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

  • STATUS
    Recruiting
  • End date
    Dec 25, 2022
  • participants needed
    48
  • sponsor
    Fox Chase Cancer Center
Updated on 25 January 2021
cancer
calcium
systemic therapy
measurable disease
small molecule
metastasis
neutrophil count
immunomodulators
liposarcoma
leiomyosarcoma

Summary

This is a two center, 2 arm, Phase II study evaluating the combination of Ribociclib and Everolimus in patients with advanced DDL and LMS who have had at least 1 prior systemic therapy. Patients will be enrolled by sarcoma histology into DDL (Arm A) and LMS (Arm B). The purpose of this study is to determine the anti-tumor activity of this doublet therapy in these patient cohorts. Ribociclib will be administered orally at 300 mg/day 3 weeks on/1 week off. Everolimus will be administered 2.5 mg orally on a continuous 28 day cycle. Clinical and laboratory assessments will be made on day 1, d15 of cycle 1 and 2, and day 1 of each subsequent cycle. Tumor response will be assessed by RECIST 1.1 at (CT or MRI) at week 8, 16, 24 and every 12 weeks thereafter. Study drug administration will continue until disease progression, unacceptable toxicity or withdrawal of consent. Patients will be followed until death or are lost to follow-up for analysis of secondary endpoints.

There will be a 1 step registration process for dedifferentiated liposarcoma patients while patients with leiomyosarcoma will require a 2 step registration process. For step 1 of registration, patients must meet all the eligibility criteria necessary for step 1. For step 2 registration, patients must meet the inclusion criteria necessary for step 2 to be enrolled into the study.

Details
Condition Connective and Soft Tissue Neoplasm, Sarcoma, All Solid Tumors, Solid Tumors, Sarcoma (Pediatric), Soft Tissue Sarcoma, sarcomas, soft tissue sarcomas
Treatment Everolimus, Ribociclib
Clinical Study IdentifierNCT03114527
SponsorFox Chase Cancer Center
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Sarcoma or Connective and Soft Tissue Neoplasm or Sarcoma (Pediatric) or Soft Tissue Sarcoma or All Solid Tumors or Solid Tumors?
Do you have any of these conditions: Sarcoma or Connective and Soft Tissue Neoplasm or sarcomas or All Solid Tumors or Soft Tissue Sarcoma or Solid Tumors or soft tissue sarcomas or Sarco...?
Patients with leiomyosarcoma must have tumors with intact Rb as documented by protein expression by IHC for study entry. Patients without sufficient archival tissue for testing will not be eligible. Please see Section 9.0 for further details on testing and interpretation of results. In the event that a patient has prior sequencing information (i.e. through commercial testing) suggestive of intact Rb, the patient may be included into the study on a case by case basis as determined by the principle investigators. The patient will still be required to submit tissue for Rb determination by IHC, but will not need to wait for these results for study entry

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
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