Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer

PRIMARY OBJECTIVES:

I. To determine if the addition of metformin (metformin hydrochloride) to the standard regimen of carboplatin and paclitaxel prolongs progression-free survival (PFS) in women with advanced or recurrent endometrial cancer. (Phase II) II. To determine if the addition of metformin to the standard regimen of carboplatin and paclitaxel prolongs overall survival (OS) in the same population if a phase III study is conducted. Both clinical trials (Phase II and III) will utilize OS as a primary endpoint if a phase III trial is opened.

SECONDARY OBJECTIVES:

I. To estimate the proportion of patients with objective response (response rate \[RR\]) in the population of patients with measurable disease by treatment.

II. To estimate the duration of response in the population of patients with measurable disease who respond by treatment.

III. To estimate overall survival (OS) and relative hazards of death for each treatment arm if the study stops after the phase II trial is completed. If the study continues with a phase III clinical trial, then PFS will be a secondary endpoint.

IV. To determine the nature, frequency and degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) for each treatment arm.

V. To estimate possible differences in RR, PFS, OS, and toxicity rates for the treatment regimens by the patients' level of obesity.

TERTIARY OBJECTIVES:

I. To test whether PIK3CA mutations/amplifications, PTEN mutations or PIK3R1/PIK3R2 mutations have a lower hazard of progression or death (PFS endpoint) among patients who are treated with metformin.

II. To test whether higher expression of MATE 2 is associated with a lower hazard of progression or death (PFS endpoint) among patients who are treated with metformin.

III. To explore the association of metabolic factors (i.e. body mass index \[BMI\], hip-to-waist ratio, diabetes status, hemoglobin A1c \[HgbA1C\], fasting insulin and glucose levels, homeostatic model assessment \[HOMA\] scores) with treatment response to metformin/paclitaxel/carboplatin, PFS, and OS.

IV. To test whether genomic profiles (i.e. PIK3CA mutations/amplifications, PTEN mutations or PIK3R1/PIK3R2 mutations) differ between the tumors of obese and non-obese endometrial cancer (EC) patients.

V. To correlate expression of key targets of the insulin/IGF-1/mTOR signaling pathway (p-IGF1R, p-S6 and p-4EBP-1) with treatment response to metformin/paclitaxel/carboplatin, PFS, OS and obesity status.

VI. To determine if the genetic variants of the metformin transporters correspond with treatment response to metformin/paclitaxel/carboplatin, PFS and OS.

VII. To estimate differences in physical functioning, physical activity, and fatigue between treatment arms.

VIII. To explore the association between metabolic factors (i.e., BMI, hip-to-waist ratio, diabetes status, HgbA1C, fasting insulin and glucose levels, HOMA scores) and physical functioning, physical activity, and fatigue.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours on day 1, carboplatin IV over 30 minutes on day 1, and metformin hydrochloride orally (PO) twice daily (BID) (approximately 10-12 hours apart) on days 1-21 (once daily \[QD\] in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising metformin hydrochloride PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive paclitaxel IV and carboplatin IV as in Arm I. Patients also receive placebo PO BID (approximately 10-12 hours apart) on days 1-21 (QD in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising placebo PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

In both arms, patients who achieve stable disease (SD) or partial response (PR) and still have measurable disease at the completion of course 6 may continue to receive paclitaxel IV and carboplatin IV (with metformin hydrochloride or placebo) for an additional 4 courses at the discretion of the treating investigator.

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

• Carboplatin (Drug), also known as Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo: Given IV
• Laboratory Biomarker Analysis (Other): Correlative studies
• Metformin Hydrochloride (Drug), also known as APO-Metformin, Cidophage, Dimefor, Glifage, Glucoformin, Glucophage, Glucophage ER, Metformin HCl, Riomet, Siofor: Given PO
• Paclitaxel (Drug), also known as Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat: Given IV
• Placebo Administration (Other): Given PO
• Quality-of-Life Assessment (Other), also known as Quality of Life Assessment: Ancillary studies
• Questionnaire Administration (Other): Ancillary studies

Primary outcomes

• Progression-free Survival (PFS) (Phase II) [From date of study entry to time of progression or death, whichever occurs first, assessed up to 5 years]: Time until disease progression, death, or date of last contact. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
• Overall Survival (OS) (Phase II and III) [From date of study entry to time of death or the date of last contact, assessed up to 5 years]: The observed length of life from randomization into the study to death or the date of last contact. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.

Secondary outcomes

• Proportion of Patients Responding to Therapy [During study treatment, up to 5 years.]: The proportion of patients who had a response (complete or partial) by RECIST 1.1. Measurable disease is defined by RECIST (version 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 CT, MRI or caliper measurement by clinical exam; or ≥ 20 mm when measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when measured by CT or MRI.
• Duration of Response by Treatment [From the date of response to disease progression, death, or date last seen assessed up to 5 years]: Duration of response until disease progression, death, or date last seen among patients who responded.
• Overall Survival (OS) (Phase II) [From date of study entry to time of death or the date of last contact, assessed up to 5 years.]: The observed length of life from randomization into the study to death or the date of last contact. For response, only those patients who had measurable disease were included in an analysis of response. Non-measurable patients are included in the ITT analysis. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
• Progression Free Survival (PFS) (Phase III) [From date of study entry to time of progression or death, whichever occurs first, assessed up to 5 years]: Time until disease progression, death, or date of last contact. For response, only those patients who had measurable disease were included in an analysis of response. Non-measurable patients are included in the ITT analysis. This study was originally designed as a phase II/III study. It passed the phase 2 threshold and started the phase 3; however, a phase 3 interim analysis stopped the trial for futility. Therefore, data available for Phase III may be identical to data reported for Phase II or Phase II/III combined.
• Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 [Up to 5 years]: Toxicities will be assessed by organ or organ system. For each category of toxicity, each patient will be evaluated by the worst grade experienced during the course of therapy. Data will be summarized by frequency and severity according to the regimen administered. The number of patients with a grade three or greater adverse event will be reported (by system organ class).
• Level of Obesity [Up to 5 years]: Obesity will be quantitative assessed by body mass index (BMI) and will be assessed for its predictive and prognostic significance. The interaction between BMI and metformin treatment will be examined with an interaction term in a Cox proportional hazards model.

Other outcomes

• Metabolic Factor Levels [Up to 5 years]: Hip-to-waist ratio, diabetes status, hemoglobin A1c, fasting insulin glucose levels, and homeostatic model assessment scores will be assessed for their predictive and prognostic significance. Variables will be analyzed as continuous covariates (or as appropriate with transformations such as the logarithm) with Cox models or logistic regression.
• Incidence of PIK3 Mutations/Amplifications [Up to 5 years]: PIK3CA mutations/amplifications and PIK3R1/PIK3R2 mutations will be examined for prognostic and predictive significance.
• Expression of MATE 2 [Up to 5 years]: Expression will be examined by immunohistochemistry with intensity of staining and the percentage of cells staining positive. From these statistics, an H-score will be calculated. Expression will be further dichotomized as high expression and low expression at the median to maximize the power of the study.
• Levels of Key Targets of the Metformin/mTOR Signaling Pathway [Up to 5 years]: Levels before and after treatment will be assessed for their predictive and prognostic significance.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

* Patients must have measurable stage III, measurable stage IVA, stage IVB (with or without measurable disease) or recurrent (with or without measurable disease) endometrial carcinoma

  * Histologic confirmation of the original primary tumor is required; patients with the following histologic epithelial cell types are eligible:

    * Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.)
* Measurable disease is defined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 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), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by CT or MRI
* Patients must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2
* Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl
* Platelets greater than or equal to 100,000/mcl
* Creatinine less than 1.4 mg/dl
* Bilirubin less than or equal to 1.5 x institutional/laboratory upper limit of normal (ULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN
* Alkaline phosphatase less than or equal to 2.5 x ULN
* Patients must NOT have received prior chemotherapy or targeted therapy, including chemotherapy used for radiation sensitization for treatment of endometrial carcinoma
* Patients may have received prior radiation therapy for treatment of endometrial carcinoma; prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy; all radiation therapy must be completed at least 4 weeks prior to the first date of study therapy
* Patients may have received prior hormonal therapy for treatment of endometrial carcinoma; all hormonal therapy must be discontinued at least one week prior to the first date of study therapy
* Patients must be able to swallow and retain orally-administered medication
* Patients must have signed an approved informed consent and authorization permitting release of personal health information; individuals with impaired decision-making capacity are not eligible to participate on the study

Exclusion Criteria:

* Patients must NOT be taking metformin or have been on metformin in the past 6 months
* Patients with 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 last three years
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Patients who are pregnant or nursing; if patients are of reproductive age and have not undergone hysterectomy, they must use an effective contraceptive method for the duration of this study
* Any condition associated with increased risk of metformin-associated lactic acidosis; (e.g. congestive heart failure defined as New York Heart Association \[NYHA\] class III or IV functional status, history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day)

Participant flow

Outcome results

• Progression-free Survival (PFS) (Phase II) (Primary), Median, Months: Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) 9.0 (8.4 to 10.5); Arm II (Paclitaxel, Carboplatin, Placebo) 8.5 (8.0 to 10.3)
• Overall Survival (OS) (Phase II and III) (Primary), Median, Months: Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) 34.6 (28.0 to 50.1); Arm II (Paclitaxel, Carboplatin, Placebo) 30.4 (24.6 to 37.8)
• Proportion of Patients Responding to Therapy (Secondary), Number, percentage of patients: Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) 61.6 (53.7 to 69.1); Arm II (Paclitaxel, Carboplatin, Placebo) 60.2 (52.5 to 67.6)
• Duration of Response by Treatment (Secondary), Median, Months: Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) 8.0 (6.3 to 9.4); Arm II (Paclitaxel, Carboplatin, Placebo) 8.0 (6.2 to 10.3)
• Overall Survival (OS) (Phase II) (Secondary), Median, Months: Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) 34.6 (28.0 to 50.1); Arm II (Paclitaxel, Carboplatin, Placebo) 30.4 (24.6 to 37.8)
• Progression Free Survival (PFS) (Phase III) (Secondary), Median, Months: Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) 9.0 (8.4 to 10.5); Arm II (Paclitaxel, Carboplatin, Placebo) 8.5 (8.0 to 10.3)
• Number of Participants With Grade 3 or Higher Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4 (Secondary), Count of participants, Participants: Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) 23; Arm II (Paclitaxel, Carboplatin, Placebo) 17
• Level of Obesity (Secondary), Number, proportion of participants obese: Arm I (Paclitaxel, Carboplatin, Metformin Hydrochloride) 0.4957; Arm II (Paclitaxel, Carboplatin, Placebo) 0.4979 (p 0.9482)
• Metabolic Factor Levels (Other pre specified)
• Incidence of PIK3 Mutations/Amplifications (Other pre specified)
• Expression of MATE 2 (Other pre specified)
• Levels of Key Targets of the Metformin/mTOR Signaling Pathway (Other pre specified)

Adverse events

Time frame: Patients are followed for the occurrence of adverse events for five years.

Serious adverse events by term

10 more terms not shown.

Other adverse events by term

234 more terms not shown.

331 more sites not listed.

• Study Protocol and Statistical Analysis Plan (PDF, 2017-06-21)

• Victoria L Bae-Jump, Principal investigator, NRG Oncology

NIH grants: U10CA180830, U10CA180868, U10CA027469