Phase II Trial of Ribociclib and Everolimus in Advanced Dedifferentiated Liposarcoma (DDL) and Leiomyosarcoma (LMS)

Exclusion Criteria

• •Patient has a known hypersensitivity to any of the excipients of Ribociclib or Everolimus.
• •Previous treatment with CDK4/6 inhibitors or mTOR inhibitors.
• •Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
• •Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
• •* At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
• •* Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme- inducing anti-epileptic medications for brain metastases.
• •Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• •Patient has a known history of HIV infection (testing not mandatory).
• •Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.).
• •Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
• •* History of angina pectoris, symptomatic pericarditis, coronary artery bypass graft (CABG) or myocardial infarction within 6 months prior to study entry.
• •* Documented cardiomyopathy
• •* Left Ventricular Ejection Fraction (LVEF) \<50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening
• •* History of cardiac failure, significant/symptomatic bradycardia, Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome or any of the following:
• •* Known risk to prolong the QT interval or induce Torsade's de Pointes.
• •* Uncorrected hypomagnesemia or hypokalemia.
• •* Systolic Blood Pressure (SBP) \>160 mmHg or \<90 mmHg.
• •* Bradycardia (heart rate \<50 at rest), by ECG or pulse.
• •* On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or not interpretable) or QTcF \>450 (based on a mean of 3 ECGs).
• •Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug (see Table 4 for details):
• •* Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
• •* That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
• •* Herbal preparations/medications, dietary supplements. Acceptable supplements include multivitamins, vitamin D and calcium
• •* Angiotensin-converting enzyme (ACE) inhibitor therapy
• •Receipt of a live vaccine within 30 days prior to starting study drug. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
• •Patient is currently receiving or has received systemic corticosteroids ≤2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment.
• •• The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
• •Patient is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.
• •Treatment with an investigational agent within 30 days prior or within 5 half-lives (whichever is longer) before the first dose of the study drug.
• •Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 weeks prior to starting study drug, and who has not recovered to Grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom ≥25% of the bone marrow (Ellis, 1961) was irradiated.
• •Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery).
• •Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-CTCAE version 4.03 Grade ≤1 (Exception to this criterion: patients with any Grade of alopecia are allowed to enter the study).
• •Patient with a Child-Pugh score B or C. See Appendix A.
• •Patient has a history of non-compliance to medical regimen or inability to grant consent.
• •Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
• •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study and for at least 3 months after completion of treatment. Highly effective contraception methods include:
• •* Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• •* Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• •* Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that patient
• •* Use of 1 highly effective method of contraception, and 1 additional (barrier) method, at the same time
• •Highly effective methods: Intra-uterine devices (IUD), Hormonal (birth control pills/oral contraceptives, injectable contraceptives, contraceptive patches, or contraceptive implants) Other effective methods (barrier methods): Latex condom, Diaphragm with spermicide; Cervical cap; Sponge
• •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 ago. 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.
• •Sexually active males unless they use a condom during intercourse while taking the drug and for 21 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.