| Eligibility |
Inclusion Criteria:
- Pathologically confirmed diagnosis of intermediate or high-grade soft tissue sarcoma
for which single-agent doxorubicin is appropriate therapy, including but not limited
to:
- Synovial sarcoma
- Fibrosarcoma
- Undifferentiated sarcoma
- Liposarcoma
- Leiomyosarcoma
- Angiosarcoma
- Malignant peripheral nerve sheath tumor
- Pleomorphic rhabdomyosarcoma
- Myxofibrosarcoma
- Epithelioid sarcoma
- Undifferentiated pleomorphic sarcoma
- Locally advanced unresectable or metastatic disease with no standard curative therapy
available
- Archival tumor tissue retinoblastoma-associated protein (pRb) positive by
immunohistochemistry (IHC)
- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria
- All races and ethnic groups will be included; for subjects between the ages of 12-18
years only, body surface area (BSA) must be >= 1.28 m^2
- Ejection fraction of >= 50% by echocardiogram or multi-gated acquisition (MUGA) scan
- Female subjects of childbearing potential must have a negative urine beta-human
chorionic gonadotropin (beta-hCG) pregnancy test at time of screening and within 14
days prior to planned first dose of ribociclib
- Willing to use adequate contraception throughout the study and for 3 weeks after study
drug discontinuation
- Meets the following standard 12-lead electrocardiography (ECG) parameters at screening
(defined as the mean of the triplicate ECGs; ECGs done in triplicate do not have a
defined interval between assessments):
- Corrected QT using Fridericia's correction formula (QTcF) interval at screening <
450 msec for males and < 470 msec for females (using Fridericia's correction)
- Resting heart rate =< 100 beats per minute (bpm)
- Absolute neutrophil count (ANC) >= 1.5 K/cu mm
- Platelets (no transfusion within prior 7 days) >= 100 K/cu mm
- Hemoglobin (no transfusion within prior 7 days) >= 9.0 g/dL
- Total bilirubin < institutional upper limit of normal (ULN), except for subjects with
documented Gilbert's syndrome, for which =< 3.0 x ULN or direct bilirubin =< 1.5 x ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT) in the
absence of liver metastases: =< 2.5 x ULN; if the subject has liver metastases: < 5 x
ULN
- Serum creatinine < 1.7 mg/dL
- Potassium within institutional normal limit (WNL)
- Corrected calcium WNL
- Magnesium WNL
- International normalized ratio (INR) =< 1.5
- Use of rivaroxaban, apixaban, edoxaban or warfarin is an exclusion criteria;
therapy with heparin, low molecular weight heparin (LMWH), dabigatran or
fondaparinux is allowed
- All prior treatment-related toxicities resolved to =< grade 1 or are determined to be
clinically stable by the investigator
- Has completed prior therapies according to the criteria below:
- Cytotoxic chemotherapy - at least 21 days since last dose prior to first dose of
ribociclib
- Small molecule inhibitors - at least 14 days since last dose prior to first dose
of ribociclib
- Monoclonal antibodies - at least 3 half-lives since last dose prior to first dose
of ribociclib; exception: denosumab for bony metastases is allowable
- Immunotherapy (e.g. tumor vaccines) - at least 42 days since last dose prior to
first dose of ribociclib
- Radiation - at least 14 days since last dose prior to first dose of ribociclib
- Able to swallow capsules
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Life expectancy > 3 months
- Ability to understand and the willingness to sign a written informed consent document;
subject has signed the informed consent (ICF) prior to any screening procedures being
performed and is able to comply with protocol requirements
Exclusion Criteria:
- Subjects with low grade tumors (histologic grade 1/3)
- Histologic diagnosis for which single-agent doxorubicin is NOT appropriate therapy,
including but not limited to:
- Alveolar or embryonal rhabdomyosarcoma
- Ewings sarcoma or primitive neuroectodermal tumor (PNET)
- Osteosarcoma
- Gastrointestinal stromal tumor (GIST)
- Prior systemic therapy with an anthracycline for any indication
- Known hypersensitivity to any of the excipients of ribociclib or doxorubicin
(including to peanut and soy)
- Currently receiving any of the following that cannot be discontinued at least 7 days
prior to starting study drug:
- Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
hybrids, pummelos, star-fruit, and Seville oranges
- Medications with a narrow therapeutic window that are predominantly metabolized
through CYP3A4/5
- Herbal supplements, such as St. John's wort; the use of marijuana or its
derivatives is allowed in States with statutes permitting the use of recreational
or medical marijuana
- Uncontrolled intercurrent medical condition including, but not limited to:
- Uncontrolled infection
- Symptomatic congestive heart failure (New York Heart Association [NYHA] class
III-IV)
- Acute coronary syndromes (including myocardial infarction, unstable angina,
coronary artery bypass grafting, coronary angioplasty, or stenting) or
symptomatic pericarditis within 6 months prior to screening
- Uncontrolled cardiac arrhythmia or arrhythmia requiring medication other than
beta blocker
- Psychiatric illness/social situations that would limit compliance with study
requirements
- Any other concurrent severe and/or uncontrolled medical condition that would, in
the investigator's judgment, cause unacceptable safety risks or compromise
compliance with the protocol (e.g. chronic pancreatitis, chronic active
hepatitis, etc.)
- Concurrent malignancy or malignancy within 3 years prior to starting study drug,
except:
- Malignancies that have completed therapy and are considered by their physician to
be at less than 30% risk of relapse, or
- Malignancies not requiring treatment (e.g., RAI stage 0 chronic lymphocytic
leukemia [CLL])
- 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
- 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 major small bowel resection)
- Known history of human immunodeficiency virus (HIV) infection (testing not mandatory);
NOTE: HIV-positive subjects on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with ribociclib; in
addition, these subjects are at increased risk of lethal infections when treated with
marrow suppressive therapy; appropriate studies will be undertaken in subjects
receiving combination antiretroviral therapy when indicated
- Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening; if initial
screening SBP is outside of the eligible range, blood pressure may be re-checked after
intervention; SBP must be documented as stable and within the eligible range prior to
starting study drug
- Currently receiving rivaroxaban, apixaban, endoxaban, warfarin or other warfarin
derived anticoagulant; therapy with heparin, low molecular weight heparin (LMWH),
dabigatran or fondaparinux is allowed; if transitioning from a prohibited
anticoagulant, a minimum washout of 7 days from last dose of the prohibited medication
is required prior to ribociclib start
- Participation in a prior investigational interventional study within 30 days prior to
enrollment or within 5 half-lives of the investigational product, whichever is longer
- Major surgery within 14 days prior to starting study drug or has not recovered from
surgical complications (tumor biopsy is not considered as major surgery)
- History of congenital long QT syndrome or torsades de pointes
- History of non-compliance to medical regimen or inability to grant consent
- Pregnant or nursing (lactating) women; breastfeeding should be discontinued
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