Clinical Trials /

Enzalutamide, Carboplatin, and Paclitaxel in Treating Patients With Stage III-IV or Recurrent Endometrioid Endometrial Cancer

NCT02684227

Description:

This phase II trial studies how well enzalutamide, carboplatin, and paclitaxel work in treating patients with endometrioid endometrial cancer that is stage III-IV or has come back. Androgens can cause the growth of endometrioid endometrial cancer. Antihormone therapy, such as enzalutamide may lessen the amount of androgen made by the body. Drugs used in chemotherapy, such as carboplatin and paclitaxel, 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. Giving enzalutamide, carboplatin, and paclitaxel may work better in treating patients with endometrioid endometrial cancer.

Related Conditions:
  • Endometrial Endometrioid Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Enzalutamide, Carboplatin, and Paclitaxel in Treating Patients With Stage III-IV or Recurrent Endometrioid Endometrial Cancer
  • Official Title: A Phase II Study With a Limited Safety Lead-In of Enzalutamide in Combination With Carboplatin and Paclitaxel in Advanced Stage or Recurrent Endometrioid Endometrial Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2015-0723
  • SECONDARY ID: NCI-2016-00562
  • SECONDARY ID: 2015-0723
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02684227

Conditions

  • Recurrent Endometrial Endometrioid Adenocarcinoma
  • Recurrent Uterine Corpus Carcinoma
  • Stage III Uterine Corpus Cancer AJCC v7
  • Stage IIIA Uterine Corpus Cancer AJCC v7
  • Stage IIIB Uterine Corpus Cancer AJCC v7
  • Stage IIIC Uterine Corpus Cancer AJCC v7
  • Stage IV Uterine Corpus Cancer AJCC v7
  • Stage IVA Uterine Corpus Cancer AJCC v7
  • Stage IVB Uterine Corpus Cancer AJCC v7

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (enzalutamide, paclitaxel, carboplatin)
EnzalutamideASP9785, MDV3100, XtandiTreatment (enzalutamide, paclitaxel, carboplatin)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratTreatment (enzalutamide, paclitaxel, carboplatin)

Purpose

This phase II trial studies how well enzalutamide, carboplatin, and paclitaxel work in treating patients with endometrioid endometrial cancer that is stage III-IV or has come back. Androgens can cause the growth of endometrioid endometrial cancer. Antihormone therapy, such as enzalutamide may lessen the amount of androgen made by the body. Drugs used in chemotherapy, such as carboplatin and paclitaxel, 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. Giving enzalutamide, carboplatin, and paclitaxel may work better in treating patients with endometrioid endometrial cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the clinical activity of combination enzalutamide, carboplatin and paclitaxel
      represented as:

      Ia. Objective tumor response (complete response [CR] + partial response [PR]). Ib. The
      proportion of patients who survive progression-free for at least 6 months after initiating
      therapy.

      II. To quantify protein and phosphoprotein expression of androgen receptor (AR) and
      AR-response genes following enzalutamide treatment in match-paired pre and post treatment
      tumor biopsies.

      III. To determine the safety and feasibility of daily enzalutamide given in combination with
      carboplatin and paclitaxel in women with advanced stage or recurrent endometrial cancer.

      SECONDARY OBJECTIVES:

      I. Determine median response duration. II. Estimate progression free survival and overall
      survival. III. Evaluate for presence of pharmacokinetic interaction between enzalutamide and
      paclitaxel.

      EXPLORATORY OBJECTIVES:

      I. Correlate molecular results, including AR receptor expression and activation, to clinical
      endpoints.

      II. Identify potential agents to synergize with enzalutamide based on pathways activated
      after enzalutamide treatment.

      OUTLINE:

      Patients receive enzalutamide orally (PO) once daily (QD) alone on days 1-28. Patients then
      receive enzalutamide PO QD on days 1-21, paclitaxel intravenously (IV) over 3 hours on day 1,
      and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 6-9 cycles in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for up to 1
      year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (enzalutamide, paclitaxel, carboplatin)ExperimentalPatients receive enzalutamide PO QD alone on days 1-28. Patients then receive enzalutamide PO QD on days 1-21, paclitaxel IV over 3 hours on day 1, and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 6-9 cycles in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Enzalutamide
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a histologically confirmed diagnosis (by either primary surgical
             specimen or biopsy for recurrence) of advanced stage (stage III or IV) or recurrent
             endometrioid endometrial cancer

          -  Measurable disease (at least one measurable lesion) IS required; a measurable lesion
             is one 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)
             scan, 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 at least one "target lesion" to be used to assess response on this
             protocol as defined by Response Evaluation Criteria in Solid Tumors (RECIST); tumors
             within a previously irradiated field will be designated as "non-target" lesions unless
             progression is documented or a biopsy is obtained to confirm persistence at least 90
             days following completion of radiation therapy

          -  Patient with an Eastern Cooperative Oncology Group (ECOG) performance status =< 1

          -  Life expectancy of greater than 3 months in the opinion of the principal investigator

          -  Recovery from effects of recent surgery, radiotherapy, or chemotherapy

          -  Patients should be free of active infection requiring antibiotics (with the exception
             of uncomplicated urinary tract infection [UTI])

          -  Any hormonal therapy directed at the malignant tumor must be discontinued at least one
             week prior to registration

          -  Any other prior therapy directed at the malignant tumor, including immunologic agents,
             must be discontinued at least three weeks prior to registration

          -  PRIOR THERAPY: Patients should have had NO prior chemotherapy agents for advanced or
             recurrent endometrial cancer; prior chemotherapy administration in conjunction with
             primary radiation therapy as a radiosensitizer would NOT exclude a patient from
             participation in this trial

          -  Absolute neutrophil count (ANC) >= 1,500/mcl, equivalent to Common Terminology
             Criteria (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4.03)
             grade 1

          -  Platelets >= 100,000/mcl

          -  Calculated creatinine clearance (Cockcroft-Gault formula) > 50 ml/min OR 24-hour urine
             creatinine clearance > 50 ml/min

          -  Bilirubin =< 1.5 x upper limit of normal (ULN) (CTCAE v4.03 grade 1; in patients with
             known Gilbert syndrome, a total bilirubin =< 3.0 x ULN, with direct bilirubin =< 1.5 x
             ULN)

          -  Aspartate aminotransferase (AST) and alkaline phosphatase =< 2.5 x ULN (CTCAE v4.03
             grade 1; AST and alanine aminotransferase [ALT] =< 3 x ULN [or =< 5.0 x ULN if hepatic
             metastases are present])

          -  Neuropathy (sensory and motor) =< CTCAE v4.03 grade 1

          -  Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 (or an
             in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic
             warfarin) and a partial thromboplastin time (PTT) =< 1.5 times the institutional upper
             limit of normal; patients receiving low molecular weight heparin for the prevention or
             treatment of venous thromboembolic disease are eligible if considered clinically
             stable on their regimen

          -  Patients must have signed an approved informed consent

          -  Because no dosing or adverse event data are currently available on the use of
             enzalutamide in combination with carboplatin and paclitaxel in patients <18 years of
             age, children are excluded from this study.

          -  The effects of enzalutamide on the developing human fetus are unknown; for this reason
             and because therapeutic agents used in this trial may be teratogenic, women of
             child-bearing potential and their partners must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation. Women of child-bearing potential (intact uterus)
             should have a negative serum pregnancy test. Should a woman become pregnant or suspect
             she is pregnant while participating in this study, she should inform her treating
             physician immediately

          -  Patients must be able to swallow whole tablets

          -  With the exception of alopecia, any unresolved toxicities from prior chemotherapy
             should be no greater than CTCAE v4 grade 1 at the time of starting study treatment

          -  Patients on the Phase II portion only must be willing to undergo pre- and
             post-treatment biopsies and have at least one lesion amenable to biopsy

        Exclusion Criteria:

          -  Patients who have isolated recurrences (vaginal, pelvic, or paraaortic) that are
             amenable to potentially curative treatment with radiation therapy or surgery

          -  Patients with the following histologies of endometrial cancer are not eligible for
             enrollment: papillary serous adenocarcinoma, clear cell carcinoma, adenosquamous
             carcinoma, mucinous adenocarcinoma, carcinosarcoma, sarcoma

          -  Prior Therapy:

               -  Prior Chemotherapy: Patients who have had a prior chemotherapy regimen for
                  advanced or metastatic disease are excluded

               -  Prior Radiation Therapy: 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, alone or with chemotherapy as a radiation
                  sensitizer; all radiation therapy must be completed at least 4 weeks prior to the
                  first date of study therapy, the prior radiation field, radiation dose, number of
                  fractions and prior radiation start and stop dates must be provided at
                  registration

          -  Patients who have previously received enzalutamide; 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 who have had radiotherapy within 4 weeks prior to entering the study or those
             who have not recovered from adverse events (CTCAE v4.03 grade 2 or greater, excluding
             alopecia) due to agents administered more than 4 weeks earlier

          -  Patients may not receive any other anti-neoplastic or investigational agents within 3
             weeks of study enrollment; patients may not be receiving any other investigational
             agents during treatment on protocol

          -  Patients may not receive strong cytochrome P450, family 2, subfamily C, polypeptide 8
             (CYP2C8) inhibitors, CYP2C8 inducers, or cytochrome P450, family 3, subfamily A,
             polypeptide 4 (CYP3A4) inducers; in addition, patients should not receive drugs that
             are metabolized by CYP3A4 or cytochrome P450, family 2, subfamily C, polypeptide 9
             (CYP2C9)

          -  Patients who are pregnant or nursing; women of childbearing potential and men must
             agree to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry and for the duration of study participation; should a
             woman become pregnant or suspect she is pregnant while participating in this study,
             she should inform her treating physician immediately

          -  Patient had major surgery within 28 days prior to starting study drug or has not
             recovered from major side effects of the surgery

          -  Patients may not have a history of other malignancies except for basal cell or
             squamous cell skin cancer, in situ cervical cancer, unless they have been disease-free
             for at least five years

          -  Patients with predisposing factors for seizure including history of seizure,
             underlying brain injury with loss of consciousness, transient ischemic attack within
             the past 12 months, cerebral vascular accident, brain metastasis, and brain
             arteriovenous malformation

          -  Patient with history of allergic reactions or hypersensitivity attributed to compounds
             of similar chemical or biologic composition to enzalutamide, carboplatin, or
             paclitaxel

          -  Patients may not have symptomatic, uncontrolled spinal cord compression and/or brain
             metastases; a scan to confirm absence of brain metastasis is not required; patients
             can receive a stable dose of corticosteroids before/ during study if these were
             started at least 28 days prior to entry

          -  As judged by the investigator, any evidence of severe or uncontrolled systemic
             diseases (e.g., severe hepatic impairment, interstitial lung disease [bilateral,
             diffuse, parenchymal lung disease], uncontrolled chronic renal diseases
             [glomerulonephritis, nephritic syndrome, Fanconi syndrome or renal tubular acidosis]),
             or current unstable or uncompensated respiratory or cardiac conditions, or
             uncontrolled hypertension (blood pressure >= 160/90), active bleeding diatheses or
             active infection including hepatitis B, hepatitis C, and human immunodeficiency virus;
             screening for chronic conditions is not required

          -  As judged by the investigator, the patient is unsuitable to participate in the study
             and the patient is unlikely to comply with study procedures, restrictions, and
             requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in androgen receptor (AR) receptor expression
Time Frame:Baseline to 26-28 days after treatment initiation
Safety Issue:
Description:Summary statistics and boxplots will be used to describe the distributions of expression of AR and its downstream signaling effectors. We will similarly describe the change from baseline for AR and its downstream signaling effectors. If the usual normality assumptions hold we will use a paired t-test to test for significant changes in expression from baseline to follow-up assessment, otherwise we will test for changes with the Wilcoxon signed-rank test. For those variables measured on a nominal scale we will cross-tabulate values at baseline and follow-up assessments, and we will test for differences between baseline and follow-up assessments with a Fisher's exact test. A time dependent covariate analysis may be conducted to assess the impact of changes in biomarker expression on progression free survival (PFS) and overall survival (OS).

Secondary Outcome Measures

Measure:OS
Time Frame:Up to 1 year
Safety Issue:
Description:Estimated using the Kaplan Meier method. Will use Cox proportional hazards regression to model PFS and OS as functions of mutation status and protein expression, and we will estimate hazard ratios with 95% confidence intervals. A time dependent covariate analysis may be conducted to assess the impact of changes in biomarker expression on PFS and OS.
Measure:PFS
Time Frame:Up to 1 year
Safety Issue:
Description:We will use Cox proportional hazards regression to model PFS and OS as functions of mutation status and protein expression, and we will estimate hazard ratios with 95% confidence intervals. A time dependent covariate analysis may be conducted to assess the impact of changes in biomarker expression on PFS and OS.
Measure:Objective tumor response (complete response/partial response) rate
Time Frame:Up to 1 year
Safety Issue:
Description:We will use Cox proportional hazards regression to model PFS and OS as functions of mutation status and protein expression, and we will estimate hazard ratios with 95% confidence intervals. A time dependent covariate analysis may be conducted to assess the impact of changes in biomarker expression on PFS and OS.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

October 22, 2019