Letrozole With or Without Paclitaxel and Carboplatin in Treating Patients With Stage II-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study Overview
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Brief Summary
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This phase III trial studies how well letrozole with or without paclitaxel and carboplatin works in treating patients with stage II-IV low-grade serous carcinoma of the ovary, fallopian tube, or peritoneum. Letrozole is an enzyme inhibitor that lowers the amount of estrogen made by the body which in turn may stop the growth of tumor cells that need estrogen to grow. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving letrozole alone or in combination with paclitaxel and carboplatin works better in treating patients with low-grade serous carcinoma of the ovary, fallopian tube, or peritoneum compared to paclitaxel and carboplatin without letrozole.

Detailed Description
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PRIMARY OBJECTIVE: I. To examine if letrozole monotherapy/maintenance (L/L) is non-inferior to intravenous (IV) paclitaxel/carboplatin and maintenance letrozole (CT/L) with respect to progression-free survival (PFS) in women with stage II-IV primary low-grade serous carcinoma of the ovary or peritoneum after primary surgical cytoreduction. SECONDARY OBJECTIVES: I. To compare the nature, frequency and maximum degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 for each treatment arm. II. To compare the relative frequency of objective tumor response in those with measurable disease after cytoreductive surgery for each treatment arm. III. To compare overall survival for each treatment arm. IV. To compare the CT/L and L/L arms with respect to patients' adherence to letrozole therapy as measured by pill counts. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Cycles repeat every 21 days for up to 6 cycles. Patients then receive letrozole orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection and tumor biopsy during screening as well as medical imaging throughout the study. ARM II: Patients receive letrozole PO QD. Cycles repeat every 21 days for up to 6 cycles. Patients then receive letrozole orally PO QD in the absence of disease progression or unacceptable toxicity as maintenance therapy. Patients undergo blood collection and tumor biopsy during screening as well as medical imaging throughout the study. After completion of study treatment/intervention, patients/participants are followed up every 3 months for 1 year, then every 6 months for 3 years, then annually thereafter.

Official Title
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A Randomized Phase III, Two-Arm Trial of Paclitaxel/Carboplatin/Maintenance Letrozole Versus Letrozole Monotherapy in Patients With Stage II-IV, Primary Low-Grade Serous Carcinoma of the Ovary or Peritoneum

Conditions
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Low Grade Fallopian Tube Serous Adenocarcinoma, Ovarian Low Grade Serous Adenocarcinoma, Primary Peritoneal Low Grade Serous Adenocarcinoma, Stage II Fallopian Tube Cancer AJCC v8, Stage II Ovarian Cancer AJCC v8, Stage II Primary Peritoneal Cancer AJCC v8, Stage III Fallopian Tube Cancer AJCC v8, Stage III Ovarian Cancer AJCC v8, Stage III Primary Peritoneal Cancer AJCC v8, Stage IV Fallopian Tube Cancer AJCC v8, Stage IV Ovarian Cancer AJCC v8, Stage IV Primary Peritoneal Cancer AJCC v8

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Drug: Carboplatin
* Procedure: Imaging Technique
* Drug: Letrozole
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have newly diagnosed, stage II-IV low-grade serous ovarian cancer (submission of pathology report[s] required). Ovarian cancer = ovarian, fallopian tube and primary peritoneal cancers NOTE: Patients with a prior history of serous borderline tumors but a new diagnosis of stage II-IV low-grade serous ovarian cancer are eligible p53 immunohistochemistry (IHC) is required and must show nonaberrant pattern (nonaberrant p53 expression is consistent with normal/wildtype TP53) A copy of the pathology report that includes the diagnosis of low grade serous ovarian cancer and nonaberrant p53 IHC result must be submitted in RAVE. NOTE: If aberrant p53 expression is found on p53 IHC, the patient is NOT eligible (aberrant p53 expression is consistent with mutant TP53 and supports diagnosis of high grade serous ovarian cancer) Appropriate stage for study entry based on the following diagnostic workup: History/physical examination within 14 days prior to registration; Radiographic tumor assessment within 28 days prior to registration. (23-MAY-2023) Age >= 18 Patients must have undergone an attempt at maximal upfront cytoreductive surgery, with either optimal (=< 1 cm diameter residual disease/nodule) or suboptimal residual disease (> 1 cm diameter residual disease/nodule) status allowed Patients must have undergone a bilateral salpingo-oophorectomy Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 14 days prior to registration Patients must be within =< 8 weeks of primary cytoreductive surgery at time of randomization Patients must be able to take per oral (P.O.) medications Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl (within 14 days prior to registration) Platelets greater than or equal to 100,000 cells/mcl (within 14 days prior to registration) Creatinine less than or equal to 1.5 x upper limit of normal (ULN) (within 14 days prior to registration) Bilirubin less than or equal to 1.5 x ULN (within 14 days prior to registration) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x ULN (within 14 days prior to registration) 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 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 Exclusion Criteria: Patients may not have received neoadjuvant or adjuvant chemotherapy or radiotherapy for the treatment of this disease Patients may not have received previous hormonal therapy for the treatment of this disease Patients with known hypersensitivity to letrozole or hypersensitivity/intolerance to carboplatin/paclitaxel therapy Patients with severe cardiac disease: Myocardial infarction or unstable angina within 6 months prior to registration New York Heart Association (NYHA) class II or greater congestive heart failure Patients with known central nervous system metastases Patients with active (except for uncomplicated urinary tract infection) or uncontrolled systemic infection Patients with >= grade 2 baseline neuropathy Known human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (paclitaxel, carboplatin, letrozole)<br>Patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Cycles repeat every 21 days for up to 6 cycles. Patients then receive letrozole PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection and tumor biopsy during screening as well as medical imaging throughout the study. | Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Imaging Technique<br>* Undergo medical imaging<br>* Other names: Type of imaging;Drug: Letrozole<br>* Given PO<br>* Other names: Fempro;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|
| Experimental: Arm II (letrozole)<br>Patients receive letrozole PO QD. Cycles repeat every 21 days for up to 6 cycles. Patients then receive letrozole orally PO QD in the absence of disease progression or unacceptable toxicity as maintenance therapy. Patients undergo blood collection and tumor biopsy during screening as well as medical imaging throughout the study. | Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Imaging Technique<br>* Undergo medical imaging<br>* Other names: Type of imaging;Drug: Letrozole<br>* Given PO<br>* Other names: Fempro;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | The PFS comparison will be assessed at the second interim and final analyses using a logrank test stratified by country and residual disease status. Estimates for the letrozole/letrozole (L/L) vs paclitaxel/carboplatin/letrozole (CT/L) hazard ratio and its confidence interval will be obtained using a stratified Cox proportional hazards model. Potential confounding factors, including the stratification factors, performance status and self-declared racial designation will be considered in a final exploratory model. A forest plot of treatment hazard ratios with confidence intervals within subgroups will also be reported. PFS will be characterized by treatment group with Kaplan-Meier plots and estimates of the median PFS. | Time from the randomized treatment assignment to documentation of disease progression (Response Evaluation Criteria in Solid Tumors 1.1) or death from any cause, whichever comes first, assessed up to 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AE) | The nature, frequency and degree of toxicity will be tabulated at the System Organ Class and AE Term levels using Common Terminology Criteria for Adverse Events version 5.0. Each patient will be represented according the maximum grade observed for each term, within randomized treatment assignment. Tabulations will show the number and percentage of patients by maximum grade, within their randomized treatment assignment. | Up to 8 years | 
| Objective response rate (ORR) | Will be estimated as the binomial proportion of patients with best overall response of complete response (CR) or partial response (PR) among patients with measurable disease after cytoreductive surgery. Response rates and their 95% Wilson-Score confidence intervals will be estimated for each treatment arm, using the randomized treatment assignment. The odds-ratio for ORR in the L/L vs CT/L arms will be estimated from the multivariable logistic regression model adjusted for stratification factors. | Up to 8 years | 
| Duration of response | Will be defined among patients with best overall response of CR or PR. Comparison of response duration between the randomized treatment arms will be supported by Kaplan Meier methods, and the corresponding estimates for median duration and its 95% confidence intervals. | Time from documentation of response under documentation of progression or death, which is observed first, assessed up to 8 years | 
| Overall survival (OS) | Differences in OS across the randomized treatment groups will be assessed using Kaplan Meier methods, with median time to death estimates and the corresponding 95% confidence intervals. The L/L vs CT/L hazard ratio will be estimated by a proportional hazards model stratified by the randomization stratification factors. | Time between randomization and death from any cause, assessed up to 8 years | 
| Adherence to letrozole maintenance therapy | Will be quantified as the mean rate of adherence (MRA), calculated as the proportion of product not returned divided by the number of days since the previous visit at which study products were dispensed. Currently, the letrozole is delivered in a 2.5 mg pill, and the recommended dose is 2.5 mg per day. This outcome will be computed for each treatment cycle (generally 21 days). The mean MRA will be compared between the randomized treatment groups using linear mixed model methods. The model will be specified with a random patient effect, and fixed effects for randomized treatment indicator, time (cycle number) and the interaction, with an adjustment for the protocol stratification factors. Primary interest is in the difference in mean (MRA) at cycles 1, 6 and 12 between the treatment group. The results will be reported as the estimated mean (MRA) and 95% confidence intervals for each treatment/time combination. Treatment differences within stratification factors may also be considered. | At cycles 1, 6, and 12 |