Samotolisib in Treating Patients with Recurrent or Persistent Endometrial Cancer
- Patients must have recurrent or persistent endometrial carcinoma; 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.), mucinous adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and carcinosarcoma
- Patients must have had at least one but no more than four prior chemotherapeutic regimens for management of endometrial carcinoma (including neo-adjuvant and/or 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 radio-sensitizer WILL be counted as a systemic chemotherapy regimen
- Patients tumors must have known PI3K pathway activation defined as EITHER of the following on a Clinical Laboratory Improvement Amendments (CLIA)-approved molecular diagnostics test: * Genomic alteration resulting in loss of phosphatase and tensin homolog (PTEN) function including a whole or partial gene deletion, frame shift mutations, or non-sense mutations; missense mutations in PTEN will not be considered qualifying * A previously characterized activating mutation in any component of the pathway including: phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), v-akt murine thymoma viral oncogene homolog 1 (AKT1), phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PIK3R1), phosphoinositide-3-kinase, regulatory subunit 2 (beta) (PIK3R2), mTOR
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Resolution of adverse effects of recent surgery, radiotherapy, or chemotherapy to grade =< 1 prior to first study treatment (with the exception of alopecia or neuropathy)
- 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 >= 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
- No active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection)
- Any other prior therapy directed at the malignant tumor, including immunologic agents and radiotherapy, must be discontinued at least 2 weeks prior to first study treatment
- Absolute neutrophil count (ANC) >= 1500/10^9 dL (within 14 days prior to first study treatment)
- Platelet count >= 100,000/10^9 dL (within 14 days prior to first study treatment)
- Hemoglobin >= 9.0 g/dL (within 14 days prior to first study treatment)
- Total bilirubin =< 1.5 x the upper limit of normal (ULN) (within 14 days prior to first study treatment)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN) (within 14 days prior to first study treatment) (unless the patient has Gilbert’s syndrome, in which case AST and ALT =< 5.0 x ULN is permitted)
- Albumin >= 3.5 g/dL (within 14 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 estimation (within 14 days prior to first study treatment)
- For all patients (regardless of known diabetes) the following is required at screening: fasting blood glucose =< 135 mg/dL (7.49 mmol/L) and glycosylated hemoglobin (HbA1c) =< 7.0%
- 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 LY3023414 dose
- Patients must have been enrolled, or agree to consent to the companion genomic profiling study MSKCC IRB# 12-245
- Willingness to sign written informed consent to this study
- Patients with known concurrent activating retrovirus-associated DNA sequence (RAS)/v-RAF-1 murine leukemia viral oncogene homolog (RAF) mutation or loss of function mutation or deletion in neurofibromin (NF)1 of NF2 resulting in mitogen-activated protein (MAP) kinase pathway activation; patients are not required to be evaluated for these alterations if not already performed
- Patients with diabetes requiring insulin or requiring more than one non-insulin hypoglycemia agents
- Patients previously treated with an mTOR, AKT, or PI3K inhibitor (including but not limited to GDC-0941, GDC-0980, BEZ235, BKM120, LY294002, PIK-75, TGX-221, XL147, XL765, SF1126, PX-866, D-87503, D-106669, GSK615, CAL101, everolimus, temsirolimus, and ridaforolimus); for agents not listed, the study principal investigator (PI) or Co-PI will make a determination
- History of myocardial infarction or unstable angina within 6 months prior to first study treatment
- New York Heart Association class II or greater congestive heart failure
- Patients with a corrected QT interval using Fridericia's formula (QTcF) interval of > 450 msec on screening electrocardiogram (ECG); Note: if > 450 msec on the first ECG, 2 additional ECGs can be ordered same day and then the average may be used to determine eligibility
- History of malabsorption syndrome or other condition that would interfere with enteral absorption
- Inability or unwillingness to swallow pills
- Clinically significant history of liver disease, including cirrhosis and current alcohol abuse
- Active hepatitis B or hepatitis C infection; patients with previously resolved hepatitis B infection are eligible; presence of positive test results for hepatitis B infection who have resolved the infection (defined by being positive for hepatitis B [HB] surface antibody [anti-HBs] and polymerase chain reaction [PCR] assay is negative for HB virus [HBV] DNA) are eligible; patients positive for hepatitis C virus (HCV) antibody are eligible only if testing for HCV ribonucleic acid (RNA) is negative
- Known human immunodeficiency virus (HIV) infection
- Need for current chronic corticosteroid therapy (>= 10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids)
- Pregnancy, lactation, or 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
- Known untreated or active central nervous system (CNS) metastases (progressing 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) * Absence of leptomeningeal disease
- 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
I. To assess the activity of samotolisib (LY3023414) in patients with PI3K pathway activated recurrent or persistent endometrial cancer as measured by the best overall response rate as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
I. To determine the clinical benefit rate (CBR) of LY3023414 therapy, defined as the percentage of patients with complete response (CR) + partial response (PR) + stable disease (SD) >= 12 weeks from the start of treatment.
II. To determine progression free survival (PFS), defined as the duration of time from start of treatment to time of recurrence, progression, or death due to any cause, whichever occurs first.
III. To determine overall survival (OS), defined as the duration of time from start of treatment until the date of death due to any cause.
IV. To determine the duration of response (DOR) of LY3023414 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 LY3023414 therapy in patients with PI3K activated recurrent/persistent endometrial cancer.
I. For patients who have not already had their tumors molecularly profiled using the Memorial Sloan Kettering (MSK)-Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) platform, pretreatment archival tumor tissue will be obtained for this purpose.
II. Serial pre-, on- and post-treatment blood samples will be collected for cell-free tumor deoxyribonucleic acid (DNA) analysis and the results descriptively correlated to clinical outcome.
III. Patients who respond to therapy and then progress will be offered consent to MSK Cancer Center (MSKCC) Institutional Review Board (IRB) # 12-245 Part B in order to obtain post-progression material for molecular profiling in order to determine the mechanism(s) underlying acquired resistance.
Patients receive samotolisib orally (PO) twice daily (BID) on days 1-21. Cycles repeat every 21 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.
Trial Phase Phase II
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
- Primary ID 15-079
- Secondary IDs NCI-2015-01639
- Clinicaltrials.gov ID NCT02549989