A Phase II/III Study of Paclitaxel/Carboplatin Alone or Combined with either Trastuzumab and Hyaluronidase-Oysk (HERCEPTIN HYLECTA) or Pertuzumab Trastuzumab and Hyaluronidase-ZZFX (PHESGO) in HER2 Positive, Stage I-IV 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 serous carcinoma or endometrial

carcinosarcoma

- Histologic confirmation of the original primary tumor is required. Submission of

surgical pathology report (or endometrial biopsy pathology report in patients who

never undergo hysterectomy) is required

- Patients must be within 8 weeks of primary surgery (or endometrial biopsy in patients

who never undergo hysterectomy) at the time of study registration

- Patients may have measurable disease, non-measurable disease, or no measurable

disease. In patients with measurable disease, lesions will be defined and monitored by

RECIST v 1.1. Measurable disease is defined as at least one lesion that can be

accurately measured in at least one dimension (longest diameter to be recorded). Each

lesion must be >= 10 mm when measured by computed tomography (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 invasive into

the myometrium. Any amount of myoinvasion is acceptable for eligibility. Patients with

non-invasive disease, endometrial intraepithelial carcinoma alone, or disease confined

to a polyp will be excluded

- Additionally, patients must have the following histologic types to be eligible:

- Serous adenocarcinoma (may include =< 10% non-serous histology)

- Carcinosarcoma with serous epithelial component (only the serous component needs

to be HER2 positive; may include =< 10% non-serous histology)

- In cases where determination of serous is equivocal or challenging, aberrant p53

immunohistochemistry (IHC) (defined as overexpression of p53 compared to internal

controls) will be sufficient for inclusion

- All patients must have tumors that are HER2 positive as defined by American Society of

Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2018 Breast Cancer

guidelines (https://documents.cap.org/documents/algorithim-evaluation-her2.pdf. In

general HER2 positivity is defined as any of the following:

- 3+ immunohistochemistry (IHC),

- 2+ IHC with positive in situ hybridization (ISH)

- Average HER2 copy number >= 6.0 signals/cell

- Average HER2 copy number >= 4.0 and < 6.0 signals/cell, with concurrent IHC 3+

- HER2/CEP17 ratio >= 4.0 signals/cell

- HER2/CEP 17 ratio >= 2.0 and < 4.0, with concurrent IHC 3+ IHC and ISH testing

will be done locally, at each participating institution and interpreted by local

pathologists. Alternatively, patients could be eligible if next generation

sequencing (NGS) demonstrates HER2 (ERBB2) amplification. NGS testing can be

performed through any designated labs as per the 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) or estimated

Glomerular filtration rate (eGFR) >= 50 mL/min using either the Cockcroft-Gault

equation, the Modification of Diet in Renal Disease Study, or as reported 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 who

have bilirubin level =< 3 x ULN may be enrolled) (within 14 days prior to

registration)

- 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-retroviral

therapy with undetectable viral load within 6 months of registration are eligible for

this trial

- Although the uterus will have been removed in the vast majority of patients, for

patients of child-bearing potential: negative urine or serum pregnancy test. If the

urine test is positive or cannot be confirmed as negative, a serum pregnancy test is

required. Patients will be considered of non-reproductive potential if they are

either:

- Postmenopausal (defined as at least 12 months with no menses without an

alternative medical cause; in women < 45 years of age, a high follicle

stimulating hormone [FSH] level in the postmenopausal range may be used to

confirm a postmenopausal state in women not using hormonal contraception or

hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single

FSH measurement is insufficient); OR

- Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or

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 treatment does

not have the potential to interfere with the safety or efficacy assessment of the

investigational regimen are eligible for this trial. NOTE: Patients with prior

anthracycline exposure are NOT eligible

- Patients with evidence of chronic hepatitis B virus (HBV) infection must have an

undetectable HBV viral load on suppressive therapy, if indicated

- Patients with a history of hepatitis C virus (HCV) infection must have been treated

and cured. For patients with HCV infection who are currently on treatment, they are

eligible if they have an undetectable HCV viral load

- Patients with treated brain metastases are eligible if follow-up brain imaging after

central nervous system (CNS)-directed therapy shows no evidence of progression

- The patient or a legally authorized representative must provide study-specific

informed 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, or targeted

therapy for treatment of endometrial carcinoma

- Patients must NOT have received prior radiation therapy for treatment of

endometrial carcinoma. Prior radiation includes external beam pelvic radiation

therapy, external beam extended field pelvic/para-aortic radiation therapy,

and/or intravaginal brachytherapy

- NOTE: Vaginal brachytherapy for treatment of endometrial cancer is permitted

during study treatment. Planned use of vaginal brachytherapy must be

declared at time of registration

- Patients may have received prior hormonal therapy for treatment of endometrial

carcinoma. All hormonal therapy must be discontinued at least one week prior to

registration

- Patients may not have a planned interval cytoreduction or hysterectomy, prior to

documentation of progression, after study registration

- Patients may not have planned external beam radiotherapy, prior to documentation of

progression, after study registration

- Significant cardiovascular disease including:

- Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm

Hg 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 include

asymptomatic, atrial fibrillation with controlled ventricular rate

- Significant lung disease: dyspnea at rest grade 2 or greater (resulting from extensive

tumor involvement or other causes), pneumonitis grade 2 or greater, interstitial lung

disease grade 2 or greater, idiopathic pulmonary fibrosis, cystic fibrosis,

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, or psychiatric

illness/social situations that would limit compliance with study requirements

- Treatment with strong CYP2C8 or CYP3A4 inhibitors or inducers within 14 days or 5

drug-elimination half-lives, whichever is longer, prior to registration

- Women who are unwilling to discontinue nursing