Clinical trial NCT02228681: Everolimus and Letrozole or Hormonal Therapy to Treat Endometrial Cancer
Official title: A Randomized Phase II Trial of Everolimus and Letrozole or Hormonal Therapy (Tamoxifen/Medroxyprogesterone Acetate) in Women With Advanced, Recurrent, or Persistent Endometria Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Advanced, Persistent, or Recurrent Endometrial Cancer
Lead sponsor: GOG Foundation
Sponsor class: NETWORK
Collaborators: name: Novartis Pharmaceuticals
First posted: 2014-08-29
Enrollment: 74
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main purpose of this study is to evaluate the effectiveness of the combination of the drugs Everolimus and Letrozole compared to Tamoxifen and Medroxyprogesterone acetate in treating endometrial cancer and to determine the types and severity of side effects caused by treatment with these drug combinations.


Eligibility criteria: Inclusion Criteria:

* Patients must have histologically confirmed advanced (FIGO Stage III or IV), persistent, or recurrent endometrial carcinoma, which is not likely to be curable by surgery or radiotherapy. Histologic documentation of the recurrence is not required.
* All patients must have measurable disease. 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 greater than or equal to 10 mm when measured by CT, MRI or caliper measurement by clinical exam; or greater than or equal to 20 mm when measured by chest x-ray. Lymph nodes must be greater than or equal to 15 mm in short axis when measured by CT or MRI (See section 8).
* Patients must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1 (Section 8.1). 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.
* Prior chemoradiotherapy for a pelvic recurrence is permitted. Prior chemotherapy in the adjuvant setting for Stage I, II or III disease is permitted.

Note: No prior chemotherapy in the setting of Stage IV disease is permitted unless the patient was without evidence of disease at the completion of chemotherapy and had at least six months of progression-free survival since the completion of chemotherapy.

Regardless of circumstances, no more than one prior chemotherapy regimen (including chemo-radiotherapy) is permitted.

* Patient must be able to take p.o. medications.
* Performance status must be 0-1.
* Patients must have adequate organ and marrow function as defined below:

NOTE: Institutional/laboratory upper limit of normal = ULN Institutional/laboratory lower limit of normal = LLN

* Bone marrow function:

  * Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl
  * Platelets greater than or equal to 100,000 cells/mcl
  * Hemoglobin greater than or equal to 9 g/dL
* Coagulation

  • INR less than or equal to 1.5 x ULN (or in range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin).
* Renal function:

  • Creatinine less than or equal to 1.5 x ULN
* Hepatic function:

  * Bilirubin less than or equal to 1.5 x ULN
  * ALT and AST less than or equal to 3 x ULN
  * Alkaline phosphatase less than or equal to 2.5 x ULN
  * Albumin greater than or equal to 2.8 g/dL
* Lipid panel:

  * Fasting serum cholesterol less than or equal to 300 mg/dL
  * Fasting triglycerides less than or equal to 300 mg/
* At least 4 weeks must have elapsed since the patient underwent any major surgery (e.g., major: hysterectomy, resection of a lung nodule; minor: central venous access catheter placement).
* At least 4 weeks must have elapsed since the patient received any radiation therapy.
* Patients who have met the pre-entry requirements specified in Section 7.0
* Patients must have signed an approved informed consent and authorization permitting release of personal health information.
* All patients must be at least 18 years of age
* Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and be practicing a highly effective form of contraception.

During the study treatment and for 8 weeks after stopping the treatment. Highly effective contraception methods include combination of any two of the following:

* Use of oral, injected or implanted hormonal methods of contraception or;
* Placement of an intrauterine device (IUD) or intrauterine system (IUS);
* Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository;
* Total abstinence or;
* Male/female sterilization. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.

Exclusion Criteria:

* Patients who have previously received everolimus, any another mTOR inhibitor or any agent targeting the PI3K/AKT/mTOR pathway.
* Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
* Patients who have previously received hormonal therapy for endometrial cancer.
* 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 receiving chronic treatment with systemic steroids or another immunosuppressive agent.
* Patients with active or uncontrolled systemic infection.
* Uncontrolled diabetes mellitus as defined by HbA1c \>8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and anti-diabetic treatment must be monitored closely throughout the trial and adjusted as necessary.
* Known severely impaired lung function, including:

  • CTCAE grade 2 (or greater) hypoxia (decreased oxygen saturation with exercise \[e.g., pulse oximeter \<88%\]; intermittent supplemental oxygen)
* Patients with a known history of cardiac disease. This includes:
* Uncontrolled hypertension, defined as systolic greater than 150 mm Hg or diastolic greater than 90 mm Hg despite antihypertensive medications.
* Myocardial infarction or unstable angina within 6 months prior to registration.
* New York Heart Association (NYHA) Class II or greater congestive heart failure.
* History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or serious cardiac arrhythmia requiring medication. This does not include asymptomatic atrial fibrillation with controlled ventricular rate.
* Cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) within 6 months prior to the first date of study therapy.
* Patients who are pregnant or breast-feeding.
* Patients with known central nervous system metastases.
* Patients with known human immunodeficiency virus (HIV) infection.
* Patients with an impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease; uncontrolled nausea, vomiting and/or diarrhea; malabsorption syndrome; clinical signs and symptoms of gastrointestinal obstruction; and/or patients who require parenteral hydration and/or nutrition).
* Patients who plan to receive live attenuated vaccines within 1 week of start of everolimus and during the study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.
* Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder or coagulopathy.
* Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 30 days prior to dosing.
* Patients must be able to follow concomitant medication restrictions:

  * Avoid the use of strong CYP3A/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole).
  * Use caution when co-administered with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem).
  * Grapefruit, grapefruit juice, and other foods known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment.
  * Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, and phenobarbital).
  * St. John's Wort may decrease everolimus exposure unpredictably and should be avoided.
* Patients with active hepatitis B or C. Screening for hepatitis B

Prior to randomization/start of everolimus, the following three categories of patients should be tested for hepatitis B viral load and serologic markers, that is, HBsAg, HBcAb, HBsAb and quantitative hepatitis B DNA PCR (HBV-DNA):

• All patients who currently live in (or have lived in) Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal and Greece.

\[http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-b.htm\]

* Patients with any of the following risk factors:
* known or suspected past hepatitis B infection,
* blood transfusion(s) prior to 1990,
* current or prior IV drug users,
* current or prior dialysis,
* household contact with hepatitis B infected patient(s),
* current or prior high-risk sexual activity,
* body piercing or tattoos,
* mother known to have hepatitis B
* history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper quadrant pain.
* Additional patients at the discretion of the investigator The management guidelines, in Section 6, are provided according to the results of the baseline assessment of viral load and serological markers for hepatitis B.

Screening for hepatitis C

Patients with any of the following risk factors for hepatitis C should be tested using quantitative RNA-PCR:

* known or suspected past hepatitis C infection (including patients with past interferon 'curative' treatment),
* blood transfusions prior to 1990,
* current or prior IV drug users,
* current or prior dialysis,
* household contact of hepatitis C infected patient(s),
* current or prior high-risk sexual activity,
* body piercing or tattoos. At the discretion of the investigator, additional patients may also be tested for hepatitis C.

The management guidelines, in Section 6 are provided according to the results of the baseline assessment of hepatitis C viral load.

Primary outcomes:
measure: Frequency of Response
timeFrame: From date of randomization until the date of first documented progression or date of death , up to 3 years.
Secondary outcomes:
measure: Median Progression-free Survival
timeFrame: Tumor measurements were done at 8 and 16 weeks after initiating treatment and then every 12 weeks and compared with baseline measurements prior to treatment. Measurements are continued until disease progression is documented or death.
measure: Frequency and Severity of CTCAE (Common Toxicity Criteria for Adverse Events) Version 4
timeFrame: Assessed throughout the treatment period and for 30 days after discontinuation of treatment. Treatment continues until progression of disease.
measure: Median Survival
timeFrame: Following treatment discontinuation, patients are followed quarterly for 2 years, semi-annually for 3 more years, annually thereafter.
Other outcomes:
measure: Hormone Receptor Immunohistochemistry
timeFrame: At study entry
measure: mTOR Pathway Immunohistochemistry
timeFrame: At study entry
measure: Mutation Analysis
timeFrame: At study entry
Locations:
city: Aurora
country: United States
facility: University of Colorado - Anschutz Cancer Pavilion
state: Colorado
city: Miami
country: United States
facility: University of Miami - Sylvester Comprehensive Cancer Center
state: Florida
city: Columbus
country: United States
facility: John B. Amos Cancer Center
state: Georgia
city: Savannah
country: United States
facility: Memorial Health University Medical Center
state: Georgia
city: Scarborough
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Worcester
country: United States
facility: University of Massachusetts Memorial Center
state: Massachusetts
city: Bemidji
country: United States
facility: Sanford Clinic North - Bemidji
state: Minnesota
city: Jackson
country: United States
facility: St. Dominic-Jackson Memorial Hospital
state: Mississippi
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Las Vegas
country: United States
facility: Women's Cancer Center of Nevada
state: Nevada
city: Albuquerque
country: United States
facility: New Mexico Cancer Alliance
state: New Mexico
city: Albuquerque
country: United States
facility: Memorial Medical Center-Cancer Center
state: New Mexico
city: Albany
country: United States
facility: Women's Cancer Care Associates
state: New York
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center
state: New York
city: Fargo
country: United States
facility: Sanford Roger Maris Cancer Center
state: North Dakota
city: Cleveland
country: United States
facility: University Hospital Case Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Abington
country: United States
facility: Abington Memorial Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: The University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Magee Women's Hospital of UPMC
state: Pennsylvania
city: Providence
country: United States
facility: Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Sioux Falls
country: United States
facility: Sanford Medical Center - Sioux Falls
state: South Dakota
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
Study officials:
affiliation: Gynecologic Oncology Group
name: Brian Slomovitz, MD
role: STUDY_CHAIR
References: