Fulvestrant and Abemaciclib in Treating Patients with Hormone Receptor Positive Recurrent or Refractory Endometrial Adenocarcinoma
This phase II trial studies how well fulvestrant and abemaciclib work in treating patients with hormone receptor positive endometrial adenocarcinoma that has come back or does not respond to treatment. Fulvestrant and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
- Patients must have signed an approved informed consent and authorization permitting release of personal information
- Patient must consent to the collection of archival tumor tissue for biomarker testing. Availability of archival tissue for biomarker testing must be confirmed by the site prior to screening of patient. Suitability of archival tissue that was not formalin-fixed paraffin-embedded (FFPE) must be discussed with the Principal Investigator. Archival tissue consists of either a minimum of 10 FFPE slides or FFPE tissue block. Patients with no available archival tissue (or if the sample is difficult to obtain) may undergo a tumor biopsy to meet eligibility criteria, as long as the patient consents to this procedure and the biopsy can be obtained with minimal risk and discomfort to the patient
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Patients must have had at least one but no more than two prior chemotherapeutic regimens for management of endometrial carcinoma (including adjuvant chemotherapy). Initial treatment may include chemotherapy, chemotherapy and radiation therapy, and/or consolidation/maintenance therapy * Chemotherapy administered in conjunction with primary radiation as a radiosensitizer WILL be counted as a systemic chemotherapy regimen
- Patients are not required to, but may have received a single line of prior hormonal therapy with either an antiestrogen, anti progesterone (or combination) or an aromatase inhibitor. Patients may not have received more than 1 line of endocrine therapy. This will not count toward prior therapy total
- Resolution of adverse effects of recent surgery, radiotherapy, chemotherapy, or hormonal therapy to grade =< 1 prior to first study treatment with the exception of peripheral neuropathy and alopecia
- Postmenopausal status due to either surgical or natural menopause. Post-menopausal status due to surgical/natural menopause requires at least 1 of the following: * History of hysterectomy * Prior bilateral oophorectomy * Age >= 60 * Age =< 60 and amenorrheic for at least 12 months (in the absence of chemotherapy, hormonal therapy or ovarian suppression) and follicle stimulating hormone (FSH) and estradiol levels in the postmenopausal range * Have a negative serum pregnancy test at baseline (within 7 days prior to -initiation of treatment) and agree to use medically approved precautions to prevent pregnancy during the study and for 12 weeks following the last dose of abemaciclib
- Disease that is measurable as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 * Tumors within a previously irradiated field will be designated as “nontarget” lesions unless progression is documented or a biopsy is obtained to confirm persistence of tumor >= 90 days following completion of radiation therapy
- No active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection). Any hormonal therapy directed at the malignant tumor must be discontinued at least 2 weeks prior to the first study treatment
- Patients must meet all the following criteria to be eligible for study entry: * Patients must have recurrent or persistent endometrial carcinoma that is refractory to curative therapy or established treatments * Histologic confirmation of the original primary tumor is required * Histologic or cytologic confirmation of the recurrent/progressive disease is desired, but not required * Patients with the following histologic epithelial cell types are eligible: endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, de-differentiated, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.), mucinous adenocarcinoma, squamous cell carcinoma, and transitional cell carcinoma * Patient must have hormone receptor positive (HR+) endometrial cancer: ** To fulfill the requirement for HR+ disease, tumor must express by immunohistochemistry (IHC), at least 1 of the hormone receptors (estrogen receptor [ER] or progesterone receptor [PgR] as defined in the relevant American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
- Any prior therapy directed at the malignant tumor, including immunologic agents and radiotherapy, must be discontinued at least 21 days prior to first study treatment
- Absolute neutrophil count (ANC) >= 1500/10^9 dL (within 7 days prior to first study treatment)
- Platelet count >= 100,000/10^9 dL (within 7 days prior to first study treatment)
- Hemoglobin >= 9.0 g/dL (within 7 days prior to first study treatment)
- Albumin >= 3.0 g/dL (within 7 days prior to first study treatment)
- Total bilirubin =< 1.5 x the upper limit of normal (ULN) (within 7 days prior to first study treatment)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN (within 7 days prior to first study treatment)
- Serum creatinine =<1.5 x ULN OR creatinine clearance >= 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate (within 14 days prior to first study treatment)
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN. For patients requiring therapeutic anticoagulation, a stable INR =< 3 x ULN is required
- Are able to swallow capsules
- Are willing to follow study procedures
- For patients of childbearing potential, agreement to use two effective forms of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants) and to continue its use for the duration of the study and for 30 days after the last abemaciclib dose
- Patients must agree to pre- and post treatment tumor biopsies
- Patients who are currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study. If a patient is currently enrolled in a clinical trial involving non-approved use of a device, then agreement with the principal investigator and Lilly is required to establish eligibility
- Patient who is experiencing a visceral crisis, lymphangitic disease spread, leptomeningeal carcinomatosis. Visceral crisis is not the mere presence of visceral metastases but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of disease
- Patients who have received prior treatment with fulvestrant, everolimus, temsirolimus, ridaforolimus or another mTor inhibitor, or any CDK4 and CDK6 inhibitor
- Patients who have received an autologous or allogenic stem-cell transplant
- Clinically significant history of liver disease, including cirrhosis and current alcohol abuse
- Presence of positive test results for hepatitis B (hepatitis B surface antigen [HBsAGg] and/or total hepatitis B [HB] core antibody [anti-HBc]) or hepatitis C (hepatitis C virus [HCV] antibody serology testing)
- Patients positive for anti-HBc are eligible only if also positive for HB surface antibody (anti-HBs) and polymerase chain reaction (PCR) assay is negative for hepatitis B virus (HBV) DNA * Patients positive for HCV antibody are eligible only if testing for HCV RNA is negative
- Known human immunodeficiency virus (HIV) infection
- Active autoimmune disease that is not controlled by nonsteroidal anti-inflammatory drugs
- Pregnancy, lactation, breastfeeding
- Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease)
- Major surgical procedure or significant traumatic injury within 28 days prior to day 1 or anticipation of the need for major surgery during the course of study treatment
- Have initiated biphosphonate or RANK ligand targeted agents (for example, denosumab) < 7 days prior to randomization
- Uncontrolled hypomagnesemia or hypokalemia, defined as values below the lower limit of normal despite optimal electrolyte supplementation or management
- Leptomeningeal disease as a manifestation of cancer
- Known untreated or active central nervous system (CNS) metastases (progression or requiring anticonvulsants or corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided that they meet all of the following criteria: * Presence of measurable disease outside the CNS * No radiographic evidence of worsening upon the completion of CNS directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study * No history of intracranial hemorrhage or spinal cord hemorrhage * No ongoing requirement for dexamethasone as therapy for CNS disease (anticonvulsants at a stable dose are allowed) * Screening CNS radiographic study is =< 6 months after most recent intervention for CNS metastases (neurological resection, radiotherapy, or brain biopsy) and >= 4 months after the discontinuation of corticosteroids
- Inability to comply with study and follow-up procedures
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
- Patients who have: * History of myocardial infarction, unstable angina, ventricular tachycardia, ventricular fibrillation or sudden cardiac arrest within 6 months prior to first study treatment * New York Heart Association class II or greater congestive heart failure * History of malabsorption syndrome or other condition that would interfere with enteral absorption * Inability or unwillingness to swallow pills
Locations & Contacts
Contact: Vicky Makker
Contact: Vicky Makker
Contact: Vicky Makker
Contact: Vicky Makker
Contact: Vicky Makker
Contact: Vicky Makker
Trial Objectives and Outline
I. To assess the activity of fulvestrant in combination with abemaciclib in patients with hormone receptor positive recurrent or persistent endometrial cancer, as measured by the objective response rate (defined as the percentage of patients with complete response [CR] + partial response [PR]) after initiating therapy.
I. To determine the clinical benefit rate (CBR) of fulvestrant in combination with abemaciclib therapy, defined as the percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD) >=16 weeks from the date of enrollment.
II. To determine progression free survival (PFS), defined as the interval from the date of enrollment until the first date on which recurrence, progression, or death due to any cause.
III. To determine overall survival (OS), defined as the interval from the date of enrollment until the date of death due to any cause.
IV. To determine the duration of response (DOR) of fulvestrant in combination with abemaciclib therapy, defined as the time from which measurement criteria are met for CR or PR (whichever status is recorded first) until the first date of documented disease progression.
V. To assess the safety profile and tolerability of fulvestrant in combination with abemaciclib therapy in patients with estrogen receptor (ER) positive recurrent/persistent endometrial cancer.
I. To assess mutational status and/or copy number variations of cancer-related genes including, but not limited to, CDK4/6, CCND1, HER2, CDKN2A, ER, progesterone receptor (PR), RB, CCNE, PIK3CA, PTEN, or RAS in responders compared to non-responders.
II. To correlate mutational status detected in tumor samples and circulating tumor deoxyribonucleic acid (DNA), as well as genetic variants in drug metabolism and transport, if deemed necessary by the sponsor.
III. To explore expression biomarkers in blood (and tumor samples, if available) related to CDK4/6 and PI3K/mTOR signaling, including, but not necessarily limited to protein, ribonucleic acid (RNA), and micro RNA, and correlated with response, if deemed necessary by the principal investigator (PI).
IV. To explore whether on serial pre-, on-and post treatment blood samples for cell-free tumor DNA results correlate with clinical outcome.
V. To determine potential mechanism(s) of acquired resistance for patients who respond to therapy and then progress utilizing Memorial Sloan Kettering Cancer Center (MSKCC) Institutional Review Board (IRB) # 12-245 Part B.
VI. To perform pre- and post treatment tumor biopsies to establish xenografts (utilizing IRB Protocol # 13-040) from patients whose tumors have been exposed to drug and demonstrated resistance.
Patients receive abemaciclib orally (PO) twice daily (BID) on days 1-28. Patients also receive fulvestrant intramuscularly (IM) over 2 injections on days 1 and 15 of cycle 1, and then on day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.
Trial Phase & Type
Memorial Sloan Kettering Cancer Center
Secondary IDs NCI-2018-01869
Clinicaltrials.gov ID NCT03643510