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About
This phase I trial studies the side effects and best dose of ribociclib and gemcitabine hydrochloride in treating patients with solid tumors that have spread to other places in the body. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib and gemcitabine hydrochloride may work better in treating patients with solid tumors.
Full description
PRIMARY OBJECTIVES:
I. To describe the dose-limiting toxicities and identify the maximum tolerated dose (MTD) and recommended phase II dose of the combination of ribociclib and gemcitabine hydrochloride (gemcitabine) in patients with advanced solid tumors.
SECONDARY OBJECTIVES:
I. To describe the safety and tolerability of the combination of ribociclib and gemcitabine.
II. To describe the pharmacokinetic (PK) of ribociclib in combination with gemcitabine.
III. To describe preliminary evidence of efficacy of the combination of ribociclib and gemcitabine.
TERTIARY OBJECTIVES:
I. To evaluate the correlation of CDK4/6, cyclin D1 and cyclin D3 amplification, retinoblastoma (RB) and P16 expression in archived and biopsied tumor tissue with treatment response.
OUTLINE: This is a dose-escalation study.
Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8 and ribociclib orally (PO) once daily (QD) on days 8-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Enrollment
Sex
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Volunteers
Inclusion criteria
Diagnosis of advanced/metastatic solid malignancy for which no standard treatment option exists that will confer clinical benefit
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Dose expansion phase only: must have at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Ability to provide written informed consent which must be obtained prior to any screening procedures and according to local guidelines
Life expectancy of >= 12 weeks
Absolute neutrophil count >= 1500/mm^3
Platelets >= 100,000/mm^3
Hemoglobin >= 9 g/dL
Potassium >= lower limit of normal (LLN) range for the institution
Calcium >= LLN (corrected for serum albumin, if albumin abnormal)
Magnesium >= LLN
Sodium >= LLN
Phosphorus >= LLN; NOTE: Supplementation may be given before the first dose of study medication
International normalized ratio (INR) =< 1.5
Serum creatinine =< 1.5 mg/dL or creatinine clearance >= 50 mL/min (calculated by Cockcroft Gault equation)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) or =< 5 x ULN if liver metastases are present
Total bilirubin =< 3.0 x ULN; if patient has known Gilbert?s syndrome direct bilirubin =< 1.5 x ULN
Standard 12-lead electrocardiography (ECG) with the following parameters at screening (defined as the mean of the triplicate ECGs):
Negative pregnancy test performed =< 7 days prior to registration (women of childbearing potential only)
Able to swallow ribociclib capsules
Willingness to return to enrolling institution for follow-up (during the active monitoring phase of the study)
Willingness to provide mandatory blood samples for research purposes
Exclusion criteria
Previous anti-cancer chemotherapy, immunotherapy or investigational agents =< 28 days prior to registration
Received radiotherapy =< 28 days or limited field radiation for palliation =< 14 days prior to registration, 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 was irradiated
Major surgery =< 14 days prior to registration or has not recovered from major side effects (tumor biopsy is not considered as major surgery)
Active clinically serious infections or other serious uncontrolled medical conditions
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)
Baseline neuropathy of > grade 2
Known hypersensitivity to any of the excipients of ribociclib
Known human immunodeficiency virus (HIV) patients with active and untreated disease
Central nervous system (CNS) involvement unless they meet ALL of the following criteria:
Clinically significant, uncontrolled heart disease and/ or cardiac repolarization abnormalities including any of the following:
History of unstable angina pectoris, symptomatic pericarditis, myocardial infarction, coronary artery bypass grafting or coronary angioplasty =< 12 months prior to registration
History of documented congestive heart failure (New York Heart Association functional classification III - IV)
Documented cardiomyopathy
Left ventricular ejection fraction (LVEF) < 50% as determined by echocardiogram (ECHO)
Clinically significant cardiac arrhythmias ( e.g ventricular tachycardia) , left bundle branch block, high-grade atrioventricular (AV) block ( e.g bifascucular block, Mobitz type II and third degree AV block)
Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
Systolic blood pressure > 160 mmHg or < 90 mmHg
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.)
Currently receiving any of the following medications and cannot be discontinued 7 days prior to starting the study
Currently receiving or has received systemic corticosteroids (=< 14 days prior to registration, or who have not fully recovered from side effects of such treatment); NOTE: 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)
History of non-compliance to medical regimen or inability to grant consent
Currently receiving warfarin or other warfarin-derived anticoagulant for treatment, prophylaxis or otherwise; Note: Therapy with heparin, direct oral anticoagulants, low molecular weight heparin (LMWH) or fondaparinux is allowed
Participation in a prior investigational study =< 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer
Failure to recover from all adverse events/toxicities related to prior anticancer therapies to grade 1 per National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; NOTE: Exception: patients with any grade of alopecia are allowed to enter the study
Child-Pugh score B or C (for cirrhosis patients only)
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 human chorionic gonadotropin (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 8 weeks after study drug discontinuation; highly effective contraception methods include:
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; Note: A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid
Known standard therapy for the patient?s disease that is potentially curative or definitely capable of extending life expectancy
Primary purpose
Allocation
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43 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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