This phase III trial tests whether adding trastuzumab and hyaluronidase-oysk (Herceptin Hylecta \[TM\]) or pertuzumab, trastuzumab and hyaluronidase-zzxf (Phesgo \[TM\]) to the usual chemotherapy (paclitaxel and carboplatin) works to shrink tumors in patients with HER2 positive endometrial cancer. Trastuzumab and pertuzumab are monoclonal antibodies and forms of targeted therapy that attach to specific molecules (receptors) on the surface of tumor cells, known as HER2 receptors. When trastuzumab or pertuzumab attach to HER2 receptors, the signals that tell the cells to grow are blocked and the tumor cell may be marked for destruction by the body's immune system. Hyaluronidase is an endoglycosidase. It helps to keep pertuzumab and trastuzumab in the body longer, so that these medications will have a greater effect. Hyaluronidase also allows trastuzumab and trastuzumab/pertuzumab to be given by injection under the skin and shortens their administration time compared to trastuzumab or pertuzumab alone. Paclitaxel is a taxane and in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Giving Herceptin Hylecta or Phesgo in combination with paclitaxel and carboplatin may shrink the tumor and prevent the cancer from coming back in patients with HER2 positive endometrial cancer.
PRIMARY OBJECTIVES: I. To evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) and pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive endometrial cancer. SECONDARY OBJECTIVES: I. To evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) and pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive endometrial cancer. II. To evaluate the overall response rate (ORR) in patients with measurable disease. III. To evaluate the duration of objective response in patients with measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. IV. To determine the nature, frequency and degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0 for each treatment arm. V. To compare quality of life (QOL), as measured by Functional Assessment of Cancer Therapy - Endometrial Trial Outcome Index (FACT-En-TOI), in the experimental versus control arms. VI. To compare patient-reported treatment-associated symptoms (diarrhea and rash) as measured with the Patient Reported Outcomes (PRO) - CTCAE, patient-reported fatigue as measured with the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue short form, and worry concerning side effects of treatment as measured by the item 'bothered by side effect', in the FACT-En TOI, respectively, in the experimental and control arms. VII. To assess the correlation of HER2 immunohistochemistry (IHC) expression and in situ hybridization (ISH) amplification with clinical outcome and response to HER2 targeted therapies. EXPLORATORY OBJECTIVE: I. To explore time to sustained deterioration in quality of life, as measured by a drop in the FACT-En-TOI by 6 or more points lasting for more than one PRO time point, in the experimental and control arms. OUTLINE: Patients are randomized to 1 of 3 arms. ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30-60 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with stable disease (SD) or partial response (PR) who still have measurable disease after completion of cycle 6 may receive 4 additional cycles of this treatment at the discretion of the treating physician. ARM II: Patients receive paclitaxel IV over 3 hours, carboplatin IV over 30-60 minutes, and trastuzumab/hyaluronidase-oysk subcutaneously (SC) over 2-5 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with SD or PR who still have measurable disease after completion of cycle 6 may receive 4 additional cycles of this treatment at the discretion of the treating physician. MAINTENANCE: Patients receive trastuzumab/hyaluronidase-oysk SC over 2-5 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients with SD or PR may continue maintenance therapy for up to 3 years from the start of treatment. ARM III: Patients receive paclitaxel IV over 3 hours, carboplatin IV over 30-60 minutes, and pertuzumab/trastuzumab/hyaluronidase-zzxf SC over 5-8 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients with SD or PR who still have measurable disease after completion of cycle 6 may receive 4 additional cycles of this treatment at the discretion of the treating physician. MAINTENANCE: Patients receive pertuzumab/trastuzumab/ hyaluronidase-zzxf SC over 5 minutes on day 1 of each cycle. Cycles repeat every 3 weeks for up to 1 year in absence of disease progression or unacceptable toxicity. Patients with SD or PR may continue maintenance for up to 3 years from the start of treatment. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and computed tomography (CT) throughout the study. Additionally, patients may optionally undergo blood sample collection throughout the study, vaginal brachytherapy on study, and urine sample collection prior to treatment. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
360
Undergo blood and urine sample collection
Given IV
Undergo CT
Undergo ECHO
Undergo vaginal brachytherapy
Given SC
Undergo MUGA
Given IV
Ancillary studies
Given SC
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
RECRUITINGAlaska Women's Cancer Care
Anchorage, Alaska, United States
RECRUITINGBanner University Medical Center - Tucson
Tucson, Arizona, United States
RECRUITINGUniversity of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
Progression free survival
At the end of Phase 2 analysis, if both experimental arms demonstrate superiority to the reference, the experimental arms will be compared to each other.
Time frame: From study entry to time of progression or death, whichever occurs first, or date of last contact if neither progression nor death has occurred, assessed up to 5 years from randomization
Overall survival
If both experimental arms demonstrate superiority to the reference arm, the experimental arms will be compared to each other.
Time frame: From study entry to time of death or the date of last contact, assessed up to 5 years from randomization
Incidence of dose limiting toxicities
A dose limiting toxicity is any treatment-related adverse event requiring permanent discontinuation of the experimental therapy prior to the completion of treatment cycle 3.
Time frame: Up to end of cycle 3 (week 12)
Objective response rate (ORR)
Defined as the binomial proportion of evaluable patients with a best overall response of complete response or partial response (by Response Evaluation Criteria in Solid Tumors 1.1) within 12 months of initiating maintenance therapy. Responses reported by the treating physician will be used for these analyses. The ORR estimates by treatment arm will be supported by their 2-sided, 95% Wilson-Score confidence intervals (Wilson, 1927; Agresti, 1998). The relative odds of response in each experimental group (versus \[vs\] the reference group) will be estimated using a multivariable logistic regression model specified with main effects for the treatment groups and covariate adjustments for the stratification factors reported at baseline.
Time frame: Within 12 months of initiating maintenance therapy
Duration of objective response
Treatment group differences in response duration will be graphed using Kaplan-Meier methods and compared using logrank tests, stratified by the minimization factors defined at randomization. The relative hazards of progression or death in each experimental group (vs the reference group) will be estimated using a multivariable proportional hazards regression model specified with main effects for the treatment indicators and covariate adjustments for the stratification factors reported at baseline.
Time frame: From documentation of either PR or CR until disease progression or death, whichever is observed first, assessed up to 5 years from randomization
Incidence of adverse events (AEs)
The nature, frequency, and degree of toxicity will be tabulated at the System Organ Class and AE-specific term levels using Common Terminology Criteria version 5.0. Each patient will be represented according to the maximum grade observed for each term. Tabulations will show the number and percentage of patients by maximum grade, within the treatment group received, regardless of the randomized treatment assignment.
Time frame: Up to 5 years from randomization
HER2 expression
Correlation of HER2 immunohistochemistry expression and in situ hybridization amplification with clinical outcome and response to HER2 targeted therapies will be explored.
Time frame: Up to 5 years from randomization
Quality of life (QoL)
Measured by Functional Assessment of Cancer Therapy - Endometrial Trial Outcome Index.
Time frame: Up to 5 years from randomization
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University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
RECRUITINGSutter Auburn Faith Hospital
Auburn, California, United States
RECRUITINGAlta Bates Summit Medical Center-Herrick Campus
Berkeley, California, United States
RECRUITINGJohn Muir Medical Center-Concord
Concord, California, United States
ACTIVE_NOT_RECRUITINGCity of Hope Comprehensive Cancer Center
Duarte, California, United States
ACTIVE_NOT_RECRUITINGCity of Hope Seacliff
Huntington Beach, California, United States
ACTIVE_NOT_RECRUITING...and 397 more locations