Testing the Addition of Herceptin Hylecta or Phesgo to the Usual Chemotherapy for HER2 Positive Endometrial Serous Carcinoma or Carcinosarcoma

Inclusion Criteria:

• Federation of Gynecology and Obstetrics (FIGO) 2009 stage IA-IVB, non-recurrent,chemotherapy (chemo)-naive, HER2-positive endometrial cancer. The followingendometrial cancer types are eligible:

• Serous

• Other endometrial cancers (including clear cell, endometrioid, mixedepithelial, dedifferentiated/undifferentiated)

• Carcinosarcoma

• NOTE: Endometrial cancers that are mismatch repair deficient (dMMR) by IHCare not eligible

• Histologic confirmation of the original primary tumor is required. Submission ofsurgical pathology report (or endometrial biopsy pathology report in patients whonever undergo hysterectomy) is required

• Patients must be within 8 weeks of primary surgery (or endometrial biopsy inpatients who never undergo hysterectomy) at the time of study registration

• Patients may have measurable disease, non-measurable disease, or no measurabledisease. In patients with measurable disease, lesions will be defined and monitoredby RECIST v 1.1. Measurable disease is defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded).Each lesion must be >= 10 mm when measured by CT or magnetic resonance imaging (MRI). Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI

• For patients with uterine-confined (stage I) disease, the tumor must be invasiveinto the myometrium. Any amount of myoinvasion is acceptable for eligibility.Patients with non-invasive disease, endometrial intraepithelial carcinoma alone, ordisease confined to a polyp will be excluded

• All patients must have tumors that are HER2 positive as defined by American Societyof Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2018 BreastCancer guidelines (https://documents.cap.org/documents/algorithim-evaluation-her2.pdf.) IHC and ISHtesting will be done locally, at each participating institution and interpreted bylocal pathologists. In general HER2 positivity is defined as any of the following:

• 3+ immunohistochemistry (IHC),

• 2+ IHC with positive in situ hybridization (ISH) Alternatively, patients couldbe eligible if next generation sequencing (NGS) demonstrates HER2 (ERBB2)amplification. NGS testing can be performed through any designated labs as perthe National Cancer Institute (NCI) MATCH/NCI Combo-MATCH trial (https://ecog-acrin.org/nci-match-eay131-designated-labs).

Pathology report showing results of institutional HER2 testing (or NGS testing results) must be submitted.

Sites must submit all results available (IHC, ISH, and NGS)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

• Age >= 18

• Platelets >= 100,000/mcl (within 14 days prior to registration)

• Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to registration)

• Creatinine =< 1.5 x institutional/laboratory upper limit of normal (ULN) orestimated Glomerular filtration rate (eGFR) >= 50 mL/min using either theCockcroft-Gault equation, the Modification of Diet in Renal Disease Study, or asreported in the comprehensive metabolic panel/basic metabolic panel (eGFR) (within 14 days prior to registration)

• Total serum bilirubin level =< 1.5 x ULN (patients with known Gilbert's disease whohave bilirubin level =< 3 x ULN may be enrolled) (within 14 days prior toregistration)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to registration)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months of registration are eligiblefor this trial

• Although the uterus will have been removed in the vast majority of patients, forpatients of child-bearing potential: negative urine or serum pregnancy test. If theurine test is positive or cannot be confirmed as negative, a serum pregnancy test isrequired. Patients will be considered of non-reproductive potential if they areeither:

• Postmenopausal (defined as at least 12 months with no menses without analternative medical cause; in women < 45 years of age, a high folliclestimulating hormone [FSH] level in the postmenopausal range may be used toconfirm a postmenopausal state in women not using hormonal contraception orhormonal replacement therapy. In the absence of 12 months of amenorrhea, asingle FSH measurement is insufficient); OR

• Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomyor bilateral tubal ligation/occlusion at least 6 weeks prior to registration

• Have a congenital or acquired condition that prevents childbearing

• 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

• Patients with evidence of chronic hepatitis B virus (HBV) infection must have anundetectable HBV viral load 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

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Prior Therapy:

• Patients must NOT have received prior chemotherapy, biologic therapy, ortargeted therapy for treatment of endometrial carcinoma

• Patients must NOT have received prior radiation therapy for treatment ofendometrial carcinoma. Prior radiation includes external beam pelvic radiationtherapy, external beam extended field pelvic/para-aortic radiation therapy,and/or intravaginal brachytherapy

• NOTE: Vaginal brachytherapy for treatment of endometrial cancer ispermitted during study treatment. Planned use of vaginal brachytherapymust be declared at time of registration

• Patients may have received prior hormonal therapy for treatment of endometrialcarcinoma. All hormonal therapy must be discontinued at least one week prior toregistration

• Patients may not have a planned interval cytoreduction or hysterectomy, prior todocumentation of progression, after study registration

• Patients may not have planned external beam radiotherapy, prior to documentation ofprogression, after study registration

• Significant cardiovascular disease including:

• Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mmHg despite antihypertensive medications

• Myocardial infarction or unstable angina within 6 months prior to registration

• New York Heart Association functional classification II, III or IV

• Serious cardiac arrhythmia requiring medication. This does not includeasymptomatic, atrial fibrillation with controlled ventricular rate

• Significant lung disease: dyspnea at rest grade 2 or greater (resulting fromextensive tumor involvement or other causes), pneumonitis grade 2 or greater,interstitial lung disease grade 2 or greater, idiopathic pulmonary fibrosis, cysticfibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia)

• Patients with uncontrolled intercurrent illness including, but not limited to:ongoing or active infection (except for uncomplicated urinary tract infection),uncontrolled interstitial lung disease, symptomatic congestive heart failure, orpsychiatric illness/social situations that would limit compliance with studyrequirements

• Treatment with strong CYP2C8 or CYP3A4 inhibitors or inducers within 14 days or 5drug-elimination half-lives, whichever is longer, prior to registration

• Women who are unwilling to discontinue nursing