Evaluating Cancer Response to Treatment With Abemaciclib and Fulvestrant in Women With Recurrent Endometrial Cancer

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT03643510

Collaborator

Eli Lilly and Company (Industry)

Enrollment

Locations

Arm

59.3

Anticipated Duration (Months)

3.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effectiveness of the combination of abemaciclib and fulvestrant in treating this type of cancer and to determine the types and severity of side effects caused by treatment with abemaciclib and fulvestrant.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of Endometrium	Drug: Fulvestrant Drug: Abemaciclib	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

25 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

This is a prospective, single arm study of combination CDK4 and CDK6 dual inhibitor Abemaciclib and selective estrogen receptor degrader Fulvestrant in hormone receptor positive recurrent endometrial carcinomas.This is a prospective, single arm study of combination CDK4 and CDK6 dual inhibitor Abemaciclib and selective estrogen receptor degrader Fulvestrant in hormone receptor positive recurrent endometrial carcinomas.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase II Study of Fulvestrant in Combination With Abemaciclib in Hormone Receptor Positive Adenocarcinoma of Endometrium

Actual Study Start Date :

Aug 21, 2018

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Aug 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fulvestrant in Combination with Abemaciclib Eligible patients will take Abemaciclib 150 milligrams mg orally once every 12 hours on days 1-28. Fulvestrant will be dosed 500mg intramuscularly (IM) on days 1 and 15 during cycle 1 and then on Day 1 during subsequent cycles. Each cycle will be 28 days in duration. Patients will receive study treatment until disease progression, intolerable toxicity, elective withdrawal from the study, or study termination.	Drug: Fulvestrant Fulvestrant will be dosed 500mg intramuscularly (IM) on days 1 and 15 during cycle 1 and then on Day 1 during subsequent cycles. Drug: Abemaciclib Abemaciclib 150 milligrams mg orally once every 12 hours on days 1-28.

Arm

Intervention/Treatment

Experimental: Fulvestrant in Combination with Abemaciclib

Eligible patients will take Abemaciclib 150 milligrams mg orally once every 12 hours on days 1-28. Fulvestrant will be dosed 500mg intramuscularly (IM) on days 1 and 15 during cycle 1 and then on Day 1 during subsequent cycles. Each cycle will be 28 days in duration. Patients will receive study treatment until disease progression, intolerable toxicity, elective withdrawal from the study, or study termination.

Drug: Fulvestrant

Fulvestrant will be dosed 500mg intramuscularly (IM) on days 1 and 15 during cycle 1 and then on Day 1 during subsequent cycles.

Drug: Abemaciclib

Abemaciclib 150 milligrams mg orally once every 12 hours on days 1-28.

Outcome Measures

Primary Outcome Measures

objective response rate [1 year]
defined as the percentage of patients with complete response (CR) + partial response (PR)]after initiating therapy. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have signed an approved informed consent and authorization permitting release of personal information.
Age ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 AND Karnofsky Performance Status (KPS) ≥ 80
Patients are not required to but may have received 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 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.
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
Disease that is measurable as per RECIST v1.1.
Tumors within a previously irradiated field wi ll 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.

For mixed epithelial cell type endometrial carcinomas, the endometrioid component should comprise at least 95% of the total tumor and the non-endometrioid component should comprise less than 5% of the total tumor.

Patient must have hormone receptor positive (HR+) endometrial cancer confirmed by

MSK pathology:

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 (Hammond et al, 2010)
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.
Adequate hematologic and end organ function, defined by the following laboratory results obtained within 7 days prior to first study treatment:
Absolute neutrophil count (ANC) ≥1500/109dL
Platelet count ≥ 100,000/109dL
Hemoglobin ≥ 9.0 g/dL
Albumin ≥ 3.0 g/dL
Total bilirubin ≤ 1.5 x the upper limit of normal (ULN)
AST and ALT ≤ 3.0x ULN
Adequate renal function defined by the following laboratory results obtained within 7 days prior to first study treatment:

Serum creatinine≤1.5x ULN OR creatinine clearance ≥50 mL/min on the basis of the

Cockcroft-Gault glomerular filtration rate :

estimation (140-age)x(weight in kg)x(0.85 if female) 72 x (serum creatinine in mg/dL)

International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 xULN. 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.

Exclusion Criteria:

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 devise, 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 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 HBV DNA.
Patients positive for HCV antibody are eligible only if testing for HCV RNA is negative.
Known 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 Cycle 1 Day 1
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 CNSdirected 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 i nvestigator"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 (see Appendix A)
History of malabsorption syndrome or other condition that would interfere with enteral absorption
Inability or unwillingness to swallow pills

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey	United States	07920
2	Memoral Sloan Kettering Monmouth	Middletown	New Jersey	United States	07748
3	Memorial Sloan Kettering Bergen	Montvale	New Jersey	United States	07645
4	Memorial Sloan Kettering Commack	Commack	New York	United States	11725
5	Memorial Sloan Kettering Westchester	Harrison	New York	United States	10604
6	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
7	Memorial Sloan Kettering Nassau	Uniondale	New York	United States	11553