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Ribociclib and Doxorubicin in Treating Patients With Metastatic or Advanced Soft Tissue Sarcomas That Cannot Be Removed by Surgery

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03009201
Recruitment Status : Active, not recruiting
First Posted : January 4, 2017
Last Update Posted : December 12, 2019
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Lara Davis, OHSU Knight Cancer Institute

Brief Summary:
This phase Ib trial studies the side effects and best dose of the CDK4/6 inhibitor ribociclib when given together with doxorubicin in treating patients with soft tissue sarcomas that has spread to other places or that cannot be removed by surgery. Ribociclib may stop the growth of sarcoma tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as doxorubicin, 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 for a week prior to standard treatment with doxorubicin may work better in treating patients with soft tissue sarcoma.

Condition or disease Intervention/treatment Phase
Metastatic Angiosarcoma Metastatic Epithelioid Sarcoma Metastatic Fibrosarcoma Metastatic Leiomyosarcoma Metastatic Liposarcoma Metastatic Malignant Peripheral Nerve Sheath Tumor Metastatic Synovial Sarcoma Metastatic Undifferentiated Pleomorphic Sarcoma Myxofibrosarcoma Pleomorphic Rhabdomyosarcoma Stage III Soft Tissue Sarcoma Stage IV Soft Tissue Sarcoma Undifferentiated (Embryonal) Sarcoma Drug: Doxorubicin Drug: Ribociclib Phase 1

Detailed Description:

This is a dose-escalation study of the CDK4/6 inhibitor ribociclib in combination with standard-dose doxorubicin.


I. To determine the recommended phase 2 dose (RP2D) of ribociclib in combination with doxorubicin in subjects with advanced soft tissue sarcomas.


I. To assess preliminary anti-tumor activity of ribociclib in combination with doxorubicin in subjects with advanced soft tissue sarcomas (Progression-Free Survival and Overall Response Rate).

II. To characterize the safety and tolerability of ribociclib in combination with doxorubicin.

A mandatory biopsy will be obtained after 7 days of ribociclib treatment.

TREATMENT: Patients receive ribociclib orally (PO) daily on days 1-7, and doxorubicin intravenously (IV) on day 10. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may receive maintenance treatment with ribociclib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

STARTING DOSE COHORT: Ribociclib 400 mg with doxorubicin 75 mg/m2.

FOLLOW-UP: After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for 12 months.

RATIONALE: Over-expression of CDK4 or loss of the CDK4 inhibitor p16 are common in sarcomas and result in a selective growth advantage by bypassing normal cell cycle checkpoints. Intact pRb is required for CDK4/6 inhibition to be effective, therefore all eligible subjects must have documented pRb expression by IHC on archival tissue. Synergy between CDK4 inhibition and chemotherapy has been documented in preclinical models when given sequentially, suggestion a role for cell cycle synchronization.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B Study of Ribociclib in Combination With Doxorubicin in Advanced Soft Tissue Sarcomas
Actual Study Start Date : March 10, 2017
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : June 30, 2022

Arm Intervention/treatment
Experimental: Treatment (ribociclib, doxorubicin hydrochloride)

Patients receive ribociclib PO daily on days 1-7, and doxorubicin hydrochloride IV on day 10. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive ribociclib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Doxorubicin
Given IV
Other Names:
  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • Doxolem
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex

Drug: Ribociclib
Given PO
Other Names:
  • LEE-011
  • LEE011

Primary Outcome Measures :
  1. Incidence of DLTs of adverse events graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03 [ Time Frame: up to 21 days ]
    All adverse events (AEs) will be tabulated and summarized by major organ category, grade, anticipation, and drug attribution. Serious adverse events (SAE) specific incidence and exact 95% confidence interval will be provided where appropriate.

Secondary Outcome Measures :
  1. Incidence of adverse events, SAEs, assessed by NCI CTCAE v 4.03 [ Time Frame: Up to 12 months ]
    Analyses will be performed for all patients having received at least one dose of study drug. Serious adverse events, and AEs will be summarized using descriptive statistics.

  2. Incidence of dose modifications (interruptions, reductions, intensity) due to adverse events [ Time Frame: Up to 12 months ]
    Analyses will be performed for all patients having received at least one dose of study drug. AEs leading to withdrawal/dose interruptions/dose modification will be summarized using descriptive statistics.

  3. Objective response rate (ORR) defined as the proportion of patients who achieved a complete response or a partial response based on RECIST v1 [ Time Frame: Up to 12 months ]
    The ORR, along with exact two-sided 95% confidence intervals, will be reported for the study.

  4. Progression-free survival (PFS) [ Time Frame: From first dose of protocol therapy to time of documented radiographic and/or clinical disease progression or death from any cause, whichever occurs first, assessed up to 12 months ]
    The Kaplan-Meier product limit method will be used to estimate PFS of the median PFS and PFS rates at clinically relevant time points will be provided with the 90% CI.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 15-18 years only, body surface area (BSA) must be >= 1.5 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):

    • Corrected QT using Fridericia's correction formula (QTcF) interval at screening < 450 msec for males and < 470 msec for females
    • 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
  • 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, with the exception of malignancies that have completed therapy and are considered by their physician to be at less than 30% risk of relapse
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03009201

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United States, Oregon
OHSU Knight Cancer Institute
Portland, Oregon, United States, 97239
Sponsors and Collaborators
OHSU Knight Cancer Institute
National Cancer Institute (NCI)
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Principal Investigator: Lara Davis OHSU Knight Cancer Institute
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Responsible Party: Lara Davis, Principal Investigator, OHSU Knight Cancer Institute Identifier: NCT03009201    
Other Study ID Numbers: STUDY00016070
NCI-2016-01794 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
STUDY00016070 ( Other Identifier: OHSU Knight Cancer Institute )
P30CA069533 ( U.S. NIH Grant/Contract )
First Posted: January 4, 2017    Key Record Dates
Last Update Posted: December 12, 2019
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sarcoma, Synovial
Nerve Sheath Neoplasms
Histiocytoma, Malignant Fibrous
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms, Muscle Tissue
Neoplasms, Adipose Tissue
Neoplasms, Connective Tissue
Neoplasms, Vascular Tissue
Neoplasms, Nerve Tissue
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Neoplasms, Fibrous Tissue
Liposomal doxorubicin
Antibiotics, Antineoplastic