3A4 that are part of the prophylactic antiemetic regimen.Chloroquine/hydroxychloroquine are metabolized by CYP3A4 and therefore, should beprohibited. For patients who have received prior moderate or strong inhibitors orinducers of CYP3A4, the required washout period is approximately 5 half-lives priorto study treatment initiation

• Patients who are receiving any other investigational agents

• Patients who have a history of allergic reactions attributed to compounds of similarchemical or biologic composition to the study drugs

• Patients who have a history of severe hypersensitivity reactions to other monoclonalantibodies (mAbs)

• Patients with clinically severe pulmonary compromise resulting from intercurrentpulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within 3 months of the study enrollment, severe asthma,severe chronic obstructive pulmonary disease, restrictive lung disease, pleuraleffusion, etc.), and any autoimmune, connective tissue or inflammatory disorderswith potential pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's,sarcoidosis, etc.), or prior pneumonectomy

• Pregnant women are excluded from this study because T-DXd (DS-8201a) and azenosertib (ZN-c3) have the potential risk for teratogenic or abortifacient effects. Becausethere is an unknown but potential risk for AEs in nursing infants secondary totreatment of the mother with T-DXd (DS-8201a) and azenosertib (ZN-c3), breastfeedingshould be discontinued if the mother is treated with T-DXd (DS-8201a) or azenosertib (ZN-c3)

• Patients with history of non-infectious pneumonitis/interstitial lung disease (ILD),current ILD, or where suspected ILD cannot be ruled out by imaging at screening

• Patients with active infections requiring antibiotics at the time of study treatmentinitiation are not eligible

• Patients with history of malabsorption syndrome or other condition that wouldinterfere with enteral absorption or results in the inability or unwillingness toswallow pills

• Patients with current signs or symptoms of bowel obstruction including sub-occlusivedisease related to underlying disease

• Patients with a medical history of myocardial infarction within 6 months beforeenrollment, symptomatic congestive heart failure (New York Heart Association classIIb to IV), and/or troponin levels consistent with myocardial infarction as definedaccording to the manufacturer 28 days prior to enrollment

• Patients with clinically significant corneal disease

• 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 history of Torsades de Pointes unless all risk factors thatcontributed to Torsades de Pointes have been corrected

• Based on an average of triplicate 12-lead electrocardiogram (ECG), patients with amean resting corrected QT (QTc) interval using Fridericia formula of > 470 msec forboth males and females at screening or a history of congenital long QT syndrome willbe excluded

• Patients with prior treatment with a WEE1 inhibitor (dose escalation and doseexpansion)

• Patients with prior treatment with T-DXd (DS-8201a) or other topoisomeraseinhibitors (dose escalation and dose expansion)

• Patients with uncontrolled intercurrent illness

• Patients with prior allogeneic organ transplantation including allogeneic stem celltransplantation

• Patients with clinically significant chronic gastrointestinal disorder with diarrheaas a major symptom; ≥ grade 2 diarrhea at baseline. Please contact the protocolprincipal investigator (PI) for any patient with more than two episodes of diarrheaper day averaged over at least a 7-day period at time of screening to determinewhether the diarrhea would be considered clinically significant

• Patients with spinal cord compression