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

I. To examine if letrozole monotherapy/maintenance is non-inferior to intravenous (IV) paclitaxel/carboplatin and maintenance letrozole 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 paclitaxel + carboplatin/letrozole (CT/L) and letrozole monotherapy (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.

ARM II: Patients receive letrozole PO QD in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, then annually thereafter.

Inclusion Criteria:

• Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up
• All women will, by definition, be considered menopausal due to surgical removal of both ovaries prior to trial enrollment
• Patients must have newly diagnosed, stage II-IV low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinoma) of the ovary or peritoneum. Tumors must be assessed for nuclear p53 staining
• Appropriate stage for study entry based on the following diagnostic workup:
  • History/physical examination within 14 days prior to registration
  • Contrast-enhanced imaging of the chest, abdomen and pelvis within 28 days prior to registration
• 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 prior to initial 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)
• Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible if there is no hydronephrosis and the estimated creatinine clearance (CCr) is >= 30 ml/min (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)
• Alkaline phosphatase less than or equal to 2.5 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

Exclusion Criteria:

• Patients with concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol
• Patients may not have received neoadjuvant 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 or uncontrolled systemic infection
• Patients with >= grade 2 baseline neuropathy
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive