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

• ClinicalTrials.gov Identifier: NCT04095364
• Recruitment Status: Recruiting
• First Posted: September 19, 2019
• Last Update Posted: November 3, 2022
• Sponsor: NRG Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): NRG Oncology

Tracking Information

• First Submitted Date: September 16, 2019
• First Posted Date: September 19, 2019
• Last Update Posted Date: November 3, 2022
• Actual Study Start Date: August 26, 2019
• Estimated Primary Completion Date: February 1, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 18, 2019)

Progression-free survival (PFS) [ Time Frame: 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 ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 8, 2019)

• Incidence of adverse events (AE) [ Time Frame: Up to 8 years ]
  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.
• Objective response rate (ORR) [ Time Frame: Up to 8 years ]
  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.
• Duration of response [ Time Frame: Time from documentation of response under documentation of progression or death, which is observed first, assessed up to 8 years ]
  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.
• Overall survival (OS) [ Time Frame: Time between randomization and death from any cause, assessed up to 8 years ]
  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.
• Adherence to letrozole maintenance therapy [ Time Frame: At cycles 1, 6, and 12 ]
  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.

Original Secondary Outcome Measures (submitted: September 18, 2019)

• Incidence of adverse events (AE) [ Time Frame: Up to 8 years ]
  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.
• Objective response rate (ORR) [ Time Frame: Up to 8 years ]
  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.
• Duration of response [ Time Frame: Time from documentation of response under documentation of progression or death, which is observed first, assessed up to 8 years ]
  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.
• Overall survival (OS) [ Time Frame: Time between randomization and death from any cause, assessed up to 8 years ]
  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.
• Adherence to letrozole maintenance therapy [ Time Frame: At cycles 1, 6, and 12 (each cycle is 21 days) ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Letrozole With or Without Paclitaxel and Carboplatin in Treating Patients With Stage II-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
• Official Title: 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
• Brief Summary: 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

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.

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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 IIA Fallopian Tube Cancer AJCC v8
• Stage IIA Ovarian Cancer AJCC v8
• Stage IIA Primary Peritoneal Cancer AJCC v8
• Stage IIB Fallopian Tube Cancer AJCC v8
• Stage IIB Ovarian Cancer AJCC v8
• Stage IIB 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 IIIA Fallopian Tube Cancer AJCC v8
• Stage IIIA Ovarian Cancer AJCC v8
• Stage IIIA Primary Peritoneal Cancer AJCC v8
• Stage IIIA1 Fallopian Tube Cancer AJCC v8
• Stage IIIA1 Ovarian Cancer AJCC v8
• Stage IIIA2 Fallopian Tube Cancer AJCC v8
• Stage IIIA2 Ovarian Cancer AJCC v8
• Stage IIIB Fallopian Tube Cancer AJCC v8
• Stage IIIB Ovarian Cancer AJCC v8
• Stage IIIB Primary Peritoneal Cancer AJCC v8
• Stage IIIC Fallopian Tube Cancer AJCC v8
• Stage IIIC Ovarian Cancer AJCC v8
• Stage IIIC 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
• Stage IVA Fallopian Tube Cancer AJCC v8
• Stage IVA Ovarian Cancer AJCC v8
• Stage IVA Primary Peritoneal Cancer AJCC v8
• Stage IVB Fallopian Tube Cancer AJCC v8
• Stage IVB Ovarian Cancer AJCC v8
• Stage IVB Primary Peritoneal Cancer AJCC v8

Intervention

• Drug: Carboplatin
  Given IV
  Other Names:

  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo
• Drug: Letrozole
  Given PO
  Other Names:

  • CGS 20267
  • Femara
• Drug: Paclitaxel
  Given IV
  Other Names:

  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

Study Arms

• Experimental: Arm I (paclitaxel, carboplatin, letrozole)
  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.
  Interventions:

  • Drug: Carboplatin
  • Drug: Letrozole
  • Drug: Paclitaxel
• Experimental: Arm II (letrozole)
  Patients receive letrozole PO QD in the absence of disease progression or unacceptable toxicity.
  Intervention: Drug: Letrozole

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 18, 2019): 450
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 1, 2028
• Estimated Primary Completion Date: February 1, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 ovarian cancer (submission of pathology report[s] required). Ovarian cancer = ovarian, fallopian tube and primary peritoneal cancers. p53 immunohistochemistry (IHC) is required and must show nonaberrant pattern (nonaberrant p53 expression is consistent with normal/wildtype TP53). 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). 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

• 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 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

Exclusion Criteria:

• 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
• 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 (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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Canada, Korea, Republic of, United States

Administrative Information

• NCT Number: NCT04095364
• Other Study ID Numbers: NRG-GY019; NCI-2019-01460 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); NRG-GY019 ( Other Identifier: NRG Oncology ); NRG-GY019 ( Other Identifier: CTEP ); U10CA180868 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: NRG Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: NRG Oncology
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Amanda N Fader; NRG Oncology

• PRS Account: NRG Oncology
• Verification Date: November 2022